Can Standardized Plant Extracts Induce Complete Remission in Patients with Metastatic Tumors? Tibor Hajtó1*, András Adámy1, Lilla Baranyai1, Zoltán Langmár2, Angelika Kirsch3, Monika Kuzma1, Lajos Ábrahám4 and Perjési Pál1
1Institute of Pharmaceutical Chemistry, Medical University Pecs, Hungary 22nd Department of Gynecology, Semmelweis University, Budapest, Hungary
Abstract Background: The prognostic significance of malignant tumor-induced imbalance in the innate immune system is well known. The innate system uses a limited number of Pattern Recognition Receptors (PRR) to recognize conserved Pathogenic Associated Molecular Pattern (PAMP) structures expressed by microbes but not by host. PRR engagement often leads to the activation of natural immune cells which are important in the tumor defense. Growing evidence supports the hypothesis that similar to microbes various plant extracts can also contain PAMP-like structures which can activate cellular immune functions. Since the chemical production of PAMP structures is hardly accomplishable, the phytotherapy may be promising for the future tumor therapy. Objectives: The aim of this article is to present and discuss several favorable clinical responses of tumor patients treated with immunologically effective and standardized plant extracts (containing PAMP-like structures) as an addition to the conventional oncologic therapy.
Course of therapy and results: Two standardized plant preparations based on lectin-sugar interactions were the patients given. The dose of the active sugar-binding mistletoe lectin (ML), applied subcutaneously by standardized mistletoe extract (ME) preparations, was between 0.5 and 1.0 ng/kg and the dose of arabinoxylan (given by standardized rice bran preparation, MGN-3/Biobran) was between 12 and 45mg/kg twice a week. In addition, wheat germ extract (WGE) standardized for 2, 6-dimethoxy-p-benzoquinone (50-80 mg/kg Avemar four times a week) was also given which can sensitize tumor cells against natural immune effector cells. Case reports gave an account of complete or nearly complete remissions in patients with sarcoma or with hepatic metastases treated with these standardized plant immunomodulators with and without conventional oncologic therapy.
Conclusion:Standardized plant extracts (such as ME/ML, MGN-3 and WGE) seem to be potent candidates to be regarded as a supportive therapy of metastatic tumors.
Is Selenium a Potential Treatment for Cancer Metastasis? Yu-Chi Chen 1, K. Sandeep Prabhu 2,3,4 and Andrea M. Mastro 1,3,4,* 1 Department of Biochemistry and Molecular Cell Biology, The Pennsylvania State University, University Park, PA 16802, USA 2 Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA 3 Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802, USA 4 Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA 16802, USA Abstract Selenium (Se) is an essential micronutrient that functions as a redox gatekeeper through its incorporation into proteins to alleviate oxidative stress in cells. Although the epidemiological data are somewhat controversial, the results of many studies suggest that inorganic and organic forms of Se negatively affect cancer progression, and that several selenoproteins, such as GPXs, also play important roles in tumor development. Recently, a few scientists have examined the relationship between Se and metastasis, a late event in cancer progression, and have evaluated the potential of Se as an anti-angiogenesis or anti-metastasis agent. In this review, we present the current knowledge about Se compounds and selenoproteins, and their effects on the development of metastasis, with an emphasis on cell migration, invasion, and angiogenesis. In the cancers of breast, prostate, colorectal, fibrosarcoma, melanoma, liver, lung, oral squamous cell carcinoma, and brain glioma, there is either clinical evidence linking selenoproteins, such as thioredoxin reductase-1 to lymph node metastasis; in vitro studies indicating that Se compounds and selenoproteins inhibited cell motility, migration, and invasion, and reduced angiogenic factors in some of these cancer cells; or animal studies showing that Se supplementation resulted in reduced microvessel density and metastasis. Together, these data support the notion that Se may be an anti-metastastatic element in addition to being a cancer preventative agent. Source : Journal Nutrition Link to Full Article 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
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.
Ds-echinoside A, a new triterpene glycoside derived from sea cucumber, exhibits antimetastatic activity via the inhibition of NF-κB-dependent MMP-9 and VEGF expressions
Qin Zhao, Zhi-dong Liu, Yong Xue, Jing-feng Wang,†‡ Hui Li, Qing-juan Tang, Yu-ming Wang, Ping Dong, and Chang-hu Xue†‡ College of Food Science and Engineering, Ocean University of China, Qingdao 266003, China
Ds-echinoside A (DSEA), a non-sulfated triterpene glycoside, was isolated from the sea cucumber Pearsonothuria graeffei. In vitro and in vivo investigations were conducted on the effects of DSEA on tumor cell adhesion, migration, invasion, and angiogenesis. In this study, we found that DSEA inhibited the proliferation of human hepatocellular liver carcinoma cells Hep G2, with a half-maximal inhibitory concentration (IC50) of 2.65 μmol/L, and suppressed Hep G2 cell adhesion, migration, and invasion in a dose-dependent manner. DSEA also reduced tube formation of human endothelial cells ECV-304 on matrigel in vitro and attenuated neovascularization in the chick embryo chorioallantoic membrane (CAM) assay in vivo. Immunocytochemical analysis revealed that DSEA significantly decreased the expression of matrix metalloproteinase-9 (MMP-9), which plays an important role in the degradation of basement membrane in tumor metastasis and angiogenesis. DSEA also increased the protein expression level of tissue inhibitor of metalloproteinase-1 (TIMP-1), an important regulator of MMP-9 activation. From the results of Western blotting, the expressions of nuclear factor-kappa B (NF-κB) and vascular endothelial growth factor (VEGF) were found to be remarkably reduced by DSEA. These findings suggest that DSEA exhibits a significant anti-metastatic activity through the specific inhibition of NF-κB-dependent MMP-9 and VEGF expressions.
In conclusion, the present study provides evidence that DSEA possesses marked anti-metastatic activity. We have shown that DSEA plays a role in the inhibition of Hep G2 cell migration, invasion, and angiogenesis through suppression of VEGF and MMP-9 and enhancement of TIMP-1 protein expression by blocking the NF-κB signaling pathway. To our knowledge, this is the first report demonstrating the anti-metastatic activity of a nonsulfated triterpene glycoside isolated from P. graeffei, and providing a scientific basis for its application in therapeutic intervention against tumor progression.
Source : J Zhejiang Univ Sci B. 2011 July; 12(7): 534–544. doi: 10.1631/jzus.B1000217 Link to Full Article
Human urinary bladder cancer T24 cells are susceptible to the Antrodia camphorata extracts Chiung-Chi Peng a, Kuan-Chou Chen a,b, Robert Y. Peng c, Ching-Hua Su a,d, Hsiu Mei Hsieh-Li a,e,*
a Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC b Department of Urology, Taipei Medical University Hospital, Taipei, Taiwan, ROC c Research Institute of Biotechnology, Hung-Kuang University, Taichung, Taiwan d Graduate Institute of Biomedical Material, Taipei Medical University, Taipei, Taiwan, ROC e Department of Life Science, National Taiwan Normal University, 88, Sec. 4, Ting-Chou Road, Taipei 116, Taiwan, ROC
Abstract Bladder cancer has been cited to result from the neoplastic lesion with environmental and/or occupational factors identified as causatives. Transitional cell carcinoma (TCC) is the most common type of bladder cancer. Most of the bladder cancer patients die from the invasive, metastatic TCC that has turned out to be resistant to chemotherapy. T24 cells, a cell line established from a human urinary bladder cancer patient, are high-grade and invasive TCC. T24 cells were found very susceptible to ACCE at concentration of 50 mg/mL. MTT assay showed that the cell growth and proliferation were inhibited to 50% of the control when treated with ACCE for 72 h, at which the cell proliferation suppressing rate revealed K4.4!103 cells/mg per day. Comparing the expressions of the cell cycle biomarkers Cdc2 and Cyclin B1 by the western blot analysis, a phase G2M arrest was confirmed. Both the wound scratch assay and the transwell motility assay indicated that ACCE was very effective anti-metastatic against T24 cells. Furthermore, the active form of matrix metalloproteinase-9 (MMP-9) was also found totally suppressed as revealed by zymography at 72 h post-incubation with ACCE, while the light and electron microscopic images have apparently revealed cell membrane damages on T24 cells when treated with ACCE (50 mg/mL). Moreover, both the wound scratch and the transwell assays have demonstrated the migration capability of T24 cells has been significantly retarded to 1.5-fold at same dosage of ACCE used. In conclusion, ACCE is a good anti-cancer agent, being effective in inducing phase G2M arrest, acting as an anti-proliferative, and an anti-metastatic agent against bladder cancer cell T24 cells.
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.
(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.
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
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.
Suppression of growth, migration and invasion of highly-metastatic human breast cancer cells by berbamine and its molecular mechanisms of action
Shan Wang,#1 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 Purpose: Increasing evidence suggests that interaction between the chemoattractant CXCL12/stromal cell-derived factor-1α and its receptor CXCR4 plays a pivotal role in the metastasis of various tumors. Our previous studies showed that multi-component Chinese herbal medicines inhibited the effects of CXCL12/CXCR4. As a result of sequential chromatographic fractionation of one herbal medicine ingredient, Lianqiao (fruit of Forsythia suspensa), we observed that tannins were, at least in part, responsible for this activity. The aim of this study was to assess the anti-CXCL12/CXCR4 activity of a commercial tannic acid and evaluate its potential to inhibit tumor cell migration and angiogenesis in vitro.
Experimental Design: The inhibitory effect of tannic acid on CXCL12/CXCR4 was measured by chemotaxis assay, ligand binding assay, and fluorescence-activated cell sorter analysis. The antiangiogenic effect of tannic acid was assessed by in vitro endothelial cell tube formation.
Results: Tannic acid, at nontoxic concentrations, specifically inhibited CXCL12-induced human monocyte migration (IC50, 7.5 μg/ml) but did not inhibit CCL2-, CCL3-, CCL5-, formylmethionylleucylphenylalanine (fMLP)-, or C5a-induced migration. The compound markedly blocked CXCL12 binding to THP-1 cells (IC50, 0.36 μg/ml). Tannic acid also inhibited CXCL12-induced, but not epidermal growth factor-induced, migration of MDA 231 breast tumor cells. Additionally, 0.5 μg/ml of tannic acid selectively inhibited CXCL12-mediated, but not basic fibroblast growth factor- or endothelial cell growth supplement-mediated, bovine aorta endothelial cell capillary tube formation.
Conclusion:These studies indicate that tannic acid is a novel selective CXCL12/CXCR4 antagonist and consequently may provide a mechanistic basis for the reported antitumor and anti-inflammatory properties of tannic acid.
Note : A tannin is an astringent chemical derived from plants. Tannicacid is one type of tannin. Tannic acid is found in tea, nettle, wood, berries, Chinese galls. Oak wood is very rich in tannic acid. When wine is kept in oak kegs some tannic acid will migrate into the wine. High levels of tannic acid are found in some plant galls. These are formed by plants when they are infected by certain insects. These insects pierce the plant leaves and when the egg hatches out into a larva the plant produces a gall which surrounds the larva.