Abstract The Chinese herbal mixture, Tien-Hsien Liquid (THL), has been proven to suppress the growth and invasiveness of cancer cells and is currently regarded as a complementary medicine for the treatment of cancer. Our previous study using acute promyelocytic leukemia cells uncovered its effect on the downregulation of DNA methyltransferase 1 (DNMT1) which is often overexpressed in cancer cells resulting in the repression of tumor suppressors via hypermethylation. Herein, we explored the effects of THL in MCF-7 breast cancer cells that also demonstrate elevated DNMT1. The results show that THL dose-dependently downregulated DNMT1 accompanied by the induction of tumor suppressors such as p21 and p15. THL arrested cell cycle in G2/M phase and decreased the protein levels of cyclin A, cyclin B1, phospho-pRb, and AKT. DNMT1 inhibition was previously reported to exert a radiosensitizing effect in cancer cells through the repression of DNA repair. We found that THL enhanced radiation-induced clonogenic cell death in MCF-7 cells and decreased the level of DNA double-strand break repair protein, Rad51. Our observations may be the result of DNMT1 downregulation. Due to the fact that DNMT1 inhibition is now a mainstream strategy for anticancer therapy, further clinical trials of THL to confirm its clinical efficacy are warranted.
Flavokawain B induced cytotoxicity in two breast cancer cell lines, MCF-7 and MDA-MB231 and inhibited the metastatic potential of MDA-MB231 via the regulation of several tyrosine kinases In vitro
M. Nadeem Akhtar,
Swee Keong Yeap,
Kian Lam Lim,
Wan Yong Ho,
Mohd Puad Abdullah,
Chai Ling Ho,
Abdul Rahman Omar,
Jamil Ismail and
Noorjahan Banu Alitheen
Abstract Background The kava-kava plant (Piper methysticum) is traditionally consumed by the pacific islanders and has been linked to be involved in several biological activities. Flavokawain B is a unique chalcone, which can be found in the roots of the kava-kava plant. In this study, the operational mechanism of the anti-cancer activity of a synthetic Flavokawain B (FKB) on two breast cancer cell lines, MCF-7 and MDA-MB231 was investigated.
Method Several in vitro assays were attempted such as MTT, flow cytometry of cell cycle analysis, annexin V analysis, and JC-1 analysis to detect apoptosis. Moreover, in vitro metastasis assays were also performed such as transwell migration assay, invasion assay, rat aorta ring and HUVEC tube formation. Molecular analysis of related genes and proteins were conducted using real-time PCR and proteome profiler analysis.
Results Based on our results, apoptosis was induced when both MCF-7 and MDA-MB231 were treated with FKB. A significant G2/M arrest was seen in MDA-MB231 cells. Additionally, FKB also inhibited the in vitro migration and invasion in MDA-MB231 cells in a dose dependent manner. Moreover, FKB can be a potential inhibitor in angiogenesis as it suppressed the formation of vessels in HUVEC cells as well as in the ex-vivo rat aortic ring assay.
Conclusion Our findings suggested that FKB also regulated several receptor tyrosine kinases. Overall, FKB is not only a potential candidate to be an anti-cancer agent, but as an anti-metastatic agent as well.
Isoflavones Extracted from Chickpea Cicer arietinum L. Sprouts Induce Mitochondria-Dependent Apoptosis in Human Breast Cancer Cells
Rui Hu1,2,3 and
Haji Akber Aisa1,2,*
Abstract Isoflavones are important chemical components of the seeds and sprouts of chickpeas. We systematically investigated the effects of isoflavones extracted from chickpea sprouts (ICS) on the human breast cancer cell lines SKBr3 and Michigan Cancer Foundation-7 (MCF-7). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays showed that ICS (10–60 µg/mL) significantly inhibited the proliferation of both cell lines in a time-dependent and dose-dependent fashion. Wright-Giemsa staining as well as annexin V-fluorescein isothiocyanate and propidium iodide (Annexin V/PI) staining showed that ICS significantly increased cytoclasis and apoptotic body formation. Quantitative Annexin V/PI assays further showed that the number of apoptotic cells increased in a dose-dependent manner following ICS treatment. Semiquantitative reverse transcription PCR showed that ICS increased the expression of the apoptosis-promoting gene Bcl-2-associated X protein and decreased the expression of the antiapoptotic gene Bcl-2. Western blot analysis showed that treatment of SKBr3 and MCF-7 cells with ICS increased the expression of caspase 7, caspase 9, P53, and P21 in a dose-dependent manner. Flow cytometry assays using the fluorescent probe 3,3′-dihexyloxacarbocyanine iodide showed a dose-dependent decrease in mitochondrial membrane potential following ICS treatment. Treatment using ICS also induced a dose-dependent increase in reactive oxygen species production. This is the first study to demonstrate that ICS may be a chemopreventive or therapeutic agent against breast cancer.
Cannabidiol Induces Programmed Cell Death in Breast Cancer Cells by Coordinating the Cross-talk between Apoptosis and Autophagy Ashutosh Shrivastava, Paula M. Kuzontkoski, Jerome E. Groopman, et al.
Cannabidiol (CBD), a major nonpsychoactive constituent of cannabis, is considered an antineoplastic agent on the basis of its in vitro and in vivo activity against tumor cells. However, the exact molecular mechanism through which CBD mediates this activity is yet to be elucidated. Here, we have shown CBD-induced cell death of breast cancer cells, independent of cannabinoid and vallinoid receptor activation. Electron microscopy revealed morphologies consistent with the coexistence of autophagy and apoptosis. Western blot analysis confirmed these findings. We showed that CBD induces endoplasmic reticulum stress and, subsequently, inhibits AKT and mTOR signaling as shown by decreased levels of phosphorylated mTOR and 4EBP1, and cyclin D1. Analyzing further the cross-talk between the autophagic and apoptotic signaling pathways, we found that beclin1 plays a central role in the induction of CBD-mediated apoptosis in MDA-MB-231 breast cancer cells. Although CBD enhances the interaction between beclin1 and Vps34, it inhibits the association between beclin1 and Bcl-2. In addition, we showed that CBD reduces mitochondrial membrane potential, triggers the translocation of BID to the mitochondria, the release of cytochrome c to the cytosol, and, ultimately, the activation of the intrinsic apoptotic pathway in breast cancer cells. CBD increased the generation of reactive oxygen species (ROS), and ROS inhibition blocked the induction of apoptosis and autophagy. Our study revealed an intricate interplay between apoptosis and autophagy in CBD-treated breast cancer cells and highlighted the value of continued investigation into the potential use of CBD as an antineoplastic agent.
Abstract PURPOSE:To compare the efficacy of the following two empirically supported group interventions to help distressed survivors of breast cancer cope: mindfulness-based cancer recovery (MBCR) and supportive-expressive group therapy (SET).
PATIENTS AND METHODS:This multisite, randomized controlled trial assigned 271 distressed survivors of stage I to III breast cancer to MBCR, SET, or a 1-day stress management control condition. MBCR focused on training in mindfulness meditation and gentle yoga, whereas SET focused on emotional expression and group support. Both intervention groups included 18 hours of professional contact. Measures were collected at baseline and after intervention by assessors blind to study condition. Primary outcome measures were mood and diurnal salivary cortisol slopes. Secondary outcomes were stress symptoms, quality of life, and social support.
RESULTS:Using linear mixed-effects models, in intent-to-treat analyses, cortisol slopes were maintained over time in both SET (P = .002) and MBCR (P = .011) groups relative to the control group, whose cortisol slopes became flatter. Women in MBCR improved more over time on stress symptoms compared with women in both the SET (P = .009) and control (P = .024) groups. Per-protocol analyses showed greater improvements in the MBCR group in quality of life compared with the control group (P = .005) and in social support compared with the SET group (P = .012).
CONCLUSION:In the largest trial to date, MBCR was superior for improving a range of psychological outcomes for distressed survivors of breast cancer. Both SET and MBCR also resulted in more normative diurnal cortisol profiles than the control condition. The clinical implications of this finding require further investigation.
1Tang Center for Herbal Medicine Research, The Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, U.S.A.
2Department of Anesthesia and Critical Care, The Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, U.S.A.
3Department of Pathology, The Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, U.S.A.
4Department of Surgery, The Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, U.S.A.
5Ben May Department for Cancer Research, The Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, U.S.A.
6Committee on Clinical Pharmacology and Pharmacogenomics, The Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, U.S.A.
Abstract Background: Former studies have shown that extract from American ginseng (Panax quinquefolius) may possess certain antiproliferative effects on cancer cells. In this study, the chemical constituents of both untreated and heat-processed American ginseng and their antiproliferative activities on human breast cancer cells were evaluated.
Materials and Methods: American ginseng roots were steamed at 120°C for 1 h or 2 h. The major ginsenosides in the two steamed and in the unsteamed extracts were quantitatively determined using high performance liquid chromatography (HPLC). The antiproliferative activities of these extracts and individual ginsenosides on MCF-7 and MDA-MB-231 breast cancer cells were assayed using the MTS method. The effects of the extracts and the ginsenosides on the induction of cell apoptosis, the expression of cyclins A and D1, and cell cycle arrest were evaluated.
Results: Compared to the untreated extract, heat-processing reduced the content of ginsenosides Rb1, Re, Rc and Rd, and increased the content of Rg2 and Rg3. After 2 h steaming, the percent content of ginsenoside Rg3 was increased from 0.06% to 5.9% . Compared to the unsteamed extract, the 2 h steamed extract significantly increased the antiproliferative activity and significantly reduced the number of viable cells. The steamed extract also significantly reduced the expression of cyclin A and cyclin D1. The cell cycle assay showed that the steamed extract and ginsenoside Rg3 arrested cancer cells in G1-phase.
Conclusion: Heat-processing of American ginseng root significantly increases antiproliferative activity and influences the cell cycle profile.
1Division of Epidemiology, Department of Family and Preventive Medicine, University of California San Diego, La Jolla CA, U.S.A.
2Naval Health Research Center, San Diego, CA, U.S.A.
3Department of Epidemiology and Biostatistics, Graduate School of Public Health, San Diego State University, San Diego CA, U.S.A.
4Department of Surgery, School of Medicine, University of California San Diego, La Jolla CA, U.S.A.
Abstract Background: Low serum levels of 25-hydroxyvitamin D [25(OH)D] have been associated with a high risk of breast cancer. Since publication of the most current meta-analysis of 25(OH)D and breast cancer risk, two new nested case–control studies have emerged.
Materials and Methods: A PubMed search for all case–control studies on risk of breast cancer by 25(OH)D concentration identified 11 eligible studies. Data from all 11 studies were combined in order to calculate the pooled odds ratio of the highest vs. lowest quantile of 25(OH)D across all studies.
Results: The overall Peto odds ratio summarizing the estimated risk in the highest compared to the lowest quantile across all 11 studies was 0.61 (95% confidence interval 0.47, 0.80).
Conclusion:This study supports the hypothesis that higher serum 25(OH)D levels reduce the risk of breast cancer. According to the review of observational studies, a serum 25(OH)D level of 47 ng/ml was associated with a 50% lower risk of breast cancer.
The Influence of Chlorella and Its Hot Water Extract Supplementation on Quality of Life in Patients with Breast Cancer Naoto Noguchi,1 Isao Maruyama,1 and Akira Yamada2
1Research Laboratory, Chlorella Industry Co., Ltd., 1343 Hisatomi, Chikugo, Fukuoka 833-0056, Japan 2Research Center for Innovative Cancer Therapy, Kurume University, Kurume 830-0011, Japan
Abstract A self-control, randomized, and open-label clinical trial was performed to test the effects of the unicellular green algae Chlorella and hot water extract supplementation on quality of life (QOL) in patients with breast cancer. Forty-five female patients with breast cancer who were living at home and not hospitalized were randomly assigned to 3 groups receiving vitamin mix tablet (control), Chlorella granules (test food-1), or Chlorella extract drink (test food-2) daily for one month. The Functional Assessment of Cancer Therapy-Breast (FACT-B), the Izumo scale for abdominal symptom-specific QOL, and a narrative-form questionnaire were used to determine outcomes. Data of thirty-six subjects were included for final analysis. FACT-B scores at presupplementation found no significant group differences in all subscales. Scores on the breast cancer subscale in the Chlorella granule group significantly increased during the supplementation period (P=0.042 ). Fifty percent of the Chlorella extract group reported positive effects by the test food such as reduction of fatigue and improvements of dry skin (P<0.1 versus control group). The findings suggested the beneficial effects of Chlorella on breast cancer-related QOL and of Chlorella extract on vitality status in breast cancer patients. These findings need to be confirmed in a larger study.
Proapoptotic and Antiproliferative Effects of Thymus caramanicus on Human Breast Cancer Cell Line (MCF-7) and Its Interaction with Anticancer Drug Vincristine Saeed Esmaeili-Mahani,1,2 Farzaneh Falahi,1,3 and Mohammad Mehdi Yaghoobi3
1Laboratory of Molecular Neuroscience, Kerman Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran 2Department of Biology, Faculty of Sciences, Shahid Bahonar University of Kerman, P.O. Box 76135-133, Kerman, Iran 3Research Department of Biotechnology, Institute of Science and High Technology and Environmental Sciences, Graduate University of Advanced Technology, Kerman, Iran
Abstract Thymus caramanicus Jalas is one of the species of thymus that grows in the wild in different regions of Iran. Traditionally, leaves of this plant are used in the treatment of diabetes, arthritis, and cancerous situation. Therefore, the present study was designed to investigate the selective cytotoxic and antiproliferative properties of Thymus caramanicus extract (TCE). MCF-7 human breast cancer cells were used in this study. Cytotoxicity of the extract was determined using MTT and neutral red assays. Biochemical markers of apoptosis (caspase 3, Bax, and Bcl-2) and cell proliferation (cyclin D1) were evaluated by immunoblotting. Vincristine was used as anticancer control drug in extract combination therapy. The data showed that incubation of cells with TCE (200 and 250 μg/mL) significantly increased cell damage, activated caspase 3 and Bax/Bcl2 ratio. In addition, cyclin D1 was significantly decreased in TCE-treated cells. Furthermore, concomitant treatment of cells with extract and anticancer drug produced a significant cytotoxic effect as compared to extract or drugs alone. In conclusion, thymus extract has a potential proapoptotic/antiproliferative property against human breast cancer cells and its combination with chemotherapeutic agent vincristine may induce cell death effectively and be a potent modality to treat this type of cancer.
Effect of Melatonin on Tumor Growth and Angiogenesis in Xenograft Model of Breast Cancer Bruna Victorasso Jardim-Perassi, Ali S. Arbab,. Lívia Carvalho Ferreira, Thaiz Ferraz Borin, Nadimpalli R. S. Varma, A. S. M. Iskander, Adarsh Shankar,Meser M. Ali, Debora Aparecida Pires de Campos Zuccari
Abstract As neovascularization is essential for tumor growth and metastasis, controlling angiogenesis is a promising tactic in limiting cancer progression. Melatonin has been studied for their inhibitory properties on angiogenesis in cancer. We performed an in vivo study to evaluate the effects of melatonin treatment on angiogenesis in breast cancer. Cell viability was measured by MTT assay after melatonin treatment in triple-negative breast cancer cells (MDA-MB-231). After, cells were implanted in athymic nude mice and treated with melatonin or vehicle daily, administered intraperitoneally 1 hour before turning the room light off. Volume of the tumors was measured weekly with a digital caliper and at the end of treatments animals underwent single photon emission computed tomography (SPECT) with Technetium-99m tagged vascular endothelial growth factor (VEGF) C to detect in vivo angiogenesis. In addition, expression of pro-angiogenic/growth factors in the tumor extracts was evaluated by membrane antibody array and collected tumor tissues were analyzed with histochemical staining. Melatonin in vitro treatment (1 mM) decreased cell viability (p<0.05). The breast cancer xenografts nude mice treated with melatonin showed reduced tumor size and cell proliferation (Ki-67) compared to control animals after 21 days of treatment (p<0.05). Expression of VEGF receptor 2 decreased significantly in the treated animals compared to that of control when determined by immunohistochemistry (p<0.05) but the changes were not significant on SPECT (p>0.05) images. In addition, there was a decrease of micro-vessel density (Von Willebrand Factor) in melatonin treated mice (p<0.05). However, semiquantitative densitometry analysis of membrane array indicated increased expression of epidermal growth factor receptor and insulin-like growth factor 1 in treated tumors compared to vehicle treated tumors (p<0.05). In conclusion, melatonin treatment showed effectiveness in reducing tumor growth and cell proliferation, as well as in the inhibition of angiogenesis.
Apoptotic and antiproliferative activity of olive oil hydroxytyrosol on breast cancer cells Maha H. Elamin1*, Zeinab K. Hassan1, Sawsan A. Omer1, Maha H. Daghestani1, Ebtesam M. Al-Olayan1, Promy Virk1, Mai A Elobeid1 and Osama B. Mohammed2
1Department of Zoology, College of Science, King Saud University, University Centre for Women Students, P. O. Box 22452, Riyadh 11495, Saudi Arabia. 2KSU Mammals Research Chair, Department of Zoology, College of Science, King Saud University, P. O. Box 2455, Riyadh 11451, Saudi Arabia.
Abstract Breast cancer is a major worldwide public health concern for women. It still remains the second most prevalent form of cancer which is terminal despite the advances made in the therapeutic approach. Polyphenols in olive oil and leaves have been known for their medicinal properties. The objective of the present study was to investigate the anti-cancer effect of hydroxytyrosol and to determine the mechanisms underlying its effects. The cytotoxic and antiproliferative effects of hydroxytyrosol were determined in SK-BR-3 and T-47D breast cancer cell lines using the WST-1 assay. Apoptosis was analysed using Annexin V, and cell cycle was investigated by flow cytometry. The key findings of the present study showed that hydroxytyrosol, a pharmacologically safe natural product of olive oil, has potent anti-breast cancer properties. Indeed, it exhibits specific cytotoxicity against SK-BR-3 and T-47D breast cancer cells. Furthermore, hydroxytyrosol triggered apoptosis that showed a dose-dependent increase in both cell lines. Moreover, hydroxytyrosol inhibited cell proliferation by delaying the cell cycle at G2/M phase. Therefore, hydroxytyrosol warrants further investigations to prove its utility in preventing/treating breast cancer.
Dietary Walnut Suppressed Mammary Gland Tumorigenesis in the C(3)1 TAg Mouse W. Elaine Hardmana, Gabriela Iona, Juliana A. Akinsetea & Theodore R. Wittea
Abstract Walnuts contain multiple ingredients that, individually, have been shown to slow cancer growth, including omega-3 fatty acids, antioxidants, and phytosterols. In previous research, consumption of walnuts has slowed the growth of implanted breast cancers. We wanted to determine whether regular walnut consumption might reduce the risk for developing cancer. Homozygous male C(3)1 TAg mice were bred with female SV129 mice consuming either the control AIN-76 diet or the walnut-containing diet. At weaning, the female hemizygous pups were randomized to control or walnut-containing diets and followed for tumor development. Compared to a diet without walnuts, consumption of walnuts significantly reduced tumor incidence (fraction of mice with at least one tumor), multiplicity (number of glands with tumor/mouse), and size. Gene expression analyses indicated that consumption of the walnut diet altered expression of multiple genes associated with proliferation and differentiation of mammary epithelial cells. A comparison with another dietary intervention indicated that the omega 3 content alone did not account for the extent of tumor suppression due to the walnut. The results of this study indicate that walnut consumption could contribute to a healthy diet to reduce risk for breast cancer.
Conclusion These data indicate that exposure to a small amount of walnut in the diet of this transgenic mouse slowed the development and reduced the multiplicity of mammary gland cancers but does not define the mechanism of action for the walnut nor an active ingredient of the walnut. Walnut in the diet was associated with alterations in cell signaling pathways involved in proliferation, cell differentiation, and apoptosis. The signaling pathways altered in mammary glands of these mice have been identified as important in the development of human breast cancer, thus this study should be relevant to humans. The fatty acid composition of the mammary glands was altered but comparison to another study with the same amount of omega 3 fatty acids in the diet indicates that increased omega 3 fatty acids in the mammary gland does not explain the altered tumor incidence. However, alterations in dietary gamma tocopherol were inversely associated with tumorigenesis.More work will need to be done to determine the components of walnut and the mechanisms associated with tumor suppression. However, humans eat the whole nut, not specific components. It seems likely that incorporation of walnuts as part of a healthy diet could reduce the risk for breast cancer in humans.
Sulphoraphane, a Dietary Component of Broccoli/Broccoli Sprouts,Inhibits Breast Cancer Stem Cells Yanyan Lia,b, Tao Zhanga, Hasan Korkayac, Suling Liuc, Hsiu-Fang Leea, Bryan Newmana,Yanke Yua, Shawn G. Clouthierc, Steven J. Schwartzb,*, Max S. Wichac,*, and Duxin Suna,*
a Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, USA b Department of Food Science and Technology, The Ohio State University, USA c Comprehensive Cancer Center, Department of Internal Medicine, University of Michigan, USA
Abstract Purpose—The existence of cancer stem cells (CSCs) in breast cancer has profound implications for cancer prevention. In this study, we evaluated sulforaphane, a natural compound derived from broccoli/broccoli sprouts, for its efficacy to inhibit breast CSCs and its potential mechanism.
Experimental Design—Aldefluor assay and mammosphere formation assay were used to evaluate the effect of sulforaphane on breast CSCs in vitro. A NOD/SCID xenograft model was employed to determine whether sulforaphane could target breast CSCs in vivo, as assessed by Aldefluor assay and tumor growth upon cell re-implantation in secondary mice. The potential mechanism was investigated utilizing Western blotting analysis and β-catenin reporter assay.
Results--Sulforaphane (1~5 μM) decreased aldehyde dehydrogenase (ALDH)-positive cellpopulation by 65%~80% in human breast cancer cells (P < 0.01), and reduced the size and number of primary mammospheres by 8~125-fold and 45%~75% (P < 0.01), respectively. Daily injection with 50 mg/kg sulforaphane for two weeks reduced ALDH-positive cells by more than 50% in NOD/SCID xenograft tumors (P = 0.003). Sulforaphane eliminated breast CSCs in vivo, thereby abrogating tumor growth after re-implantation of primary tumor cells into the secondary mice (P < 0.01).Western blotting analysis and β-catenin reporter assay showed that sulforaphane down-regulated Wnt/β-catenin self-renewal pathway.
Conclusions—Sulforaphane inhibits breast CSCs and down-regulates Wnt/β-catenin self-renewal pathway. These findings support the use of sulforaphane for chemoprevention of breast cancer stem cells and warrant further clinical evaluation.
Source : Cancer Res. 2010 May 1; 16(9): 2580–2590. doi:10.1158/1078-0432.CCR-09-2937. Link to Full Study
Differential Control of Growth, Apoptotic Activity, and Gene Expression in Human Breast Cancer Cells by Extracts Derived from Medicinal Herbs Zingiber officinale Ayman I. Elkady,1,2 Osama A. Abuzinadah,1 Nabih A. Baeshen,1 and Tarek R. Rahmy1,31Biological
Sciences Department, Faculty of Sciences, King Abdulaziz University, P. O. Box 80203, Jeddah 21589, Saudi Arabia 2Zoology Department, Faculty of Science, Alexandria University, Alexandria, Egypt 3Zoology Department, Faculty of Science, Suez Canal University, Ismailia, Egypt
Abstract The present study aimed to examine the antiproliferative potentiality of an extract derived from the medicinal plant ginger (Zingiber officinale) on growth of breast cancer cells. Ginger treatment suppressed the proliferation and colony formation in breast cancer cell lines, MCF-7 and MDA-MB-231. Meanwhile, it did not significantly affect viability of nontumorigenic normal mammary epithelial cell line (MCF-10A). Treatment of MCF-7 and MDA-MB-231 with ginger resulted in sequences of events marked by apoptosis, accompanied by loss of cell viability, chromatin condensation, DNA fragmentation, activation of caspase 3, and cleavage of poly(ADP-ribose) polymerase. At the molecular level, the apoptotic cell death mediated by ginger could be attributed in part to upregulation of Bax and downregulation of Bcl-2 proteins. Ginger treatment downregulated expression of prosurvival genes, such as NF-κB, Bcl-X, Mcl-1, and Survivin, and cell cycle-regulating proteins, including cyclin D1 and cyclin-dependent kinase-4 (CDK-4). On the other hand, it increased expression of CDK inhibitor, p21. It also inhibited the expression of the two prominent molecular targets of cancer, c-Myc and the human telomerase reverse transcriptase (hTERT). These findings suggested that the ginger may be a promising candidate for the treatment of breast carcinomas.
Source : Journal of Biomedicine and Biotechnology Volume 2012 (2012), Article ID 614356, 14 pages doi:10.1155/2012/614356 Link to Full Article
Gallotannin-rich Caesalpinia spinosa fraction decreases the primary tumor and factors associated with poor prognosis in a murine breast cancer model Claudia Urueña, Juan Mancipe, John Hernandez, Diana Castañeda, Luis Pombo, Alejandra Gomez, Alexzander Asea and Susana Fiorentino
Background Several treatment alternatives are available for primary breast cancer, although those for metastatic disease or inflammation associated with tumor progression are ineffective. Therefore, there is a great need for new therapeutic alternatives capable of generating an immune response against residual tumor cells, thus contributing to eradication of micrometastases and cancer stem cells. The use of complex natural products is an excellent therapeutic alternative widely used by Chinese, Hindu, Egyptian, and ancestral Latin-American Indian populations.
Methods The present study evaluated cytotoxic, antitumor, and tumor progression activities of a gallotannin-rich fraction derived from Caesalpinia spinosa (P2Et). The parameters evaluated in vitro were mitochondrial membrane depolarization, phosphatidylserine externalization, caspase 3 activation, DNA fragmentation, and clonogenic activity. The parameters evaluated in vivo were tumor growth, leukocyte number, metastatic cell number, and cytokine production by flow cytometry.
Results The in vitro results showed that the P2Et fraction induced apoptosis with mitochondrial membrane potential loss, phosphatidylserine externalization, caspase 3 activation, DNA fragmentation, and decreased clonogenic capacity of 4T1 cells. In vivo, the P2Et fraction induced primary tumor reduction in terms of diameter and weight in BALB/c mice transplanted with 4T1 cells and decreased numbers of metastatic cells, mainly in the spleen. Furthermore, decreases in the number of peripheral blood leukocytes (leukemoid reaction) and interleukin 6 (IL-6) serum levels were found, which are events associated with a poor prognosis. The P2Et fraction exerts its activity on the primary tumor, reduces cell migration to distant organs, and decreases IL-6 serum levels, implying tumor microenvironment mechanisms.
Conclusions Overall, the P2Et fraction lessens risk factors associated with tumor progression and diminishes primary tumor size, showing good potential for use as an adjuvant in breast cancer ER(+) treatment.
α-Mangostin extracted from the pericarp of the mangosteen (Garcinia mangostana Linn) reduces tumor growth and lymph node metastasis in an immunocompetent xenograft model of metastatic mammary cancer carrying a p53 mutation Masa-Aki Shibata1,2*, Munekazu Iinuma3, Junji Morimoto4, Hitomi Kurose2, Kanako Akamatsu5, Yasushi Okuno5, Yukihiro Akao6 and Yoshinori Otsuki2
1 Laboratory of Anatomy and Histopathology, Faculty of Health Science, Osaka Health Science University, Osaka, Japan 2 Department of Anatomy and Cell Biology, Division of Life Sciences, Osaka Medical College, Takatsuki, Osaka, Japan 3 Laboratory of Pharmacognosy, Gifu Pharmaceutical University, Gifu, Japan 4 Laboratory Animal Center, Osaka Medical College, Osaka, Japan 5 Department of Systems Bioscience for Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan 6 United Graduate School of Drug Discovery and Medical Information Science, Gifu University, Gifu, Japan
Abstract Background The mangosteen fruit has a long history of medicinal use in Chinese and Ayurvedic medicine. Recently, the compound α-mangostin, which is isolated from the pericarp of the fruit, was shown to induce cell death in various types of cancer cells in in vitro studies. This led us to investigate the antitumor growth and antimetastatic activities of α-mangostin in an immunocompetent xenograft model of mouse metastatic mammary cancer having a p53 mutation that induces a metastatic spectrum similar to that seen in human breast cancers.
Methods Mammary tumors, induced by inoculation of BALB/c mice syngeneic with metastatic BJMC3879luc2 cells, were subsequently treated with α-mangostin at 0, 10 and 20 mg/kg/day using mini-osmotic pumps and histopathologically examined. To investigate the mechanisms of antitumor ability by α-mangostin, in vitro studies were also conducted.
Results Not only were in vivo survival rates significantly higher in the 20 mg/kg/day α-mangostin group versus controls, but both tumor volume and the multiplicity of lymph node metastases were significantly suppressed. Apoptotic levels were significantly increased in the mammary tumors of mice receiving 20 mg/kg/day and were associated with increased expression of active caspase-3 and -9. Other significant effects noted at this dose level were decreased microvessel density and lower numbers of dilated lymphatic vessels containing intraluminal tumor cells in mammary carcinoma tissues.
In vitro, α-mangostin induced mitochondria-mediated apoptosis and G1-phase arrest and S-phase suppression in the cell cycle. Since activation by Akt phosphorylation plays a central role in a variety of oncogenic processes, including cell proliferation, anti-apoptotic cell death, angiogenesis and metastasis, we also investigated alterations in Akt phosphorylation induced by α-mangostin treatment both in vitro and in vivo. Quantitative analysis and immunohistochemistry showed that α-mangostin significantly decreased the levels of phospho-Akt-threonine 308 (Thr308), but not serine 473 (Ser473), in both mammary carcinoma cell cultures and mammary carcinoma tissues in vivo.
Conclusions Since lymph node involvement is the most important prognostic factor in breast cancer patients, the antimetastatic activity of α-mangostin as detected in mammary cancers carrying a p53 mutation in the present study may have specific clinical applications. In addition, α-mangostin may have chemopreventive benefits and/or prove useful as an adjuvant therapy, or as a complementary alternative medicine in the treatment of breast cancer.
Effects of sangu decoction on osteoclast activity in a rat model of breast cancer bone metastasis. Deng B, Jia LQ, Tan HY, Yao X, Gao FY, Pan L, Cui J, Xiang Q.
Department of Oncology of Integrative Chinese and Western Medicine, China-Japan Friendship Hospital, Beijing 100029, China ; School of Clinical Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
Abstract Bone metastasis (BM) is a major clinical problem for which current treatments lack full efficacy. The Traditional Chinese Medicine (TCM) Sangu Decoction (SGD) has been widely used to treat BM in China. However, no in vivo experiments to date have investigated the effects of TCM on osteoclast activity in BM. In this study, the protective effect and probable mechanism of SGD were evaluated. The model was established using the breast cancer MRMT-1 cells injected into the tibia of rat. SGD was administrated, compared with Zoledronic acid as a positive control. The development of the bone tumor and osteoclast activity was monitored by radiological analysis. TRAP stain was used to identify osteoclasts quantity and activity. TRAP-5b in serum or bone tumor and TRAP mRNA were also quantified. Radiological examination showed that SGD inhibited tumor proliferation and preserved the cortical and trabecular bone structure. In addition, a dramatic reduction of TRAP positive osteoclasts was observed and TRAP-5b levels in serum and bone tumor decreased significantly. It also reduced the mRNA expression of TRAP. The results indicated that SGD exerted potent antiosteoclast property that could be directly related to its TRAP inhibited activity. In addition it prevented bone tumor proliferation in BM model.
Conclusion In summary, our data are the first to show in well-controlled bone metastasis animal models that SGD has significant antiosteoclasts effect, that could be directly related to its TRAP inhibit activity. In addition it prevented bone tumor proliferation in bone cancer models.
Source : Evid Based Complement Alternat Med. 2012;2012:381904. doi: 10.1155/2012/381904 Link to Full Article
Uncaria tomentosa—Adjuvant Treatment for Breast Cancer: Clinical Trial
Maria do Carmo Santos Araújo,1,2 Iria Luiza Farias,1,2 Jessie Gutierres,1 Sergio L. Dalmora,3,4 Nélia Flores,2 Julia Farias,1 Ivana de Cruz,5 Juarez Chiesa,2 Vera Maria Morsch,1 and Maria Rosa Chitolina Schetinger1
1Department of Chemistry, Federal University of Santa Maria, Avenida Roraima, Predio18, 97105-900 Santa Maria, Rs, Brazil 2Santa Maria University Hospital, Federal University of Santa Maria, Avenida Roraima, Predio18, 97105-900 Santa Maria, Rs, Brazil 3Department of Biology, Federal University of Santa Maria, Avenida Roraima, Predio18, 97105-900 Santa Maria, Rs, Brazil 4Department of Industrial Pharmacy, Federal University of Santa Maria, Avenida Roraima, Predio18, 97105-900 Santa Maria, Rs, Brazil 5Department of Morphology, Federal University of Santa Maria, Avenida Roraima, Predio18, 97105-900 Santa Maria, Rs, Brazil
Abstract Breast cancer is the most frequent neoplasm affecting women worldwide. Some of the recommended treatments involve chemotherapy whose toxic effects include leukopenia and neutropenia. This study assessed the effectiveness of Uncaria tomentosa (Ut) in reducing the adverse effects of chemotherapy through a randomized clinical trial. Patients with Invasive Ductal Carcinoma—Stage II, who underwent a treatment regimen known as FAC (Fluorouracil, Doxorubicin, Cyclophosphamide), were divided into two groups: the UtCa received chemotherapy plus 300 mg dry Ut extract per day and the Ca group that only received chemotherapy and served as the control experiment. Blood samples were collected before each one of the six chemotherapy cycles and blood counts, immunological parameters, antioxidant enzymes, and oxidative stress were analyzed. Uncaria tomentosa reduced the neutropenia caused by chemotherapy and was also able to restore cellular DNA damage. We concluded that Ut is an effective adjuvant treatment for breast cancer.
Source : Evidence-Based Complementary and Alternative Medicine Volume 2012 (2012) Link to Full Article
Guarana (Paullinia cupana) Improves Fatigue in Breast Cancer Patients Undergoing Systemic Chemotherapy Maira Paschoin de Oliveira Campos, MD,1 Rachel Riechelmann, MD, PhD,2 Lourdes Conceic¸a˜o Martins,1 Benjamin J. Hassan, MD,3 Fernanda Branco Assunc¸a˜o Casa,4 and Auro Del Giglio, MD, PhD2,5
Abstract Background: In patients with breast cancer (BC) undergoing systemic chemotherapy, cancer-related fatigue (CRF) is a common problem that can negatively impact quality of life. Guarana (Paullinia cupana) is a plant native to the Amazon basin that has been used as a stimulant since pre-Columbian times.
Objective: The purpose of this study was to evaluate the effectiveness of guarana extract on fatigue, sleep quality, anxiety, depression symptoms, and menopause in a group of BC chemotherapy patients.Patients and methods: Patients with progressive fatigue after their first cycle of chemotherapy were randomized to receive either guarana 50mg by mouth twice daily (32 patients) or placebo (43 patients) for 21 days. After a 7-day washout period, patients were crossed over to the opposite experimental arm. All patients were evaluated on days 1, 21, and 49. The primary endpoint was the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire score, and secondary endpoints were the results of the Functional Assessment of Chronic Illness Therapy-Endocrine Symptoms (FACT-ES), Brief Fatigue Inventory (BFI), Pittsburg Sleep Quality Index, Chalder Fatigue Scale, and Hospital Anxiety and Depression Scale.
Results: Guarana significantly improved the FACIT-F, FACT-ES, and BFI global scores compared to placebo on days 21 and 49 ( p<0.01). The Chalder Scale improved significantly on day 21 ( p<0.01) but not on day 49 ( p¼0.27). Guarana did not produce any Common Terminology Criteria for Adverse Events grades 2, 3, or 4 toxicities and did not worsen sleep quality or cause anxiety or depression.
Conclusions: Guarana is an effective, inexpensive, and nontoxic alternative for the short-term treatment of fatigue in BC patients receiving systemic chemotherapy. Further studies are needed to confirm these results and to evaluate their generalizability to chronic CRF and to other types of cancer.
Source : THE JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE Volume 17, Number 6, 2011, pp. 505–512 Link to Full Article
Apigenin Induces Apoptosis and Blocks Growth of Medroxyprogesterone Acetate-Dependent BT-474 Xenograft Tumors
Abstract Recent clinical and epidemiological evidence shows that hormone replacement therapy (HRT) containing both estrogen and progestin increases the risk of primary and metastatic breast cancer in post-menopausal women while HRT containing only estrogen does not. We and others previously showed that progestins promote the growth of human breast cancer cells in vitro and in vivo. In this study, we sought to determine whether apigenin, a low molecular weight anticarcinogenic flavonoid, inhibits the growth of aggressive Her2/neu-positive BT-474 xenograft tumors in nude mice exposed to medroxyprogesterone acetate (MPA), the most commonly used progestin in the USA. Our data clearly show that apigenin (50 mg/kg) inhibits progression and development of these xenograft tumors by inducing apoptosis, inhibiting cell proliferation, and reducing expression of Her2/neu.Moreover, apigenin reduced levels of vascular endothelial growth factor (VEGF) without altering blood vessel density, indicating that continued expression of VEGF may be required to promote tumor cell survival and maintain blood flow. While previous studies showed that MPA induces receptor activator of nuclear factor kappa-B ligand (RANKL) expression in rodent mammary gland, MPA reduced levels of RANKL in human tumor xenografts. RANKL levels remained suppressed in the presence of apigenin. Exposure of BT-474 cells to MPA in vitro also resulted in lower levels of RANKL; an effect that was independent of progesterone receptors since it occurred both in the presence and absence of the antiprogestin RU-486. In contrast to our in vivo observations, apigenin protected against MPA-dependent RANKL loss in vitro, suggesting that MPA and apigenin modulate RANKL levels differently in breast cancer cells in vivo and in vitro. These preclinical findings suggest that apigenin has potential as an agent for the treatment of progestin-dependent breast disease.
Bitter melon (Momordica charantia) extract inhibits breast cancer cell proliferation by modulating cell cycle regulatory genes and promotes apoptosis. Ray RB, Raychoudhuri A, Steele R, Nerurkar P.
Department of Pathology, Saint Louis University, St. Louis, Missouri 63104, USA.
Abstract Breast cancer is one of the most common cancers among women in the United States. Although there are effective drugs for treating advanced stages of breast cancers, women eventually develop resistance. One of the approaches to control breast cancer is prevention through diet, which inhibits one or more neoplastic events and reduces cancer risk. In this study, we have used human breast cancer cells, MCF-7 and MDA-MB-231, and primary human mammary epithelial cells as an in vitro model to assess the efficacy of bitter melon (Momordica charantia) extract (BME) as an anticancer agent. BME treatment of breast cancer cells resulted in a significant decrease in cell proliferation and induced apoptotic cell death. Apoptosis of breast cancer cells was accompanied by increased poly(ADP-ribose) polymerase cleavage and caspase activation. Subsequent studies showed that BME treatment of breast cancer cells inhibited survivin and claspin expression. Fluorescence-activated cell sorting analysis suggested that MCF-7 cells treated with BME accumulated during the G2-M phase of the cell cycle. Further studies revealed that BME treatment enhanced p53, p21, and pChk1/2 and inhibited cyclin B1 and cyclin D1 expression, suggesting an additional mechanism involving cell cycle regulation. Together, these results show that BME modulates signal transduction pathways for inhibition of breast cancer cell growth and can be used as a dietary supplement for prevention of breast cancer.
Blueberry Phytochemicals Inhibit Growth and Metastatic Potential of MDA-MB-231 Breast Cancer Cells through Modulation of the Phosphatidylinositol 3-Kinase Pathway
Lynn S. Adams1,
Navindra P. Seeram2,
Liya Li2, and
Abstract Dietary phytochemicals are known to exhibit a variety of anticarcinogenic properties. This study investigated the chemopreventive activity of blueberry extract in triple-negative breast cancer cell lines in vitro and in vivo. Blueberry decreased cell proliferation in HCC38, HCC1937, and MDA-MB-231 cells with no effect on the nontumorigenic MCF-10A cell line. Decreased metastatic potential of MDA-MB-231 cells by blueberry was shown through inhibition of cell motility using wound-healing assays and migration through a polyethylene terephthalate membrane. Blueberry treatment decreased the activity of matrix metalloproteinase-9 and the secretion of urokinase-type plasminogen activator while increasing tissue inhibitor of metalloproteinase-1 and plasminogen activator inhibitor-1 secretion in MDA-MB-231 conditioned medium as shown by Western blotting. Cell signaling pathways that control the expression/activation of these processes were investigated via Western blotting and reporter gene assay. Treatment with blueberry decreased phosphatidylinositol 3-kinase (PI3K)/AKT and NFκB activation in MDA-MB-231 cells, where protein kinase C and extracellular signal-regulated kinase (ERK) were not affected. In vivo, the efficacy of blueberry to inhibit triple-negative breast tumor growth was evaluated using the MDA-MB-231 xenograft model. Tumor weight and proliferation (Ki-67 expression) were decreased in blueberry-treated mice, where apoptosis (caspase-3 expression) was increased compared with controls. Immunohistochemical analysis of tumors from blueberry-fed mice showed decreased activation of AKT and p65 NFκB signaling proteins with no effect on the phosphorylation of ERK. These data illustrate the inhibitory effect of blueberry phytochemicals on the growth and metastatic potential of MDA-MB-231 cells through modulation of the PI3K/AKT/NFκB pathway.
Phytochemicals, antioxidant properties and anticancer investigations of the different parts of several gingers species (Boesenbergia rotunda, Boesenbergia pulchella var attenuata and Boesenbergia armeniaca) Ling Jing Jing1, Maryati Mohamed2, Asmah Rahmat3 and Mohd Fadzelly Abu Bakar1*
1Laboratory of Natural Products, Institute for Tropical Biology and Conservation, Universiti Malaysia Sabah, Locked Bag No. 2073, 88999, Kota Kinabalu, Sabah, Malaysia. 2Faculty of Civil Engineering and Environment, Universiti Tun Hussein Onn Malaysia, 86400 Parit Raja, Batu Pahat, Johor, Malaysia. 3Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, UPM, Serdang, Selangor, Malaysia.
Abstract Extracts (methanol) of the leaves, stem and rhizome of Boesenbergia species were studied for their phytochemical constituents, total phenolics and flavonoid contents, antioxidant as well as anticancer properties. The plants revealed the presence of polyphenols such as quercetin, kaempferol, rutin, naringin, hesperidin, caffeic acid, p-coumaric acid, ferulic acid, sinapic acid, chlorogenic acid, gallic acid, luteolin and diosmin by using High Performance Liquid Chromatographic (HPLC). It was indicated with significant composition of hesperidin and naringin in B. pulchella var attenuata (leaves and stem); quercetin and kaempferol in B. rotunda; luteolin in B. armeniaca. The results of antioxidant assessments conducted were similar to the trend of total phenolic and flavonoid contents: B. pulchella var attenuata> B. rotunda> B. armeniaca. In the cytotoxicity assay, B. rotunda showed the most prominent and promising result as anticancer medicinal plant. It showed positive antiproliferative effect against five cancer cell lines: ovarian (CaOV3), breast (MDA-MB-231 and MCF-7), cervical (HeLa) and colon (HT-29) cancer cell lines with 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay conducted. In addition, the rhizome of B. pulchella var attenuata and B. armeniaca shown positive result in cytotoxicity assay tested against breast cancer (MCF-7). Thus, the Boesenbergia species investigated would be a promising anticancer remedy for breast cancer.
Source : Journal of Medicinal Plants Research Vol. 4(1), pp. 027-032, 4 January, 2010 Link to Full Article
The Impact of Fish Oil on the Chemopreventive Efficacy of Tamoxifen against Development of N-Methyl-N-Nitrosourea–Induced Rat Mammary Carcinogenesis
Andrea Manni1, Haifang Xu1,Sharlene Washington1,Cesar Aliaga2,Timothy Cooper3,John P. Richie, Jr.4,Richard Bruggeman5,Bogdan Prokopczyk6,Ana Calcagnotto4,Neil Trushin6,David Mauger4,Michael F. Verderame1, and Karam El-Bayoumy2
Abstract The antiestrogen tamoxifen reduces breast cancer incidence in high-risk women but is unable to inhibit the development of hormone-independent tumors. Omega-3 polyunsaturated fatty acids (n-3 PUFA), known ligands of the peroxisome proliferator activated receptor-γ (PPARγ), generally exert tumor-suppressive effects. Based on the known crosstalk between the estrogen and the PPARγ receptors, we tested the hypothesis that the combination of tamoxifen with n-3 PUFA results in a superior antitumor action over the individual interventions. In this study, we report for the first time that the combination of a fish oil diet rich in n-3 PUFA and tamoxifen seemed to inhibit N-methyl-N-nitrosourea–induced mammary carcinogenesis, tumor multiplicity, and volume to a greater extent than the individual interventions. The potential superiority of the combination was particularly evident at a suboptimal dose of tamoxifen, which, by itself, was unable to significantly decrease tumor development. Because activation of PPARγ is known to inhibit oxidative stress, we examined the effects of our interventions on circulating and tumor levels of glutathione, a major intracellular antioxidant. Our results indicate that reduction in the level of oxidative stress may be a potential mechanism by which the n-3 PUFA–rich diet potentiated the tumor-suppressive effect of tamoxifen. Our interventions were well tolerated without evidence of toxicity. Combined administration of tamoxifen and n-3 PUFA is a promising new approach to breast cancer prevention. Because of its safety, this combination can quickly be translated to the clinic if its superiority can be supported by future studies.
Cytotoxicity Effects of Amoora rohituka and chittagonga on Breast and Pancreatic Cancer Cells Leo L. Chan,1 Sherine George,2 Irfan Ahmad,3 Saujanya L. Gosangari,4,5 Atiya Abbasi,6 Brian T. Cunningham,1,2 and Kenneth L. Watkin4,5,7
1Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA 2Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA 3Micro and Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA 4Bioimaging Science and Technology Group, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA 5College of Applied Health Science, University of Illinois at Urbana-Champaign, Champaign, IL 61820, USA 6Medical Imaging Research Laboratory, Department of Speech and Hearing Science, University of Jllinois at Urbana-Champaign, Urbana, IL 61801, USA 7International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
Abstract Chemotherapeutic agents for cancer are highly toxic to healthy tissues and hence alternative medicine avenues are widely researched. Majority of the recent studies on alternative medicine suggested that Amoora rohituka possesses considerable antitumor and antibacterial properties. In this work, rohituka and chittagonga, fractionated with petroleum ether, dichloromethane, and ethanol, were explored for their anticancer potential against two breast cancer (MCF-7 and HTB-126) and three pancreatic cancer (Panc-1, Mia-Paca2, and Capan1). The human foreskin fibroblast, Hs68, was also included. Cytotoxicity of each extract was analyzed using the MTT assay and label-free photonic crystal biosensor assay. A concentration series of each extract was performed on the six cell lines.For MCF-7 cancer cells, the chittagonga (Pet-Ether and CH2Cl2) and rohituka (Pet-Ether) extracts induced cytotoxicity; the chittagonga (EtoAC) and rohituka (MeOH) extracts did not induce cytotoxicity. For HTB126, Panc-1, Mia-Paca2, and Capan-1 cancer cells, only the chittagonga CH2Cl2 extract showed a significant cytotoxic effect. The extracts were not cytotoxic to normal fibroblast Hs68 cells, which may be correlated to the specificity of Amoora extracts in targeting cancerous cells. Based on these results, further examination of the potential anticancer properties Amoora species and the identification of the active ingredients of these extracts is warranted.
Source : Evidence-Based Complementary and Alternative Medicine Volume 2011 (2011), Article ID 860605, 8 pages doi:10.1155/2011/860605 Link to Full Article
Injectable Sustained Release Microparticles of Curcumin: A New Concept for Cancer Chemoprevention
Suresh Kumar Swaminathan2,
Linan Ma4, and
Abstract Poor oral bioavailability limits the use of curcumin and other dietary polyphenols in the prevention and treatment of cancer. Minimally invasive strategies that can provide effective and sustained tissue concentrations of these agents will be highly valuable tools in the fight against cancer. The objective of this study was to investigate the use of an injectable sustained release microparticle formulation of curcumin as a novel approach to breast cancer chemoprevention. A biodegradable and biocompatible polymer, poly(d,l-lactide-co-glycolide), was used to fabricate curcumin microparticles. When injected s.c. in mice, a single dose of microparticles sustained curcumin levels in the blood and other tissues for nearly a month. Curcumin levels in the lungs and brain, frequent sites of breast cancer metastases, were 10- to 30-fold higher than that in the blood. Further, curcumin microparticles showed marked anticancer efficacy in nude mice bearing MDA-MB-231 xenografts compared with other controls. Repeated systemic injections of curcumin were not effective in inhibiting tumor growth. Treatment with curcumin microparticles resulted in diminished vascular endothelial growth factor expression and poorly developed tumor microvessels, indicating a significant effect on tumor angiogenesis. These results suggest that sustained delivery of chemopreventives such as curcumin using polymeric microparticles is a promising new approach to cancer chemoprevention and therapy.
1'S-1'-Acetoxyeugenol acetate: a new chemotherapeutic natural compound against MCF-7 human breast cancer cells by Noor Hasima, Lionel In Lian Aun, Mohamad Nurul Azmi, Ahmad Nazif Aziz, Eswary Thirthagiri, Halijah Ibrahim, Khalijah Awang
Medicinal plants containing active natural compounds have been used as an alternative treatment for cancer patients in many parts of the world especially in Asia (Itharat et al. 2004). In this report, we describe the cytotoxic and apoptotic properties of 1'S-1'-acetoxyeugenol acetate (AEA), an analogue of 1'S-1'-acetoxychavicol acetate (ACA), isolated from the Malaysian ethno-medicinal plant Alpinia conchigera Griff (Zingiberaceae) on human breast cancer cells. Data from MTT cell viability assays indicated that AEA induced both time- and dose-dependant cytotoxicity with an [IC.sub.50] value of 14.0 [mu]M within 36 h of treatment on MCF-7 cells, but not in HMEC normal control cells. Both annexin V-FITC/PI flow cytometric analysis and DNA fragmentation assays confirmed that AEA induced cell death via apoptosis. AEA was also found to induce cell cycle arrest in MCF-7 cells at the [G.sub.0]/[G.sub.1] phase with no adverse cell cycle arrest effects on HMEC normal control cells. It was concluded that AEA isolated from the Malaysian tropical ginger represents a potential chemotherapeutic agent against human breast cancer cells with higher cytotoxicity potency than its analogue, ACA.
Note Alpinia conchigera, also known locally as 'lengkuas ranting', 'lengkuas kecil', 'lengkuas padang', 'lengkuas getting' or 'chengkenam' (Janssen and Scheffer 1985) is a herbaceous perennial, 2-5 feet tall, found in eastern Bengal and southwards to Peninsular Malaysia and Sumatera (Burkill 1966). It is used as a condiment in the northern states of Peninsular Malaysia and occasionally in traditional medicine in the east coast to treat fungal infections. In Thailand, the rhizomes are used in traditional Thai medicine to relieve the gastro-intestinal disorders and in the preparation of Thai food dishes (Matsuda et al. 2005).
In vitro and in vivo antitumor activity of Macrothelypteris torresiana and its acute/subacute oral toxicity by X.H. Huang, P.C. Xiong, C.M. Xiong, Y.L. Cai, A.H. Wei, J.P. Wang, X.F. Liang, J.L. Ruan
The aim of this study was to evaluate the antitumor potential of Macrothelypteris torresiana by studying in vitro antitumor activity of the protoapigenone, as well as in vivo antitumor activity and acute/subacute oral toxicity of the total flavonoid fraction from the roots of M. torresiana. Considering that the protoapigenone is a main constituent of the total flavonoid fraction and it might play a key role in the antitumor activity of M. torresiana, the MTT assay was used to investigate the in vitro antitumor activity of the protoapigenone. Our study revealed that the protoapigenone of M. torresiana showed significant antitumor activity towards Hep G2, Tca-8113, MCF-7, M5 and K562 with [IC.sub.50] values of 2.3, 0.6, 0.8, 0.3 and 0.9 [mu]g/ml, respectively. The antitumor potential of the total flavonoid fraction was evaluated using preparations 1, 2 and 3, which were prepared by total flavonoid fraction directly diluted with sterile saline, dissolved using sodium carboxymethyl cellulose (CMC-Na) and included by hydroxypropyl-[beta]-cyclodextrin, respectively. These were investigated in vivo using mouse sarcoma S-180 in BALB/c mice after completing tumor inoculation for 24 h. Pronounced antitumor activity was observed in the treated groups for preparations 2 and 3, and the high and medium doses in particular showed very high inhibition ratio of tumor growth (<50%). No significant difference was observed when compared to the positive control group (5-fluorouracil). The acute/subacute oral toxicity test was performed, and the results of acute oral toxicity showed that the [LD.sub.50] values of preparations 2 and 3 were 2.76 and 0.87 g/kg body wt., respectively. According to the results of the subacute oral toxicity study, the total flavonoid fraction had low toxicity. The overall results of this study suggest that the total flavonoid fraction from the roots of M. torresiana shows significant antitumor activity and represents a potential source of medicine for the treatment of cancer.
NOTE Macrothelypteris torresiana (Gaud.) Ching (Thelypteridaceae) is widely distributed in the south of China and has been used as folk medicine mainly for the treatment of diseases such as hydropsy and traumatic bleeding (Institute of Botany, 1976; Ding, 1982). This recent scientific attention was because of some unusual flavonoids isolated from the species M. torresiana showing significant antitumor activities. Among of them, a unique flavonoid named protoapigenone showed significant antitumor activity against human cancer cell lines Hep G2, Hep 3B (liver), MCF-7 (breast), A549 (lung) and MDA-MB-231 with [IC.sub.50] values of 1.60, 0.23, 0.78, 3.88 and 0.27 ([mu]g/ml, respectively (Lin et al., 2005).
Anti-proliferative effects of carvacrol on a human metastatic breast cancer cell line, MDA-MB 231 Arunasree KM. Institute of Life Sciences, University of Hyderabad Campus, Biology, Hyderabad 500 046, AP, India.
Carvacrol, (2-methyl-5-(l-methylethyl)-phenol), is a major component of the essential oils of oregano and thyme
Purpose: Although the anti-tumor effects of carvacrol have been demonstrated earlier, the exact underlying molecular mechanisms involved in its action have not been defined and in the present study an attempt has been made to identify the mechanism of carvacrol induced cell death in human metastatic breast cancer cells, MDA-MB 231.
Methods: Apoptosis induced by carvacrol was determined based on different assays like MTT assay, Annexin V, mitochondrial membrane potential assay, multicaspase activation assay and cell cycle analysis by flow cytometer. Cleavage of PARP, cytochrome c release and modulation of Bax and Bcl2 ratio by Western blot analysis were also studied.
Results: The study clearly showed induction of apoptosis by carvacrol in MDA-MB 231 cells dose dependently at an [IC.sub.50] of 100 [micro]M with a decrease in the mitochondrial membrane potential of the cells resulting in release of cytochrome c from mitochondria, caspase activation and cleavage of PARP.
Conclusion: The data in the present study clearly demonstrated anti-tumor effects of carvacrol on human metastatic breast cancer cells, MDA-MB 231, and that the compound could have a potential therapeutic significance in treating cancer.
Effects of exercise on breast cancer patients and survivors: a systematic review and meta-analysis Margaret L. McNeely, Kristin L. Campbell, Brian H. Rowe, Terry P. Klassen, John R. Mackey and Kerry S. Courneya
From the Department of Behavioural Medicine, Faculty of Physical Education, University of Alberta (McNeely, Campbell, Courneya), the Department of Emergency Medicine, University of Alberta and Capital Health (Rowe), the Department of Paediatrics, Stollery Children's Hospital and University of Alberta (Klassen) and the Department of Medical Oncology, Cross Cancer Institute and University of Alberta (Mackey), Edmonton, Alta.
Background: Physical exercise has been identified as a potentialintervention to improve quality of life in women with breastcancer. We sought to summarize the available evidence concerningthe effects of exercise on breast cancer patients and survivors.
Methods: We searched the Cochrane Central Register of ControlledTrials, MEDLINE, EMBASE, CINAHL, PsychINFO, CancerLit, PEDroand SportDiscus as well as conference proceedings, clinical practice guidelines and other unpublished literature resources.We included only randomized controlled trials that examined exercise interventions for breast cancer patients or survivors with quality of life, cardiorespiratory fitness or physica lfunctioning as primary outcomes. We also extracted data on symptoms of fatigue, body composition and adverse effects.
Results: Of 136 studies identified, 14 met all the inclusioncriteria. Despite significant heterogeneity and relatively smallsamples, the point estimates in terms of the benefits of exercisefor all outcomes were positive even when statistical significancewas not achieved. Exercise led to statistically significan timprovements in quality of life as assessed by the Functional Assessment of Cancer Therapy–General (weighted mean difference[WMD] 4.58, 95% confidence interval [CI] 0.35 to 8.80) and Functional Assessment of Cancer Therapy–Breast (WMD 6.62, 95% CI1.21 to 12.03). Exercise also led to significant improvements in physical functioning and peak oxygen consumption and in reducing symptoms of fatigue.
Interpretation: Exercise is an effective intervention to improve quality of life, cardiorespiratory fitness, physical functioning and fatigue in breast cancer patients and survivors. Larger trials that have a greater focus on study quality and adverse effects and that examine the long-term benefits of exercise are needed for this patient group.
Effect of soy isoflavones on breast cancer recurrence and death for patients receiving adjuvant endocrine therapy Xinmei Kang, MD PhD, Qingyuan Zhang, MD PhD, Shuhuai Wang, MD, Xu Huang, MD and Shi Jin, MD
From the Departments of Medical Oncology (Kang, Zhang, Huang, Jin) and Pathology (Wang), Cancer Hospital of Harbin Medical University, Harbin, China
Background: The intake of soy isoflavones among women with breastcancer has become a public health concern, because these compoundshave weak estrogenic effects. There is little clinical evidence about their safety for patients with breast cancer who are receiving adjuvant endocrine therapy.
Methods: For patients who underwent surgery for breast cancerbetween August 2002 and July 2003 and who were receiving adjuvantendocrine therapy, we examined associations between dietary intake of soy isoflavones and recurrence of breast cancer and death. We measured dietary intake of soy isoflavones at baseline using a validated food frequency questionnaire. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) by meansof multivariable Cox proportional hazards regression models.We further stratified the analyses by hormonal receptor statusand endocrine therapy.
Results: The median follow-up period for the 524 patients inthis study was 5.1 years. Among premenopausal patients, theoverall death rate (30.6%) was not related to intake of soyisoflavones (HR = 1.05, 95% CI 0.78–1.71 for the highes tquartile [> 42.3 mg/day] v. the lowest quartile [< 15.2mg/day], p for trend = 0.87). Relative to post-menopausal patientsin the lowest quartile of soy isoflavone intake, the risk ofrecurrence for post-menopausal patients in the highest quartile was significantly lower (HR = 0.67, 95% CI 0.54–0.85,p for trend = 0.02). Inverse associations were observed in patientswith estrogen and progesterone receptor positive disease andthose receiving anastrozole therapy.
Interpretation: High dietary intake of soy isoflavones was associated with lower risk of recurrence among post-menopausal patients with breast cancer positive for estrogen and progesterone receptorand those who were receiving anastrozole as endocrine therapy.
Exogenous coenzyme Q10 modulates MMP-2 activity in MCF-7 cell line as a breast cancer cellular model Massih Bahar1 , Shahnaz Khaghani1 , Parvin Pasalar1 , Maliheh Paknejad1 , Mohammad Reza Khorramizadeh2 , Hossein Mirmiranpour2 and Siavash Gerayesh Nejad1
1 Department of Clinical Biochemistry, Tehran University of Medical Sciences, Faculty of Medicine, Tehran, Iran 2 Department of Pathology, Tehran University of Medical Sciences, Faculty of Public Health, Tehran, Iran
Background/Aims Matrix Metalloproteinases 2 is a key molecule in cellular invasion and metastasis. Mitochondrial ROS has been established as a mediator of MMP activity. Coenzyme Q10 contributes to intracellular ROS regulation. Coenzyme Q10 beneficial effects on cancer are still in controversy but there are indications of Coenzyme Q10 complementing effect on tamoxifen receiving breast cancer patients.
Methods In this study we aimed to investigate the correlation of the effects of co-incubation of coenzyme Q10 and N-acetyl-L-cysteine (NAC) on intracellular H2O2 content and Matrix Metalloproteinase 2 (MMP-2) activity in MCF-7 cell line.
Results and Discussion Our experiment was designed to assess the effect in a time and dose related manner. Gelatin zymography and Flowcytometric measurement of H2O2 by 2'7',-dichlorofluorescin-diacetate probe were employed. The results showed that both coenzyme Q10 and N-acetyl-L-cysteine reduce MMP-2 activity along with the pro-oxidant capacity of the MCF-7 cell in a dose proportionate manner.
Conclusions Collectively, the present study highlights the significance of Coenzyme Q10 effect on the cell invasion/metastasis effecter molecules.
Source : Nutrition Journal 2010, 9:62doi:10.1186/1475-2891-9-62 Link to Source
Anticancer activity of a sub-fraction of dichloromethane extract of Strobilanthes crispus on human breast and prostate cancer cells in vitro Nik Soriani Yaacob,1 Nurraihana Hamzah,2 Nik Nursyazni Nik Mohamed Kamal,1 Siti Amalina Zainal Abidin,1 Choon Sheen Lai,2 Visweswaran Navaratnam,2 and Mohd Nor Norazmi3
1Department of Chemical Pathology, School of Medical Sciences, Universiti Sains Malaysia Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia 2Centre for Drug Research, Universiti Sains Malaysia, 11800 Minden, Pulau Pinang, Malaysia 3School of Health Sciences, Universiti Sains Malaysia Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia
Background The leaves of Strobilanthes crispus (S. crispus) which is native to the regions of Madagascar to the Malay Archipelago, are used in folk medicine for their antidiabetic, diuretic, anticancer and blood pressure lowering properties. Crude extracts of this plant have been found to be cytotoxic to human cancer cell lines and protective against chemically-induced hepatocarcinogenesis in rats. In this study, the cytotoxicity of various sub-fractions of dichloromethane extract isolated from the leaves of S. crispus was determined and the anticancer activity of one of the bioactive sub-fractions, SC/D-F9, was further analysed in breast and prostate cancer cell lines.
Methods The dichloromethane extract of S. crispus was chromatographed on silica gel by flash column chromatography. The ability of the various sub-fractions obtained to induce cell death of MCF-7, MDA-MB-231, PC-3 and DU-145 cell lines was determined using the LDH assay. The dose-response effect and the EC50 values of the active sub-fraction, SC/D-F9, were determined. Apoptosis was detected using Annexin V antibody and propidium iodide staining and analysed by fluorescence microscopy and flow cytometry, while caspase 3/7 activity was detected using FLICA caspase inhibitor and analysed by fluorescence microscopy.
Results Selected sub-fractions of the dichloromethane extract induced death of MCF-7, MDA-MB-231, PC-3 and DU-145 cells. The sub-fraction SC/D-F9, consistently killed breast and prostate cancer cell lines with low EC50 values but is non-cytotoxic to the normal breast epithelial cell line, MCF-10A. SC/D-F9 displayed relatively higher cytotoxicity compared to tamoxifen, paclitaxel, docetaxel and doxorubicin. Cell death induced by SC/D-F9 occurred via apoptosis with the involvement of caspase 3 and/or 7
Conclusions A dichloromethane sub-fraction of S. crispus displayed potent anticancer activities in vitro that can be further exploited for the development of a potential therapeutic anticancer agent.
The extract of huanglian, a medicinal herb, induces cell growth arrest and apoptosis by upregulation of interferon-β and TNF-α in human breast cancer cells
Jing X. Kang*,Jing Liu,Jingdong Wang,Chengwei He and Frederick P. Li1
Abstract Huanglian (Coptidis rhizoma), a widely used herb in traditional Chinese medicine, has been shown recently to possess anticancer activities. However, the molecular mechanism underlying the anticancer effect of the herb is poorly understood. Specifically, whether huanglian extract affects the expression of cancer-related genes has not been defined. This study used DNA microarray technology to examine the effect of the herbal extract on expression of the common genes involved in carcinogenesis in two human breast cancer cell lines, the ER-positive MCF-7 and ER-negative MDA-MB-231 cells. Treatment of the cancer cells with huanglian extract markedly inhibited their proliferation in a dose- and time-dependent manner. The growth inhibitory effect was much more profound in MCF-7 cell line than that in MDA-MB-231 cells. DNA microarray assay revealed that treatment with huanglian dramatically increased the mRNA expression of interferon-β (IFN-β) and tumor necrosis factor-α in MCF-7 cells. Quantitative analysis by real-time PCR or western blotting confirmed the upregulation of the two genes (especially IFN-β) in MCF-7 cells, but not in MDA-MB-231 cells. Addition of neutralizing antibody against IFN-β to culture medium markedly inhibited the huanglian-induced antiproliferative effect, confirming the involvement of IFN-β in the huanglian's effect and also suggesting an autocrine pathway for the action of IFN-β in this setting. Given that IFN-β is among the most important anticancer cytokines, the upregulation of this gene by huanglian is, at least in part, responsible for its antiproliferative effect. The results of this study implicate huanglian as a promising herb for chemoprevention and chemotherapy of certain cancers.
Discussion The data presented here demonstrate that huanglian extract is highly effective in inhibiting cell proliferation and inducing apoptotic cell death in MCF-7 breast cancer cells. The observed anticancer effects of the herbal extract result mainly from its ability to enhance the expression of two anticancer cytokines, IFN-β and TNF-α (especially IFN-β), as evidenced by the increased levels of mRNA and protein of these cytokines in the cells treated with the herbal extract. The upregulated cytokines act through an autocrine pathway to induce cell growth arrest and apoptosis, as indicated by the fact that addition of a neutralizing antibody against IFN-β to culture medium could significantly attenuate the growth inhibitory effect of huanglian extract. Thus, the results of this study provide evidence for the anticancer activity of huanglian and, more importantly, the molecular basis for its effect.
Our results showed that the two breast cancer cell lines MCF-7 (estrogen receptor positive) and MDA-MB-231 (estrogen receptor negative) responded to the herbal treatment differently. The MDA-MB-231 cells did not increase the synthesis of IFN-β and TNF-α in response to huanglian treatment and, accordingly, exhibited a much smaller degree of growth arrest and apoptosis when compared with the MCF-7 cells. This phenomenon supports the notion that the upregulation of IFN-β and TNF-α is probably the mechanism underlying the growth inhibitory effect of huanglian in this particular cell type. The differential responses of the two cell lines also raise a question as to whether estrogen receptor is involved in or essential for the action of huanglian. Future study on this subject matter and experiments to elucidate the whole signal transduction pathway for huanglian are warranted.
The extract of huanglian contains several components (15). Berberine is known to be the dominant one (7,15). In this study, we found that purified berberine was significantly less effective than the whole huanglian extract. Similar results have been reported previously by others (7,8). This indicates that there are constituents in the herb other than berberine that are critical for its growth inhibitory effect. In this context, it seems better to develop the whole herbal extract, rather than its dominant components, for cancer therapy. Nevertheless, identification and characterization of the active components present in the whole extract of huanglian is needed.
Both INF-β and TNF-α are the important cytokines that regulate cell growth and death (16–19). The biological effects of these cytokines have been investigated extensively over the last decades. The anticancer activity of INF-β has been well recognized (16–19), whereas TNF-α plays a paradoxical role in carcinogenesis (20). It is well known that IFN-β can inhibit cell growth and kill cancer cells. Thus, enhancing the production of IFN-β in cancer cells seems to be an effective anticancer mechanism and the identification of compounds that have such a property should be a new direction of cancer drug development. Our finding that huanglian is highly effective in enhancing synthesis of IFN-β in MCF-7 cancer cells provides a molecular basis for huanglian as a promising anticancer agent. Although huanglian has been previously shown to alter expression of some genes in several different cancer cell lines (7,8), the present study is the first to show upregulation by huanglian of the two anticancer cytokines, IFN-β and TNF-α, in human cancer cells. Previously, Iizuka et al. (8) reported that use of oligonucleotide microarray identified 13 various genes whose levels of expression were correlated with the ID50 values of both berberine and C.rhizoma in pancreatic cancer cell lines. Li et al. (7) found that huanglian extract suppressed the expression of cyclin B1 in a human gastric cancer cell line (MKN-74). It is possible that the genetic effects of huanglian are different in different cell types. Whether the effect of huanglian on cytokine expression also occurs in non-cancer cells are now under investigation in our laboratory.
Since IFN and TNF are also potent immunomodulators and play critical roles in treatment of certain infections, the finding of the present study that huanglian can enhance the expression of these two cytokines (especially IFN) might provide an explanation for the use of huanglian as a key herb to treat infectious conditions in Chinese medicine.
A full understanding of molecular effect (i.e. gene expression) of a herb is very important for evaluation of its efficacy as well as safety (side effect). Microarray technology seems to be quite helpful in this regard. DNA chip studies may help identifying compounds with novel therapeutic effect and clarify the roles of various compounds of herbs in the physiological activity. Our strategy, as used in the present study, could serve as a framework to study medicinal herbs.
Huanglian has been widely used in China for several thousand years, mainly, for the treatment of infectious conditions. This herb has been shown to be quite safe for human consumption (21). This advantage plus the emerging evidence of its anticancer effects make huanglian a very promising candidate for being an effective and safe anticancer agent.
Source Carcinogenesis (November 2005) 26 (11): 1934-1939. doi: 10.1093/carcin/bgi154 LINK TO FULL ARTICLE
Abalone visceral extract inhibit tumor growth and metastasis by modulating Cox-2 levels and CD8+ T cell activity Choong-Gu Lee,1 Ho-Keun Kwon,1 Jae Ha Ryu,1 Sung Jin Kang,1 Chang-Rok Im,2 Jae II Kim,1 and Sin-Hyeog Im1
1School of Life Sciences and Immune Synapse Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Republic of Korea2Global leader program, Bugil Academy, Cheonan, Chungchengnamdo 330-941, Republic of Korea
Background Abalone has long been used as a valuable food source in East Asian countries. Although the nutritional importance of abalone has been reported through in vitro and in vivo studies, there is little evidence about the potential anti-tumor effects of abalone visceral extract. The aim of the present study is to examine anti-tumor efficacy of abalone visceral extract and to elucidate its working mechanism.
Methods In the present study, we used breast cancer model using BALB/c mouse-derived 4T1 mammary carcinoma and investigated the effect of abalone visceral extract on tumor development. Inhibitory effect against tumor metastasis was assessed by histopathology of lungs. Cox-2 productions by primary and secondary tumor were measured by real-time RT-PCR and immunoblotting (IB). Proliferation assay based on [3H]-thymidine incorporation and measurement of cytokines and effector molecules by RT-PCR were used to confirm tumor suppression efficacy of abalone visceral extract by modulating cytolytic CD8+ T cells. The cytotoxicity of CD8+ T cell was compared by JAM test.
Results Oral administration of abalone visceral extract reduced tumor growth (tumor volume and weight) and showed reduced metastasis as confirmed by decreased level of splenomegaly (spleen size and weight) and histological analysis of the lung metastasis (gross analysis and histological staining). Reduced expression of Cox-2 (mRNA and protein) from primary tumor and metastasized lung was also detected. In addition, treatment of abalone visceral extract increased anti-tumor activities of CD8+ T cells by increasing the proliferation capacity and their cytolytic activity.
Conclusions Our results suggest that abalone visceral extract has anti-tumor effects by suppressing tumor growth and lung metastasis through decreasing Cox-2 expression level as well as promoting proliferation and cytolytic function of CD8+ T cells.
Multi-targeted Therapy of Cancer by Omega-3 Fatty Acids
Isabelle M. Berquin1,2, Iris J. Edwards2, and Yong Q. Chen1* 1Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina. 2Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) are essential fatty acids necessary for human health. Currently, the Western diet contains a disproportionally high amount of n-6 PUFAs and low amount of n-3 PUFAs, and the resulting high n-6/n-3 ratio is thought to contribute to cardiovascular disease, inflammation, and cancer. Studies in human populations have linked high consumption of fish or fish oil to reduced risk of colon, prostate and breast cancer, although other studies failed to find a significant association. Nonetheless, the available epidemiological evidence, combined with the demonstrated effects of n-3 PUFAs on cancer in animal and cell culture models, has motivated the development of clinical interventions using n-3 PUFAs in the prevention and treatment of cancer, as well as for nutritional support of cancer patients to reduce weight loss and modulate the immune system. In this review, we discuss the rationale for using long-chain n-3 PUFAs in cancer prevention and treatment and the challenges that such approaches pose in the design of clinical trials.
Source Cancer Lett. 2008 October 8; 269(2): 363–377. doi:10.1016/j.canlet.2008.03.044 LINK TO FULL ARTICLE
Urinary Melatonin Levels and Postmenopausal Breast Cancer Risk in the Nurses' Health Study Cohort
Background: Melatonin seems to play a role in breast cancer etiology, but data addressing the association between melatonin levels and breast cancer risk in postmenopausal women is sparse.
Methods: We conducted a nested case-control study in the Nurses' Health Study cohort. First spot morning urine was collected from 18,643 cancer-free women from March 2000 through December 2002. The concentration of the major metabolite of melatonin, 6-sulfatoxymelatonin (aMT6s), was available for 357 postmenopausal women who developed incident breast cancer through May 31, 2006, along with 533 matched control subjects. We used multivariable conditional logistic regression models to investigate associations. All statistical tests were two sided.
Results: An increased concentration of urinary aMT6s was statistically significantly associated with a lower risk of breast cancer (odds ratio for the highest versus lowest quartile of morning urinary aMT6s, 0.62; 95% confidence interval, 0.41-0.95; Ptrend = 0.004). There was no apparent modification of risk by hormone receptor status of breast tumors, age, body mass index, or smoking status.
Conclusion: Results from this prospective study add substantially to the growing literature that supports an inverse association between melatonin levels and breast cancer risk.
Viscum album L. extracts in breast and gynaecological cancers: a systematic review of clinical and preclinical research Gunver S Kienle,1 Anja Glockmann,1 Michael Schink,2 and Helmut Kiene11Institute for Applied Epistemology and Medical Methodology, Zechenweg 6, D-79111 Freiburg, Germany2Verein Filderklinik e.V, Research Department, Im Haberschlai 7, D-70794 Filderstadt, Germany
Background Breast and gynaecological cancers (i.e. ovarian, endometrial, cervical, vaginal, vulval, and fallopian cancers) account for a significant amount of morbidity and mortality in women. In Europe an estimated 429,900 cases were diagnosed as breast cancer in 2006 (13.5% of all cancer cases) and 131,900 died from it, despite substantially improved treatment options (surgery, chemotherapy, radiation, hormonal and targeted therapies) . Of female cancer survivors more than half had suffered from breast or gynaecological cancer . 40% to 80% of these patients use complementary therapies additionally to well-established treatments [3-8]. This includes a variety of medicinal plants, but also acupuncture, psychosocial support, yoga, art therapies and others. These are supportive measures to control symptoms, improve quality of life, boost the immune system, and possibly prolong life. Sufficient evaluation is often lacking, however, of the extent to which these therapeutic goals are achieved, as well as of issues relating to safety and mode of action. Medicinal plants in particular have a long history in the treatment of cancer and other conditions connected with tumours, and also play a major role in the development of new drugs today. Over 60% of currently used anti-cancer agents originally derive from natural sources such as plants, marine organisms and microorganisms .
Across Europe, Viscum album L. extracts (VAE or European mistletoe, not to be confused with the Phoradendron species or "American mistletoe") are among the most common herbal extracts applied in cancer treatment [3,7,8,10]. Viscum album is a hemi-parasitic shrub and contains a variety of biologically active compounds. Mistletoe lectins (ML I, II and III) have been most thoroughly investigated. MLs consist of two polypeptide chains: a carbohydrate-binding B-chain that can bind on cell surface receptors, which enables the protein to enter the cell [11-13]; and the catalytic A-chain which can subsequently inhibit protein synthesis, due to its ribosome-inactivating properties, by removing an adenine residue from the 28S RNA of the 60S subunit of the ribosome . Other pharmacologically relevant VAE compounds are viscotoxins and other low molecular proteins, VisalbCBA (Viscum album chitin-binding agglutinin) , oligo- and polysaccharids [15,16], flavonoids , vesicles , triterpene acids , and others [20,21]. Whole VAE as well as several of the compounds are cytotoxic and the MLs in particular have strong apoptosis-inducing effects [22-24]. MLs also display cytotoxic effects on multidrug-resistant cancer cells (e.g. MDR+ colon cancer cells ) and enhance cytotoxicity of anticancer drugs [26,27]. In mononuclear cells VAE also possess DNA-stabilizing properties. VAE and its compounds stimulate the immune system (in vivo and in vitro activation of monocytes/macrophages, granulocytes, natural killer (NK) cells, T-cells, dendritic cells, induction of a variety of cytokines such as IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, GM-CSF, TNF-α, IFN-γ (overview see [20,21]). The cytotoxicity of human natural and lymphokine-activated killer cells, for instance, can be markedly enhanced in vitro by VAE rhamnogalacturonans, which bridge these killer cells with NK-sensitive or insensitive tumour cells [28,29]. Furthermore, VAE seem to interfere with tumoural angiogenesis [30,31]. Injected into tumour-bearing animals, VAE and several of their compounds (MLs, a 5 kDa protein not specified further, protein complexes isolated by Vester and colleagues, oligosaccharids) display growth-inhibiting and tumourreducing effects [20,21]. Despite extensive experimental analyses of their biological properties, many questions regarding the precise mode of action of VAE still remain.
For clinical application VAE are made from mistletoes grown on different host trees [Host trees of VAE: Fir (Abies, A); maple (Acer, Ac); almond tree (Amygdalus, Am); birch (Betula, B); whitethorn (Crataegus, C); ash tree (Fraxinu , F); appletree (Malus, M); pine (Pinus, P); poplar (Populus, Po); oak (Quercus, Qu); willow (Salix, S); lime (Tilia, T), elm (Ulmus, U)], either by aqueous extraction, partly combined with fermentation, or by pressing procedures. Depending on host tree, harvesting time and extraction procedure, VAE vary in regard to their active compounds and biological properties. Different commercial VAE preparations are available, and a recombinant ML (rML) drug is currently being developed and tested in clinical trials [32,33]. Clinical effects of VAE in cancer have been investigated in a variety of studies and assessed in systematic reviews [34-39]. These reviews, however, had inconsistent results, they are outdated, incomplete or concentrate on partial aspects. No review has yet assessed clinical and preclinical effects specifically and comprehensively for breast and gynaecological cancer, although there is widespread usage in these patients [3,7]. Our primary aim was therefore to assess the potential therapeutic effectiveness of VAE, and their potential biological effects on breast and gynaecological cancer in clinical and preclinical studies.
Methods: Systematic review to evaluate clinical studies and preclinical research on the therapeutic effectiveness and biological effects of VAE on gynaecological and breast cancer. Search of databases, reference lists and expert consultations. Criteria-based assessment of methodological study quality. Results: 19 randomized (RCT), 16 non-randomized (non-RCT) controlled studies, and 11 singlearm cohort studies were identified that investigated VAE treatment of breast or gynaecological cancer. They included 2420, 6399 and 1130 patients respectively. 8 RCTs and 8 non-RCTs were embedded in the same large epidemiological cohort study. 9 RCTs and 13 non-RCTs assessed survival; 12 reported a statistically significant benefit, the others either a trend or no difference. 3RCTs and 6 non-RCTs assessed tumour behaviour (remission or time to relapse); 3 reported statistically significant benefit, the others either a trend, no difference or mixed results. Quality of life (QoL) and tolerability of chemotherapy, radiotherapy or surgery was assessed in 15 RCTs and 9 non-RCTs. 21 reported a statistically significant positive result, the others either a trend, no difference, or mixed results. Methodological quality of the studies differed substantially; some had major limitations, especially RCTs on survival and tumour behaviour had very small sample sizes. Some recent studies, however, especially on QoL were reasonably well conducted. Single-arm cohort studies investigated tumour behaviour, QoL, pharmacokinetics and safety of VAE. Tumour remission was observed after high dosage and local application. VAE application was well tolerated. 34 animal experiments investigated VAE and isolated or recombinant compounds in various breast and gynaecological cancer models in mice and rats. VAE showed increase of survival and tumour remission especially in mice, while application in rats as well as application of VAE compounds had mixed results. In vitro VAE and its compounds have strong cytotoxic effects on cancer cells.
Conclusion: VAE shows some positive effects in breast and gynaecological cancer. More research into clinical efficacy is warranted
Suppression of growth, migration and invasion of highly-metastatic human breast cancer cells by berbamine and its molecular mechanisms of action Shang Wang1 Qian Liu,#1 Ying Zhang,#2 Ke Liu,#1 Pengfei Yu,#1 Kun Liu,1 Jinling Luan,1 Huiying Duan,1 Zhaoqiao Lu,1 Fengfei Wang,3 Erxi Wu,3 Kazumi Yagasaki,4 and Guoying Zhang1 1Laboratory of Molecular Pharmacology, School of Pharmacy, Yantai University, No 30, Qing Quan Lu, Lai Shan Qu, Yantai, Shandong Province 264005, China 2Clinical Medicine, Clinical College of Anhui Medical University, No 15, Feicuilu, Hefei, Anhui Province 230601, China 3Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, 58105, USA 4Department of Applied Biological Science, Tokyo Noko University, Saiwai-cho 3-5-8, Fuchu, Tokyo 183-8509, Japan
BACKGROUND Breast cancer is the second leading cause of cancer-related deaths among females in the United States . Its rate in China and other Asian countries is also increasing rapidly [2,3]. To find novel natural compounds with low toxicity and high selectivity for killing cancer cells is an important area in cancer research. To date, chemotherapy has been the most frequently used treatment for breast cancer and other cancers. However, some normal cells are destroyed as well by this method of treatment. Due to their wide range of biological activities and low toxicity in animal models, some natural products have been used as alternative treatments for cancers including breast cancer. Berbamine (BER) is a naturally occurring small-molecule compound from Traditional Chinese Medicine (TCM) Berberis amurensis (xiaoboan). In China, BER has been used to treat the clinical patients with inflammation and various cancers including breast cancer, hepatoma, leukemia for many years. BER is also a clinical drug to treat the patients with low levels of white blood cells, which are caused by chemotherapy and/or radiotherapy. The chemical structure of BER is shown in Fig. Fig.1A.1A. BER-induced apoptosis and growth inhibition of human leukemia HL-60 and K562 cell lines without cytotoxicity to normal hematopoietic cells [4-6]. It induced caspase-3-dependent apoptosis of leukemia NB4 cells via survivin-mediated pathway . BER also caused apoptosis and cell cycle arrest, and led to loss of mitochondrial membrane potential and activated caspase-3 and caspase-9 in human hepatoma cells . However, whether or not BER has inhibitory activities against highly-metastatic human breast cancer cells is unclear. In this study, we investigated the effects of BER on growth, migration and invasion of highly-metastatic human breast cancer cells and its molecular mechanisms of action. We showed that BER inhibited the growth, migration and invasion of the highly-metastatic human breast cancer cells as well as induced the apoptosis in the cancer cells. Such anti-cancer activities of BER involved suppression of Akt and NF-κB signaling and its upstream and downstream targets by reducing expressions of the related proteins and mRNA as well as pro-MMP-9/pro-MMP-2 activation in the cells.
Results In our study, we found that BER inhibits growth of highly-metastatic human breast cancer cell lines MDA-MB-231 and MDA-MB-435S cells dose-dependently and time-dependently. The sera from BER-treated rats suppress the growth of MDA-MB-231 cells. BER shows synergistic effects with some existing anticancer agents such as trichostatin A (TSA, the histone deacetylase inhibitor), celecoxib (the inhibitor of COX-2), and carmofur against the growth of MDA-MB-231 cells. BER also displays the strong activity of inducing apoptosis in both estrogen receptor-negative MDA-MB-231 cells and estrogen receptor-alpha-positive MCF-7 breast cancer cells, but not in normal human mammary epithelial cell line MCF10A. BER down-regulates anti-apoptotic protein Bcl-2 levels and up-regulates pro-apoptotic protein Bax expressions in MDA-MB-231 and MDA-MB-435S cells. BER also has synergistic effects with anticancer agents trichostatin A, celecoxib and/or carmofur on reducing Bcl-2/Bax ratios and VEGF secretions in MDA-MB-231 cells. In addition, BER significantly suppresses cell migration and invasion, as well as decreases pro-MMP-9/pro-MMP-2 activation in breast cancer cells. Furthermore, BER suppresses Akt and nuclear factor κB signaling by reducing the phosphorylation of c-Met and Akt, and inhibiting their downstream targets such as nuclear factor κB p-65, Bcl-2/Bax, osteopontin, VEGF, MMP-9 and MMP-2 on protein and/or mRNA levels in breast cancer cells.
Conclusion Our findings have showed that BER suppresses the growth, migration and invasion in highly-metastatic human breast cancer cells by possibly inhibiting Akt and NF-κB signaling with their upstream target c-Met and downstream targets Bcl-2/Bax, osteopontin, VEGF, MMP-9 and MMP-2. BER has synergistic effects with anticancer agents trichostatin A, celecoxib and carmofur on inhibiting the growth of MDA-MB-231 cells and reducing the ratio of Bcl-2/Bax and/or VEGF expressions in the cancer cells. These findings suggest that BER may have the wide therapeutic and/or adjuvant therapeutic application in the treatment of human breast cancer and other cancers.
Abstract Withaferin A (WA) is derived from the medicinal plant Withania somnifera, which has been safely used for centuries in Indian Ayurvedic medicine for treatment of different ailments. We now show, for the first time, that WA exhibits significant activity against human breast cancer cells in culture and in vivo. The WA treatment decreased viability of MCF-7 (estrogen-responsive) and MDA-MB-231 (estrogen-independent) human breast cancer cells in a concentration-dependent manner. The WA-mediated suppression of breast cancer cell viability correlated with apoptosis induction characterized by DNA condensation, cytoplasmic histone–associated DNA fragmentation, and cleavage of poly-(ADP-ribose)-polymerase. On the other hand, a spontaneously immortalized normal mammary epithelial cell line (MCF-10A) was relatively more resistant to WA-induced apoptosis compared with breast cancer cells. The WA-mediated apoptosis was accompanied by induction of Bim-s and Bim-L in MCF-7 cells and induction of Bim-s and Bim-EL isoforms in MDA-MB-231 cells. The cytoplasmic histone–associated DNA fragmentation resulting from WA exposure was significantly attenuated by knockdown of protein levels of Bim and its transcriptional regulator FOXO3a in both cell lines. Moreover, FOXO3a knockdown conferred marked protection against WA-mediated induction of Bim-s expression. The growth of MDA-MB-231 cells implanted in female nude mice was significantly retarded by 5 weekly i.p. injections of 4 mg WA/kg body weight. The tumors from WA-treated mice exhibited reduced cell proliferation and increased apoptosis compared with tumors from control mice. These results point toward an important role of FOXO3a and Bim in regulation of WA-mediated apoptosis in human breast cancer cells.
Is exercise effective in reducing the risk of breast cancer in postmenopausal women
McTiernan A, Kooperberg C, White E, Wilcox S, Coates R, Adams-Campbell LL, et al.
Recreational physical activity and the risk of breast cancer in postmenopausal women: the Women’s Health Initiative Cohort Study. JAMA 2003;290:1331-6.
Reports have shown that excess weight and large sizes have been associated to a higher risk of breast cancer. It remains unclear the amount or intensity of exercise that is needed to produce this effect and at what age the physical activity must occur. The study consisted of a group of 74,171 women aged 50-79 from 40 U.S. clinical centers between 1993-1998 for the Women’s Health Initiative Observational Study.
Information collected was based on factors such as medical, family history, physical activity, diet, height, weight and lifetime use of hormone therapy.
In a four-and-a-half year follow-up of the study, breast cancer was newly diagnosed in 1,780 of the women. The study also revealed that women who participated in regular strenuous physical activities at the age of 35 decreased their risk of breast cancer by 14 percent compared with less active women.
This is further evidence that exercise before and after menopause are linked to breast cancer prevention. The effect was realized even with small increments of exercise equivalent to one to two hours per week of brisk walking. The results have shared similarities to those associated with decreasing the risk of cardiovascular disease among postmenopausal women and those with diabetes.
Cytotoxic and antibacterial activities of endophytic fungi isolated from plants at the National Park, Pahang, Malaysia Nurul AMN Hazalin,1 Kalavathy Ramasamy,1 Siong Meng Lim,1 Ibtisam Abdul Wahab,2 Anthony LJ Cole,3 and Abu Bakar Abdul Majeed4
1Collaborative Drug Discovery Research (CDDR) Group, Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), 40450 Shah Alam, Selangor Darul Ehsan, Malaysia 2Institute for the Study of Natural Remedies (iKUS), Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), 40450 Shah Alam, Selangor Darul Ehsan, Malaysia 3School of Biological Sciences, University of Canterbury, Private Bag 4800, Christchurch, New Zealand 4Brain Research Laboratory, Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), 40450 Shah Alam, Selangor Darul Ehsan, Malaysia
Abstract Background Endophytes, microorganisms which reside in plant tissues, have potential in producing novel metabolites for exploitation in medicine. Cytotoxic and antibacterial activities of a total of 300 endophytic fungi were investigated.
Methods Endophytic fungi were isolated from various parts of 43 plants from the National Park Pahang, Malaysia. Extracts from solid state culture were tested for cytotoxicity against a number of cancer cell lines using the MTT assay. Antibacterial activity was determined using the disc diffusion method
Results A total of 300 endophytes were isolated from various parts of plants from the National Park, Pahang. 3.3% of extracts showed potent (IC50 < 0.01 μg/ml) cytotoxic activity against the murine leukemic P388 cell line and 1.7% against a human chronic myeloid leukemic cell line K562. Sporothrix sp. (KK29FL1) isolated from Costus speciosus showed strong cytotoxicity against colorectal carcinoma (HCT116) and human breast adenocarcinoma (MCF7) cell lines with IC50 values of 0.05 μg/ml and 0.02 μg/ml, respectively. Antibacterial activity was demonstrated for 8% of the extracts.
Conclusion Results indicate the potential for production of bioactive agents from endophytes of the tropical rainforest flora.
Dietary phytoestrogen intake—lignans and isoflavones—and breast cancer risk (Canada) Michelle Cotterchio Æ Beatrice A. Boucher Æ Nancy Kreiger Æ Catherine A. Mills Æ Lilian U. Thompson
Abstract Objective To evaluate whether phytoestrogen intake is associated with reduced breast cancer risk, using a novel phytoestrogen database. Methods Population-based breast cancer cases aged 25–74 years (diagnosed 2002–2003) were identified using Ontario Cancer Registry (n = 3,063) and controls (n = 3,430) were an age-stratified random sample of women identified through random digit dialing. An epidemiologic and Block food frequency questionnaire—expanded to include phytoestrogen-containing foods—was mailed to all subjects. The recently published Ontario phytoestrogen database was applied to FFQ responses to estimate intake. Multivariate logistic regression provided odds ratio (OR) estimates, while controlling for confounders. Results Among all women, lignan intake was associated with a reduced breast cancer risk (Q5 vs. Q1 MVOR: 0.81, 95% CI: 0.65, 0.99); however, following stratification by BMI, this reduction in risk was statistically significant only among overweight (BMI[25) women. Total phytoestrogen intake was also associated with a risk reduction among overweight women only. Among pre-menopausal women. total phytoestrogen intake was associated with a significant reduction in breast cancer risk among overweight women only (Q5 vs. Q1 MVOR: 0.51, 95% CI: 0.30, 0.87). Among post-menopausal women, no statistically significant association was observed between breast cancer risk and isoflavones or lignans.Conclusion Lignan intake may be associated with reduced breast cancer risk among pre-menopausal women, and our data suggest BMI modifies this association.
NOTE Lignans are phytoestrogens with estrogenic or anti-estrogenic activity. Lignans may also have antioxidant activity. Plant lignans come from sources such as flax seed (highest source) whole grain cereals, rye, legumes, seeds and nuts, berries, vegetables and fruits. Isoflavones are a class of phytoestrogens—plant-derived compounds with estrogenic activity. Soybeans and soy products are the richest sources of isoflavones in the human diet.
Source:Cancer Causes Control (2008) 19:259–272 DOI 10.1007/s10552-007-9089-2 LINK TO SOURCE
Dietary Flavonoid Intake and Breast Cancer Risk among Women on Long Island
Brian N. Fink1, Susan E. Steck2, Mary S. Wolff3, Julie A. Britton3, Geoffrey C. Kabat4, Mia M. Gaudet1, Page E. Abrahamson1, Paula Bell1, Jane C. Schroeder1, Susan L. Teitelbaum3, Alfred I. Neugut5,6, and Marilie D. Gammon1
1 Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC. 2 Department of Nutrition, School of Public Health, University of North Carolina, Chapel Hill, NC. 3 Department of Community and Preventive Medicine, Mt. Sinai School of Medicine, New York, NY. 4 Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY. 5 Department of Epidemiology, Joseph L. Mailman School of Public Health, Columbia University, New York, NY. 6 Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY.
Flavonoids are found in a variety of foods and have anticarcinogenic properties in experimental models. Few epidemiologic studies have examined whether flavonoid intake is associated with breast cancer in humans. In this study, the authors investigated whether dietary flavonoid intake was associated with reduced risk of breast cancer in a population-based sample of US women. They conducted a case-control study among women who resided in Nassau and Suffolk counties on Long Island, New York. Cases and controls were interviewed about known and suspected risk factors and asked to complete a food frequency questionnaire regarding their average intake in the prior 12 months. A total of 1,434 breast cancer cases and 1,440 controls provided adequate responses. A decrease in breast cancer risk was associated with flavonoid intake; the decrease was most pronounced among postmenopausal women for flavonols (odds ratio (OR) ¼ 0.54, 95% confidence interval (CI): 0.40, 0.73), flavones (OR ¼0.61, 95% CI: 0.45, 0.83), flavan-3-ols (OR ¼ 0.74, 95% CI: 0.55, 0.99), and lignans (OR ¼ 0.69, 95% CI: 0.51,0.94).
The authors conclude that intake of flavonols, flavones, flavan-3-ols, and lignans is associated with reduced risk of incident postmenopausal breast cancer among Long Island women. These results suggest that US women can consume sufficient levels of flavonoids to benefit from their potential chemopreventive effects
NOTE Flavonoids are found in a variety of foods.. The most important dietary sources are fruits, tea and soybean. Green and black tea contains about 25% percent flavonoids. Other important sources of flavonoids are apple (quercetin), citrus fruits (rutin and hesperidin),
Source: American Journal of Epidemiology Advance Access published December 11, 2006 LINK TO FULL ARTICLE
The Signaling Cascades of Ginkgolide B-Induced Apoptosis in MCF-7 Breast Cancer Cells Wen-Hsiung Chan* Department of Bioscience Technology and Center for Nanotechnology, Chung Yuan Christian University, Chung Li, Taiwan 32023
Abstract: Ginkgolide B, the major active component of Ginkgo biloba extracts, can both stimulate and inhibit apoptotic signaling. Here, we demonstrate that ginkgolide B can induce the production of reactive oxygen species in MCF-7 breast cancer cells, leading to an increase in the intracellular concentrations of cytoplasmic free Ca2+ and nitric oxide (NO), loss of mitochondrial membrane potential (MMP), activation of caspase-9 and -3, and increase the mRNA expression levels of p53 and p21, which are known to be involved in apoptotic signaling. In addition, prevention of ROS generation by pretreatment with N-acetyl cysteine (NAC) could effectively block intracellular Ca2+ concentrations increases and apoptosis in ginkgolide B-treated MCF-7 cells. Moreover, pretreatment with nitric oxide (NO) scavengers could inhibit ginkgolide B-induced MMP change and sequent apoptotic processes. Overall, our results signify that both ROS and NO played important roles in ginkgolide B-induced apoptosis of MCF-7 cells. Based on these study results, we propose a model for ginkgolide B-induced cell apoptosis signaling cascades in MCF-7 cells.
Conclusions Based on the results of the present study, we propose a possible model of ginkgolide B-induced cell apoptosis signaling in MCF-7 cells (Figure 8). Our results collectively show that both intracellular ROS and NO play critical roles in ginkgolide B-induced cell apoptosis of MCF-7 cells.
Figure 8. Scheme of events occurring during ginkgolide B-induced cell apoptosis in MCF-7 cells.
MCF-7 cells --(Ginkgolide B treatment) ------> ROS generation ------> Increase of [Ca2+]i ------>NO increases ------> Increase of p53 and p21, Loss of MMP , Caspases activation ------> Cell apoptosis
Apoptogenic effects of black tea on Ehrlich’s ascites carcinoma cell
Arindam Bhattacharyya, Tathagata Choudhuri, Suman Pal, Sreya Chattopadhyay, Goutam K. Datta, Gaurisankar Sa and Tanya Das1
Bose Institute, P-1/12 CIT Scheme VII M, Kolkata-700 054, India
Next to water, tea is the most ancient and widely consumed beverage in the world. Epidemiological studies have suggested a cancer protective effect, but the results obtained so far are not conclusive.In the current study, mechanisms of the apoptogenic effect of black tea extract were delineated. Black tea administration to Ehrlich’s ascites carcinoma (EAC)-bearing Swiss albino mice caused a significant decrease in the tumor cell count in a dose-dependent manner. Flowcyto metric analysis showed an increase in the number of cells in the sub-G0/G1 population signifying tumor cell apoptosis by black tea. These results were further confirmed by nuclear staining that demonstrated distinct morphological features of apoptosis. Our data also revealed an increase inthe expression of pro-apoptotic protein p53 in EAC. It is known that upon p53 induction, multiple downstream factors contribute to the decision making between growth arrest and apoptosis.Among those, pro-apoptotic gene Bax is up regulated during p53-mediated apoptosis. On the other hand, p53-mediated growth arrest involvesp21 as a major effecter. In our system, increase in p53 expressionwas followed by moderate expression of p21/Waf-1 and high expression of Bax at protein levels. Interestingly, anti-apoptotic protein Bcl-2 was down regulated resulting in decrease in Bcl-2/Baxratio. All these observations together signify that black tea-induced apoptogenic signals overrode the growth-arresting message ofp21, thereby leading the tumor cells towards death.
Inhibition of proteasome activity by the dietary flavonoid apigenin is associated with growth inhibition in cultured breast cancer cells and xenografts
Di Chen,1 Kristin R Landis-Piwowar,1 Marina S Chen,1 and Q Ping Dou1
1The Prevention Program, Barbara Ann Karmanos Cancer Institute and Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan 48201-2013, USA
Introduction Proteasome inhibition is an attractive approach to anticancer therapy and may have relevancy in breast cancer treatment. Natural products, such as dietary flavonoids, have been suggested as natural proteasome inhibitors with potential use for cancer prevention and therapeutics. We previously reported that apigenin, a flavonoid widely distributed in many fruits and vegetables, can inhibit proteasome activity and can induce apoptosis in cultured leukemia Jurkat T cells. Whether apigenin has proteasome-inhibitory activity in the highly metastatic human breast MDA-MB-231 cells and xenografts, however, is unknown.
Methods MDA-MB-231 breast cancer cell cultures and xenografts were treated with apigenin, followed by measurement of reduced cellular viability/proliferation, proteasome inhibition, and apoptosis induction. Inhibition of the proteasome was determined by levels of the proteasomal chymotrypsin-like activity, by ubiquitinated proteins, and by accumulation of proteasome target proteins in extracts of the treated cells or tumors. Apoptotic cell death was measured by capase-3/caspase-7 activation, poly(ADP-ribose) polymerase cleavage, and immunohistochemistry for terminal nucleotidyl transferase-mediated nick end labeling positivity.
Results We report for the first time that apigenin inhibits the proteasomal chymotrypsin-like activity and induces apoptosis not only in cultured MDA-MB-231 cells but also in MDA-MB-231 xenografts. Furthermore, while apigenin has antibreast tumor activity, no apparent toxicity to the tested animals was observed.
Conclusion We have shown that apigenin is an effective proteasome inhibitor in cultured breast cancer cells and in breast cancer xenografts. Furthermore, apigenin induces apoptotic cell death in human breast cancer cells and exhibits anticancer activities in tumors. The results suggest its potential benefits in breast cancer prevention and treatment.
Cytotoxic effects of ultra-diluted remedies on breast cancer cells
Authors: Moshe Frenkel, Bal Mukund Mishra, Subrata Sen, Peiying Yang, Alison Pawlus, Luis Vence, Aimee Leblanc, Lorenzo Cohen, Pratip Banerji, Prasanta Banerji
Affiliations: Integrative Medicine Program-Unit 145, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030-4009, USA. firstname.lastname@example.org Pages: 395-403
Abstract: The use of ultra-diluted natural products in the management of disease and treatment of cancer has generated a lot of interest and controversy. We conducted an in vitro study to determine if products prescribed by a clinic in India have any effect on breast cancer cell lines. We studied four ultra-diluted remedies (Carcinosin, Phytolacca, Conium and Thuja) against two human breast adenocarcinoma cell lines (MCF-7 and MDA-MB-231) and a cell line derived from immortalized normal human mammary epithelial cells (HMLE). The remedies exerted preferential cytotoxic effects against the two breast cancer cell lines, causing cell cycle delay/arrest and apoptosis. These effects were accompanied by altered expression of the cell cycle regulatory proteins, including downregulation of phosphorylated Rb and upregulation of the CDK inhibitor p27, which were likely responsible for the cell cycle delay/arrest as well as induction of the apoptotic cascade that manifested in the activation of caspase 7 and cleavage of PARP in the treated cells. The findings demonstrate biological activity of these natural products when presented at ultra-diluted doses. Further in-depth studies with additional cell lines and animal models are warranted to explore the clinical applicability of these agents.
In summary, our study demonstrates that the ultra-diluted natural product remedies prescribed in the ‘Banerji Protocol’ induce cell cycle delay/arrest with subsequent apoptosis in breast adenocarcinoma cells. Though the degree of the antisurvival effect appeared to correlate with the presence of the wild-type p53 gene, overall susceptibility to the inhibitory effects of the remedies appeared independent of the functional p53 and estrogen-receptor status of the breast carcinoma cells. Finally, the preferentially elevated cytotoxic effects on breast adenocarcinoma cells compared with cells derived from normal mammary epithelium raises the excitingpossibility of a window of therapeutic opportunity for preferentially eliminating breast cancer cells with minimal damage to the surrounding normal mammary tissue by using the ultra-diluted remedies investigated in this report. The findings of this study should encourage further preclinical and animal investigation of these remedies as preventive and/or therapeutic treatments for breast cancer.
Faculté des Sciences Pharmaceutiques. UMR IRD/UPS 152. 35 ch. des Maraîchers, F-31062 Toulouse, France. email@example.com
INTRODUCTION: In our work, we evaluate the potential antioxidant, antimalarial activity and also activity against human breast cancer cells (MCF7) of Argan fruit extracts using in vitro models to validate the traditional use of this plant. Its chemical composition was also studied to begin the understanding of its activities, waiting to find the structure-activity relationship.
RESULTS: Polyphenols (89.4-218.5 eqGallic acid (mg/g dry)), tannins (39.3-214.0 eqCatechin (mg/g dry)), flavonoids (3.4-11.1 eqQuercetin (mg/g dry)) and anthocyanins (0.74-10.92 eqCyanindin (mug/g dry)) were quantified. A good (ethyl acetate and decoction) and moderate (petroleum ether) antioxidant activity were obtained for DPPH (IC(50) 32.3-600.8 microg/ml) and ABTS (IC(50) 11.9-988.8 microg/ml) assays. In addition, we found a good antimalarial activity (IC(50) 35 to >100 microg/ml) and human breast cancer cells activity (IC(50) 42 to >100 microg/ml).
Discussion Tocopherols and saponins derived from A. spinosa exert an antiproliferative effect on human prostate cancer (Drissi et al., 2006). In our work, we showed that the EA extract of A. spinosa was cytotoxic at 42 [micro]g/ml against human breast cancer cells (MCF7).
CONCLUSIONS: The ethyl acetate extract and the decoction show interesting antimalarial and antioxidant activities. The results indicate a good correlations between anthocyanins quantitiy and the potential antioxidant (R(2)=0.9867) and also to antimalarial activity
Early Diagnosis of Hereditary Breast Cancer by Magnetic Resonance Imaging: What Is Realistic?
Jan G.M. Klijn, Department of Medical Oncology, Erasmus MC/Daniel den Hoed Cancer Center, Erasmus University Rotterdam, the Netherlands See accompanying article doi: 10.1200/JCO.2009.23.0839
A family history of breast cancer is one of the major risk factorsfor breast cancer. It is estimated that hereditary factors play a causativerole in more than25%of patients. Currently, many genetic alterations associated with highly (4 to 10), moderately (2 to 4), and slightly(1 to 2) increased risk for developing breast cancer have been identified.1 However, in daily clinical practice, mutations in a few high-riskgenes are mainly being determined (ie, BRCA1, BRCA2, TP53, and PTEN). Mutations in these genes are roughly associated with a cumulativelife-time risk (CLTR) of 50% to 85% and are characterized by early onset of disease, starting from the age of 25. However, such highly dominant genetic alterations occur in only a small minority(approximately 5%) of patients with breast cancer. In women with a family history of breast cancer without a proven gene mutation, theCLTR of breast cancer varies between 15% and 50% depending on the pedigree and other risk factors.Women with a moderately to highly increased genetic risk ofbreast cancer have the option to reduce their risk by prophylactic surgery or chemoprevention.1,2 Prophylactic bilateral mastectomyreduces the risk of breast cancer by nearly 100% and prophylactic bilateral salpingo-oophorectomy by approximately 50%. Chemopreventionfor 5 years reduces the risk by 40% to 50%, but is used by only a very small minority (10%) of high-risk women, mainly in North-America.2A promising strategy to reduce the risk of breast cancer death in women with a genetic predisposition is early diagnosis by intensive surveillance, usually from the age of 25.1In the 1990s, several retrospective and prospective studies were performed assessing the efficacy of yearly mammography screening, sometimes in combination with (semi-annual) clinical breast examination (CBE) and/or ultrasound.6-8 Indeed, it was possible to detect breast cancer in a significant number of asymptomatic women, but the sensitivity (40% to 60%) appeared to be low in comparison with the results of population-based mammographic screening in women between 50 and 75 years of age. Especially in carriers of BRCA1/2 gene mutations, interval cancers frequently occurred (ie, in approximately 40% to 60% of breast cancers).5-8 Since the late 1990s, a new approach has involved the addition of magnetic resonance imaging (MRI) to yearlymammographic screening. In the past 10 years, results of different pilot studies and large prospective clinical trials investigating this approach have been published3-5,9-13—all nonrandomized because of practical and ethical reasons. The first results of five large prospective studies (with at least 20 breast cancers detected)9-13 have shown that MRI appears to be about twice as sensitive as mammography in detecting tumors in women with a genetic susceptibility to breast cancer (Table 14,9-15 ); in the pooled analysis of Sardanelli3 involving 3,571 women the sensitivity of MRI was 81% versus 40% similar to the review of Warner4 of 11 studies (77% v 39%). Subsequently, the application of MRI has been incorporated in national guidelines in various Western countries,16-18 but no consensus on the optimal screening protocol exists for all risk groups. Meanwhile, inconsistent results of the sensitivity of MRI in detecting ductal carcinoma in situ (DCIS) have been reported.3,4,9-13,15,19,20 Currently, in daily clinical practice, the combination of yearly MRI and mammography is being used in women with a genetic risk of breast cancer because mammography adds significantly to the diagnostic accuracy of MRI, especially in DCIS.4
Prospective Multicenter Cohort Study to Refine Management Recommendations for Women at Elevated Familial Risk of Breast Cancer: The EVA Trial
Christiane Kuhl,* Stefanie Weigel, Simone Schrading, Birke Arand, Heribert Bieling, Roy König, Bernd Tombach, Claudia Leutner, Andrea Rieber-Brambs, Dennis Nordhoff, Walter Heindel, Maximilian Reiser, and Hans H. Schild
From the Department of Radiology and Special Section of Bioinformatics, University of Bonn, Bonn; Department of Radiology, University of Munster, Munster; Department of Radiology, University of Ulm, Ulm; and the Department of Radiology, University of Munich, Grosshadern, Germany.
Purpose: We investigated the respective contribution (in terms of cancer yield and stage at diagnosis) of clinical breast examination(CBE), mammography, ultrasound, and quality-assured breast magnetic resonance imaging (MRI), used alone or in different combination,for screening women at elevated risk for breast cancer.
Methods:Prospective multicenter observational cohort study. Six hundred eighty-seven asymptomatic women at elevated familial risk (20% lifetime) underwent 1,679 annual screening rounds consisting of CBE, mammography, ultrasound, and MRI, read independently and in different combinations. In a subgroup of 371 women, additional half-yearly ultrasound and CBE was performed more than 869 screening rounds. Mean and median follow-up was 29.18 and 29.09 months.
Results:Twenty-seven women were diagnosed with breast cancer: 11 ductal carcinoma in situ (41%) and 16 invasive cancers (59%). Three(11%) of 27 were node positive. All cancers were detected during annual screening; no interval cancer occurred; no cancer was identified during half-yearly ultrasound. The cancer yield of ultrasound (6.0 of 1,000) and mammography (5.4 of 1,000) was equivalent; it increased non significantly (7.7 of 1,000) if both methods were combined. Cancer yield achieved by MRI alone(14.9 of 1,000) was significantly higher; it was not significantly improved by adding mammography (MRI plus mammography: 16.0 of1,000) and did not change by adding ultrasound (MRI plus ultrasound:14.9 of 1,000). Positive predictive value was 39% for mammography,36% for ultrasound, and 48% for MRI.
Conclusion: In women at elevated familial risk, quality-assured MRI screening shifts the distribution of screen-detected breast cancers toward the preinvasive stage. In women undergoing quality-assured MRI annually,neither mammography, nor annual or half-yearly ultrasound or CBE will add to the cancer yield achieved by MRI alone.
Growth inhibitory activity of extracts and compounds from Cimicifuga species on human breast cancer cells
Linda Saxe Einbond,a* Ye Wen-Cai,b† Kan He,c† Hsan-au Wu,a Erica Cruz,a Marc Roller,c and Fredi Kronenberga
aDepartment of Rehabilitation Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032 bInstitute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou, ChinacNaturex, Hackensack, New Jersey.Abstract
The purpose of this report is to explore the growth inhibitory effect of extracts and compounds from black cohosh and related Cimicifuga species on human breast cancer cells and to determine the nature of the active components. Black cohosh fractions enriched for triterpene glycosides and purified components from black cohosh and related Asian species were tested for growth inhibition of the ER− Her2 over expressing human breast cancer cell line MDA-MB-453. Growth inhibitory activity was assayed using the Coulter Counter, MTT and colony formation assays.Results suggested that the growth inhibitory activity of black cohosh extracts appears to be related to their triterpene glycoside composition. The most potent Cimicifuga component tested was 25-acetyl-7,8-didehydrocimigenol 3-O-β-D-xylopyranoside, which has an acetyl group at position C-25. It had an IC50 of 3.2 µg/ml (5 µM) compared to7.2 µg/ml (12.1 µM) for the parent compound 7,8-didehydrocimigenol 3-O-β-D-xylopyranoside. Thus, the acetyl group at position C-25 enhances growth inhibitory activity.The purified triterpene glycoside actein (β-D-xylopyranoside), with an IC50 equal to 5.7 µg/ml (8.4 µM), exhibited activity comparable to cimigenol 3-O-β-D-xyloside. MCF7 (ER+Her2 low) cells transfected for Her2 are more sensitive than the parental MCF7 cells to the growth inhibitory effects of actein from black cohosh, indicating that Her2 plays a role in the action of actein. The effect of actein on Her2 overexpressing MDA-MB-453 and MCF7 (ER+Her2 low) human breast cancer cells was examined by fluorescent microscopy. Treatment with actein altered the distribution of actin filaments and induced apoptosis in these cells.These findings, coupled with our previous evidence that treatment with the triterpene glycoside actein induced a stress response and apoptosis in human breast cancer cells, suggest that compounds from Cimicifuga species may be useful in the prevention and treatment of human breast cancer.
Black Cohosh Increases Metastatic Mammary Cancer in Transgenic Mice Expressing c-erbB2
Vicki L. Davis1, Manuel J. Jayo2, Arline Ho3, Mary P. Kotlarczyk1, Mary L. Hardy4, Warren G. Foster5 and Claude L. Hughes6
1 Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania; 2 Tengion Laboratories, Winston-Salem, North Carolina; 3 Cedars-Sinai Medical Center and 4 Simms/Mann-UCLA Center for Integrative Oncology, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California; 5 Obstetrics and Gynecology, McMaster University, Hamilton, Ontario, Canada; and 6 Medical and Scientific Services, Quintiles, Research Triangle Park, North Carolina
Black cohosh is an herbal extract that is often used as an alternative to estrogen-based replacement therapies to treat hot flushesthat frequently accompany the transition to menopause. Althoughcancer-free women as well as breast cancer patients and survivors use black cohosh to relieve vasomotor symptoms, there is limited information on its potential to influence breast cancer developmentor progression. Therefore, in this study, the effects of blackcohosh on mammary tumorigenesis were investigated in the MMTV-neumouse model due to its similarities to HER2+ breast cancer,including stochastic development of mammary tumors, which frequently progress to metastatic disease. Using an adjusted dose for the mice to correlate to the recommended dose in women (40 mg/d),no differences were detected in the incidence or onset of mammary tumors in black cohosh–treated versus control females.The lack of effect on mammary tumor development suggests that black cohosh would not influence breast cancer risk if given to women before tumor formation. In contrast, black cohosh significantly increased the incidence of lung metastases in tumor-bearing animals compared with mice fed the isoflavone-free control diet. Additional studies will be needed to correlate these findings to women taking different black cohosh products at various times during breast cancer development; however, these results suggest caution for women using black cohosh, especially for extended periods of time. As metastatic progression is linked to patient survival, these data stress the importance of investigating how women's therapies influence all stages of mammary tumorigenesis,particularly for assessing their safety. [Cancer Res 2008;68(20):8377–83]
Abstract (provisional) Introduction Recent, international declines in breast cancer incidence are unprecedented, and the causes remain controversial. Few data sources can address breast cancer incidence trends according to pertinent characteristics like hormone therapy use history.
Methods We used the prospective California Teachers Study to evaluate changes in self-reported use of menopausal hormone therapy (HT) between 1995 to 1996 and 2005 to 2006 and age-adjusted breast cancer incidence among 74,647 participants aged 50 years or older. Breast cancer occurrence was determined by linkage with the California Cancer Registry.
Results During 517,286 woman years of follow up, 565 in situ and 2,668 invasive breast cancers were diagnosed. In situ breast cancer incidence rates in this population did not change significantly from 2000 to 2002 to 2003 to 2005, whereas rates of invasive breast cancer declined significantly by 26.0% from 528.0 (95% confidence intervals (CI) = 491.1, 564.9) per 100,000 women in 2000 to 2002 to 390.6 (95% CI = 355.6, 425.7) in 2003 to 2005. The decline in invasive breast cancer incidence rates was restricted to estrogen receptor-positive tumors. In 1996 to 1999 and 2000 to 2002 invasive breast cancer incidence was higher for women who reported current HT use especially estrogen-progestin (EP) use at baseline than for never or past users; but by 2003 to 2005 rates were comparable between these groups. For women who were taking EP in 2001 to 2002,75% of whom had stopped use by 2005 to 06, incidence had declined 30.6% by 2003 to 2005 (P =.001); whereas incidence did not change significantly for those who never took HT (P =.33).
Conclusions Few data resources can examine prospectively individual HT use and breast cancer diagnosis. Stable in situ breast cancer rates imply consistent levels of screening and suggest recent declines in invasive breast cancer to be explained predominantly by changes in HT use.
Recent declines in breast cancer incidence: mounting evidence that reduced use of menopausal hormones is largely responsible
Emily Banks*1 and Karen Canfell2,3
Abstract Substantial reductions in breast cancer incidence in women 50 years old or older have been observed recently in many developed countries, and falling use of menopausal hormone therapy (HT) remains the most plausible explanation. In keeping with recent observations from the Women’s Health Initiative, a report from the California Teachers Study cohort in this issue of Breast Cancer Research adds to this growing evidence. The investigators found a 26% reduction in invasive breast cancer in the cohort from 2000-2002 to 2003-2005, which accompanied an estimated 64% drop in HT use between 2000-2001 and 2005-2006. By collating individual data on the use of HT and breast cancer incidence, they also demonstrated that the decline in incidence was concentrated in women who had ceased HT use. The decline reflected a decrease predominantly in oestrogen receptor-positive tumours in the context of stable screening patterns over the study period. Millions of women continue to use HT, and these findings support carefully targeted short duration use as an important ongoing strategy to minimise breast cancer risk.
A Novel Natural Inhibitor of Extracellular Signal-Regulated Kinases and Human Breast Cancer Cell Growth
Ernest B. Izevbigie*1, Joseph L. Bryant and Alice Walker* *
The Molecular Genetics and Molecular & Cellular Signaling Laboratory, Department of Biology, and National Institutes of Health Center for Environmental Health, Jackson State University, Jackson, Mississippi 39217; and Institute of Human Virology, Animal Model Division, University of Maryland Biotechnology Institute, Baltimore, Maryland 21201
Water-soluble extracts of edible Vernonia amygdalina leaves were recently reported as potent inhibitors of cultured MCF-7cells. The mechanism by which V. amygdalina inhibits MCF-7 cell growth has not been previously studied. The objective of this study was to evaluate the effects of V. amygdalina on the activities,DNA synthesis, and subsequent cell growth of extracellular signal-regulated protein kinases 1 and 2 (ERKs 1/2;). Treatment of cells with various concentrations (3–100 mg/ml) of water-solubleV. amygdalina extract potently inhibited ERK activities, DNA synthesis (P < 0.005), and cell growth (P < 0.01) in a concentration-dependent fashion, both in the absence and presence of serum. The growth rate of cells pretreated with 10 mg/mlV. amygdalina for 48 hrs before transfer to V. amygdalina-free medium was not significantly different (P > 0.05) from untreated cells. These results suggest that V. amygdalina, at least at concentrations up to 10 mg/ml, exhibits cytostatic action to retard the growth of human breast cancer cells. In addition,the ERK signaling pathways may be one or more of the intracellular targets for V. amygdalina antineoplastic actions.
Discovery of Water-Soluble Anticancer Agents (Edotides) from a Vegetable Found in Benin City, Nigeria
Ernest B. Izevbigie
Molecular Genetics and Molecular and Cellular Signaling Laboratory, Department of Biology, and Center for Environmental Health, Jackson State University, Jackson, Mississippi 39217
Abstract Cancer claims the lives of more than six million people each year in the world. About 1,268,000 new cancer cases, and 553,400deaths were reported in the United States in 2001. Current treatment approaches have yielded significant progress in the fight against cancer, but the incidence of developing certain types of cancer continues to rise. This is especially true in the African-American communities. African Americans are about 33% more likely todie of cancer than are whites and more than twice likely to die of cancer as are Asian-Islander, American-Indians, and Hispanics.This increase coupled with the harsh side effects of some of the cancer chemotherapies have led to the search for more natural biological products, especially those derived from plant products,currently known as herbal medicine. There is a need for a continuedsearch for novel natural products that may be used as cancer chemopreventive and/or chemotherapeutic agents. The objectiveof this study was to evaluate the effect(s) of a novel water-solubleleaf extract of Vernonia amygdalina (VA) on human breast cancer cell DNA synthesis. MCF-7 cell line, considered a suitable model,was used in this study. Treatment of cells with physiologically relevant concentrations of water-soluble VA extract potently inhibited DNA synthesis in a concentration-dependent fashion both in the absence and presence of serum. Fractions of VA extract separated using preparative reverse-phase chromatography also inhibited DNA synthesis (P < 0.005). These results suggest that VA vegetable, if incorporated in the diet, may prevent or delay the on-set of breast cancer.
Soy phytochemicals synergistically enhance the preventive effect of tamoxifen on the growth of estrogen-dependent human breast carcinoma in mice
Zhiming Mai, George L. Blackburn, and Jin-Rong Zhou*
Nutrition/Metabolism Laboratory, Department of Surgery, Beth Israel, Deaconess Medical Center, Harvard Medical School, Burlington-5, 330, Brookline Avenue, Boston, MA 02215, USA
The objective of this work was to determine the interactive effects between soy bioactive components and tamoxifen (TAM) on prevention of estrogen-dependent breast cancer (BRCA). We initially investigated the effects of soy isoflavone genistein and TAM on the growth and cell cycle progression of estrogen-dependent MCF-7 human BRCA cells, and on the expression of ERα, pS2 and EGFR genes in vitro. Genistein or TAM alone inhibited the growth of MCF-7 cells in part via G1 phase arrest, but their combinations showed suggestive antagonistic effects. We further evaluated the effects of bioactive soy components and TAM on the growth inhibition of MCF-7 tumors in a clinically relevant breast tumor model. TAM and bioactive soy components, genistein and soy phytochemical concentrate (SPC), delayed the growth of MCF-7 tumors. The combination of TAM with genistein or SPC, especially at the lower dose of TAM, had synergistic effects on delaying the growth of MCF-7 tumors. Biomarker determination suggests that the combination of TAM and soy components may synergistically delay the growth of MCF-7 tumors via their combined effects on induction of tumor cell apoptosis and inhibition of tumor cell proliferation. In addition, genistein and TAM combination synergistically delayed the growth of breast tumor via decreased estrogen level and activity, and down-regulation of EGFR expression. The results from our studies suggest that further investigations may be warranted to determine if the combination of TAM and bioactive soy components may be used for prevention and/or treatment of estrogen-dependent BRCA.
Green Tea Inhibits Vascular Endothelial Growth Factor (VEGF) Induction in Human Breast Cancer Cells
Maryam R. Sartippour, Zhi-Ming Shao, David Heber,* Perrin Beatty, Liping Zhang, Canhui Liu, Lee Ellis,† Wen Liu,† Vay Liang Go* and Mai N. Brooks3 Department of Surgery, Division of Oncology and *Center for Human Nutrition, University of California, Los Angeles, CA and †University of Texas, MD Anderson Cancer Center, Houston, TX1,2
Investigators have shown that green tea and its main catechin epigallocatechin-3 gallate (EGCG) may decrease the risk of cancer. Our previous study showed that green tea extract (GTE) as well as its individual catechin components inhibited MDA-MB231 breast cancer cell and human umbilical vein endothelial cell (HUVEC) proliferation. Further, GTE suppressed breast cancer xenograft size and decreased the tumor vessel density in vivo. In the current study, we investigated the effect of GTE on the major angiogenic factor vascular endothelial growth factor (VEGF) in an in vitro experiment. GTE or EGCG (40 mg/L) significantly decreased the levels of the VEGF peptide secreted into conditioned media. This occurred in both HUVEC and human breast cancer cells and the effect was dose dependent. Furthermore, GTE and EGCG decreased the RNA levels of VEGF in MDA-MB231 cells. This inhibition occurred at the transcriptional regulation level and was accompanied by a significant decrease in VEGF promoter activity. We also showed that GTE decreased c-fos and c-jun RNA transcripts, suggesting that activator protein (AP)-1–responsive regions present in the human VEGF promoter may be involved in the inhibitory effect of GTE. Furthermore, GTE suppressed the expression of protein kinase C, another VEGF transcription modulator, in breast cancer cells. Inhibition of VEGF transcription appeared to be one of the molecular mechanism(s) involved in the antiangiogenic effects of green tea, which may contribute to its potential use for breast cancer treatment and/or prevention. J. Nutr. 132: 2307–2311, 2002.
The aim of the present study was to evaluate the possible protective role of olive oil on mammary carcinogenesis. Experimental studies can support epidemiologic data on the influence of some nutrients that can affect risk and prognosis of neoplastic lesions. In the present study, seventy two Sprague-dawley female rats 42 days old were equally divided in tree groups, being group C supplemented with olive oil (5%) and submitted to chemical carcinogenesis induction with 20 mg kg-1 of 7, 12-dimethylbenzanthracene (group B and C). At 150 days, all the animals were sacrificed and necropsy process was conducted. Animals from group A did not developed neoplastic lesions and group C showed significant differences on the number and volume of the neoplastic lesions when compared to animals from the group that was not supplemented with olive oil, it was also verified the absence of metastases in this group. The present data suggests a possible protective role of olive oil, due to its content of oleic acid and phenolic compounds, on growth and differentiation of mammary neoplastic lesions that should be confirmed on further investigation projects.
Abstract: Leaves of Cayratia carnosa have been ethnomedically claimed to possess a wide array of biological activities including anticancer activity. To verify the folklore claim, this study was performed in a Human breast carcinoma cell lines, MCF-7 and MDA-MB-231. Methanol and aqueous extracts of the leaves of C. carnosa showed cytotoxic effect on MCF-7 and MDA-MB-231 cell line, as determined with 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) microculture tetrazolium viability assay. Subcellular alterations were evaluated by using normal inverted microscope. Cells treated with methanol extract showed degeneration of cytoplasmic organelles, profound shrinkage of cells and apoptotic characteristics. The results showed that the methanol extract possesses cytotoxic effect which was greater than aqueous extract when compared to that of the control.