Dendrosomal curcumin increases expression of the long non-coding RNA gene MEG3 via up-regulation of epi-miRs in hepatocellular cancer
Background: Hepatocellular carcinoma is the fifth most common cancer worldwide, with poor prognosis and resistance to chemotherapy. This gives novel cancer treatment methods an overwhelming significance. Epigenetic therapy of cancer is useful in reversing some of the cancer defects because of reversibility of the epigenetic alterations. Non-protein coding transcripts are the major part of our transcriptome. MEC3 is a tumor suppressor long non-coding RNA being expressed in many normal tissues. Methylation of MEG3 promoter region elicits the decrease in its expression in hepatocellular cancer cells. Bioactive nutrients including curcumin offer great potential in altering DNA methylation status which is catalyzed via DNMT1, DNMT3A and 3B.
Purpose: Herein, we aimed to study RNA-based epigenetic effects of dendrosomal curcumin (DNC) on hepatocellular cancer (HCC).
Study design: To this end miRNA-dependent regulation of MEG3 expression under treatment with DNC was studied by evaluating the modulatory involvement of miR-29a for DNMT3A and 3B and miR-185 for DNMT1. Methods: We evaluated DNC entrance to HCC cells with the use of fluorescent characteristics of curcumin. Next we performed the MTT assay to evaluate DNC and dendrosome effects on HCC cell viability. The coding and non-coding genes expression analyses were done using quantitative-PCR.
Results: In result we found that the DNC dependent overexpression of miR-29a and miR-185 (P < 0.01) can down-regulate the expression of DNMT1, 3A and 3B (P < 0.05) and subsequently overexpresses MEG3 (P < 0.05)
Conclusion: DNC potentially can induce DNA hypomethylation and reexpression of silenced tumor suppressor genes in HCC. These data suggest that DNC could be an effective choice for epigenetic therapy of HCC
Source : Phytomedicine: International Journal of Phytotherapy + Phytopharmacology
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Anti-Inflammatory and Pro-apoptotic Effects of Curcumin and Resveratrol on the Human Lung Fibroblast
Cell Line MRC-5
Burkhard Kloesch1*, Elisabeth Dietersdorfer1, Silvia Loebsch1 and Guenter Steiner1,2
1Ludwig Boltzmann Institute for Rheumatology and Balneology, Cluster Rheumatology, Balneology and Rehabilitation, Vienna, Austria
2Division of Rheumatology, Department of Internal Medicine III, Medical University Vienna, Austria
Background: The naturally occuring polyphenols curcumin and resveratrol are considered to be powerful antioxidants and anti-inflammatory compounds and both inhibit the proliferation of different types of cancer cells. In the present study, we investigated possible anti-inflammatory and pro-apoptotic effects of curcumin and resveratrol on the human lung fibroblast cell line MRC-5.
Methods: MRC-5 cells were stimulated for 6 h with interleukin (IL)-1β or phorbol 12- myristate 13-acetate (PMA) in the absence or presence of different concentrations of curcumin or resveratrol. The release of interleukin (IL)-6 was quantified by enzyme-linked immunosorbent assay (ELISA). The modulation in phosphorylation of the transcription factor nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) such as p38 and ERK1/2 were analyzed by Western blot. Cytotoxic and pro-apoptotic effects of curcumin and resveratrol were monitored by the measurement of lactate dehydrogenase (LDH) activity and by Annexin-V/7-AAD staining.
Results: Both curcumin and resveratrol effectively attenuated IL-1β and PMA-induced IL-6 expression in MRC-5 cells. Furthermore, curcumin treatment induced apoptosis via caspase-3 signaling and caused endoplasmic reticulum (ER) stress. Salubrinal, an inhibitor of serine/threonine phosphatase PP1, and antioxidants such as N-acetyl-cysteine (NAC), reduced glutathione (GSH) and sodium hydrogen sulfide (NaHS) diminished the cytotoxic effects of curcumin on MRC-5 cells. In contrast to curcumin, resveratrol had no negative effects on cell viability
Source : Alternative and Integrative Medicine
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Notch-1 down-regulation by curcumin is associated with the inhibition of cell growth and the induction of apoptosis in pancreatic cancer cells.
Wang Z, Zhang Y, Banerjee S, Li Y, Sarkar FH.
Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
BACKGROUND: Notch signaling plays a critical role in maintaining the balance between cell proliferation, differentiation, and apoptosis, and thereby may contribute to the development of pancreatic cancer. Therefore, the down-regulation of Notch signaling may be a novel approach for pancreatic cancer therapy. It has been reported that curcumin down-regulates many genes that are known to promote survival and also up-regulates genes that are known promoters of apoptosis in pancreatic cancer cells in vitro. It also has been reported that there is cross-talk between Notch-1 and another major cell growth and apoptotic regulatory pathway, the nuclear factor kappaB (NF-kappaB) pathway, which is down-regulated by both curcumin and reduction of Notch-1 levels. However, to the authors' knowledge to date, no studies have determined whether the down-regulation of Notch-1 signaling, resulting in the inactivation of NF-kappaB activity, contributes to curcumin-induced cell growth inhibition and apoptosis in pancreatic cancer cells.
METHODS: The authors used multiple molecular approaches, such as the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, an apoptosis assay, gene transfection, real-time reverse transcriptase-polymerase chain reaction analysis, Western blot analysis, and an electrophoretic mobility shift assay to measure the DNA binding activity of NF-kappaB.
RESULTS: Curcumin inhibited cell growth and induced apoptosis in pancreatic cancer cells. Notch-1, Hes-1, and Bcl-XL expression levels concomitantly were down-regulated by curcumin treatment. These results correlated with the inactivation of NF-kappaB activity and increased apoptosis induced by curcumin. The down-regulation of Notch-1 by small-interfering RNA prior to curcumin treatment resulted in enhanced cell growth inhibition and apoptosis.
CONCLUSIONS: The current results provide the first demonstration to the authors' knowledge that the Notch-1 signaling pathway is associated mechanistically with NF-kappaB activity during curcumin-induced cell growth inhibition and apoptosis of pancreatic cells. These results suggest that the down-regulation of Notch signaling by curcumin may be a novel strategy for the treatment of patients with pancreatic cancer.
Source : Cancer. 2006 Jun 1;106(11):2503-13.
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Curcumin, the Golden Spice From Indian Saffron, Is a Chemosensitizer and Radiosensitizer for Tumors and Chemoprotector and Radioprotector for Normal Organs
Ajay Goela & Bharat B. Aggarwalb
Curcumin (diferuloylmethane), the yellow pigment in Indian saffron (Curcuma longa; also called turmeric, haldi, or haridara in the East and curry powder in the West), has been consumed by people for centuries as a dietary component and for a variety of proinflammatory ailments. Extensive research within the last decade in cell culture and in rodents has revealed that curcumin can sensitize tumors to different chemotherapeutic agents including doxorubicin, 5-FU, paclitaxel, vincristine, melphalan, butyrate, cisplatin, celecoxib, vinorelbine, gemcitabine, oxaliplatin, etoposide, sulfinosine, thalidomide, and bortezomib. Chemosensitization has been observed in cancers of the breast, colon, pancreas, gastric, liver, blood, lung, prostate, bladder, cervix, ovary, head and neck, and brain and in multiple myeloma, leukemia, and lymphoma. Similar studies have also revealed that this agent can sensitize a variety of tumors to gamma radiation including glioma, neuroblastoma, cervical carcinoma, epidermal carcinoma, prostate cancer, and colon cancer. How curcumin acts as a chemosensitizer and radiosensitizer has also been studied extensively. For example, it downregulates various growth regulatory pathways and specific genetic targets including genes for NF-κB, STAT3, COX2, Akt, antiapoptotic proteins, growth factor receptors, and multidrug-resistance proteins. Although it acts as a chemosensitizer and radiosensitizer for tumors in some cases, curcumin has also been shown to protect normal organs such as liver, kidney, oral mucosa, and heart from chemotherapy and radiotherapy-induced toxicity. The protective effects of curcumin appear to be mediated through its ability to induce the activation of NRF2 and induce the expression of antioxidant enzymes (e.g., hemeoxygenase-1, glutathione peroxidase, modulatory subunit of gamma-glutamyl-cysteine ligase, and NAD(P)H:quinone oxidoreductase 1, increase glutathione (a product of the modulatory subunit of gamma-glutamyl-cysteine ligase), directly quench free radicals, and inhibit p300 HAT activity. These preclinical studies are expected to lead to clinical trials to prove the potential of this age-old golden spice for treating cancer patients.
Given the shortcomings of current chemotherapy and radiation treatments for cancer management, it is obvious that such treatments in the future must be combined with more effective and safer drugs/compounds. In this regard, given all the encouraging evidence summarized in the previous sections, curcumin seems to be an ideal, safe, and highly effective compound that can be used as an adjunct in such therapeutic strategies. Use of a curcumin-based, anticancer therapeutic strategy would also allow use of lower doses of chemotherapeutic drugs and radiation but still achieve much higher antitumor efficacy and yet lower toxicity and resistance in the management of variety of human cancers. In this context, it may also be important to gain more meticulous insights into identifying cancer stem cells in various solid organ tumors and determine how these differ from normal stem cells and other neoplastic cells within the same tissue. We believe that given the undisputed and encouraging data for curcumin as a safe and effective cancer preventive and newer data as a potential therapeutic agent, combining curcumin with current chemotherapy and/or radiation may also reduce the need for palliative surgery in some instances, as cancers may be stopped before they become invasive and widely metastatic. These effects combined with its ability to prevent depression, fatigue, neuropathic pain, lack of sleep, and lack of appetite, all symptoms that induced by cancer and cancer treatment, makes curcumin an ideal agent for cancer patients."
Source : Nutrition and Cancer
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Potential applications of curcumin and its novel synthetic analogs and nanotechnology-based formulations in cancer prevention and therapy
Murielle Mimeault and Surinder K Batra
Department of Biochemistry and Molecular Biology, College of Medicine, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
Curcumin has attracted great attention in the therapeutic arsenal in clinical oncology due to its chemopreventive, antitumoral, radiosensibilizing and chemosensibilizing activities against various types of aggressive and recurrent cancers. These malignancies include leukemias, lymphomas, multiple myeloma, brain cancer, melanoma and skin, lung, prostate, breast, ovarian, liver, gastrointestinal, pancreatic and colorectal epithelial cancers. Curcumin mediates its anti-proliferative, anti-invasive and apoptotic effects on cancer cells, including cancer stem/progenitor cells and their progenies, through multiple molecular mechanisms. The oncogenic pathways inhibited by curcumin encompass the members of epidermal growth factor receptors (EGFR and erbB2), sonic hedgehog (SHH)/GLIs and Wnt/β-catenin and downstream signaling elements such as Akt, nuclear factor-kappa B (NF-κB) and signal transducers and activators of transcription (STATs). In counterbalance, the high metabolic instability and poor systemic bioavailability of curcumin limit its therapeutic efficacy in human. Of great therapeutic interest, the selective delivery of synthetic analogs or nanotechnology-based formulations of curcumin to tumors, alone or in combination with other anticancer drugs, may improve their chemopreventive and chemotherapeutic efficacies against cancer progression and relapse. Novel curcumin formulations may also be used to reverse drug resistance, eradicate the total cancer cell mass and improve the anticarcinogenic efficacy of the current anti-hormonal and chemotherapeutic treatments for patients with various aggressive and lethal cancers.
Source : Chinese Medicine Journal
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Cardioprotective effects of Curcuma longa L. extracts against doxorubicin-induced cardiotoxicity in rats
Eman M. El-Sayed1, Amal S. Abd El-azeem1, Abeer A. Afify1, Manal H. Shabana2 and Hanaa H. Ahmed3
1Food Sciences and Nutrition Department, National Research Centre, Dokki, Cairo, Egypt.
2Phytochemistry and Plant Systematic Department, National Research Centre, Dokki, Cairo, Egypt.
3Hormones Department, National Research Centre, Dokki, Cairo, Egypt.
This study was designed to investigate the possible mechanisms whereby Curcuma longa could protect against cardiotoxicity induced by doxorubicin. Administration of doxorubicin (15 mg/kg i.p.) induced cardiomyopathy manifested by significant elevation in serum creatine kinase MB (Ck-MB) and lactate dehydrogenase (LDH) activities. In addition, cardiotoxicity was further confirmed by significant increase in each of serum and cardiac malondialdehyde (MDA) level, serum iron and nitric oxide concentrations, cardiac calcium level, catalase and glucose-6 phosphate dehydrogenase activities as well as by the noticeable reduction in cardiac total antioxidant capacity, vitamin C levels and blood glutathione (GSH) concentration. Oral administration of Curcuma longa ethanolic or water extract (200 mg/kg) prior to doxorubicin produced a significant protection which was evidenced by significant reduction in mortality, CK-MB and LDH -activities. Moreover, they significantly increased GSH markedly, decreased cardiac calcium, and cardiac and serum MDA. In addition, both extracts significantly reduced serum nitric oxide, increased cardiac ascorbic acid, and ameliorated the antioxidant enzymes activities. In conclusion, Curcuma longa extracts renders resiliency against doxorubicin cardiotoxicity due to their contents of polyphenolic compounds that might serve as novel adjuvant therapy with doxorubicin.
Source : Journal of Medicinal Plants Research Vol. 5(17), pp. 4049-4058, September 2011
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Injectable Sustained Release Microparticles of Curcumin: A New Concept for Cancer Chemoprevention
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.
Source : Cancer Research
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Curcumin sensitizes TRAIL-resistant xenografts: molecular mechanisms of apoptosis, metastasis and angiogenesis
Sharmila Shankar, Suthakar Ganapathy, Qinghe Chen and Rakesh K Srivastava
We have recently shown that curcumin (a diferuloylmethane, the yellow pigment in turmeric) enhances apoptosis-inducing potential of TRAIL in prostate cancer PC-3 cells, and sensitizes TRAIL-resistant LNCaP cells in vitro through multiple mechanisms. The objectives of this study were to investigate the molecular mechanisms by which curcumin sensitized TRAIL-resistant LNCaP xenografts in vivo.
Prostate cancer TRAIL-resistant LNCaP cells were implanted in Balb c nude mice to examine the effects of curcumin and/or TRAIL on tumor growth and genes related to apoptosis, metastasis and angiogenesis.
Curcumin inhibited growth of LNCaP xenografts in nude mice by inducing apoptosis (TUNEL staining) and inhibiting proliferation (PCNA and Ki67 staining), and sensitized these tumors to undergo apoptosis by TRAIL. In xenogrfated tumors, curcumin upregulated the expression of TRAIL-R1/DR4, TRAIL-R2/DR5, Bax, Bak, p21/WAF1, and p27/KIP1, and inhibited the activation of NFκB and its gene products such as cyclin D1, VEGF, uPA, MMP-2, MMP-9, Bcl-2 and Bcl-XL. The regulation of death receptors and members of Bcl-2 family, and inactivation of NFκB may sensitize TRAIL-resistant LNCaP xenografts. Curcumin also inhibited number of blood vessels in tumors, and circulating endothelial growth factor receptor 2-positive endothelial cells in mice.
The ability of curcumin to inhibit tumor growth, metastasis and angiogenesis, and enhance the therapeutic potential of TRAIL suggests that curcumin alone or in combination with TRAIL can be used for prostate cancer prevention and/or therapy.
Source : Molecular Cancer
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Curcumin Sensitizes Human Colorectal Cancer Xenografts in Nude Mice to γ-Radiation by Targeting Nuclear Factor-κB–Regulated Gene Products
How colorectal cancer develops resistance to γ-radiation is not fully understood, but the transcription factor nuclear factor-κB (NF-κB) and NF-κB–regulated gene products have been proposed as mediators. Because curcumin, a component of turmeric (Curcuma longa), has been shown to suppress NF-κB activation, whether it can sensitize the colorectal cancer to γ-radiation was investigated in colorectal cancer xenografts in nude mice.
We established HCT 116 xenograft in nude mice, randomized into four groups, and treated with vehicle (corn oil), curcumin, γ-radiation, and curcumin in combination with γ-radiation. NF-κB modulation was ascertained using electrophoretic mobility shift assay and immunohistochemistry. Markers of proliferation, angiogenesis, and invasion were monitored by immunohistochemistry and Western blot analysis.
Curcumin significantly enhanced the efficacy of fractionated radiation therapy by prolonging the time to tumor regrowth (P = 0.02) and by reducing the Ki-67 proliferation index (P < 0. 001). Moreover, curcumin suppressed NF-κB activity and the expression of NF-κB–regulated gene products (cyclin D1, c-myc, Bcl-2, Bcl-xL, cellular inhibitor of apoptosis protein-1, cyclooxygenase-2, matrix metalloproteinase-9, and vascular endothelial growth factor), many of which were induced by radiation therapy and mediate radioresistance. The combination of curcumin and radiation therapy also suppressed angiogenesis, as indicated by a decrease in vascular endothelial growth factor and microvessel density (P = 0.002 versus radiation alone).
Collectively, our results suggest that curcumin potentiates the antitumor effects of radiation therapy in colorectal cancer by suppressing NF-κB and NF-κB–regulated gene products, leading to inhibition of proliferation and angiogenesis
Source Clinical Cancer Research:
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Chemopreventive potential of curcumin in prostate cancer
Marie-Hélène Teiten, François Gaascht, Serge Eifes, Mario Dicato, and Marc DiederichLaboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9 rue Edward Steichen, 2540 Luxembourg, Luxembourg
The long latency and high incidence of prostate carcinogenesis provides the opportunity to intervene with chemoprevention in order to prevent or eradicate prostate malignancies. We present here an overview of the chemopreventive potential of curcumin (diferuloylmethane), a well-known natural compound that exhibits therapeutic promise for prostate cancer. In fact, it interferes with prostate cancer proliferation and metastasis development through the down-regulation of androgen receptor and epidermal growth factor receptor, but also through the induction of cell cycle arrest. It regulates the inflammatory response through the inhibition of pro-inflammatory mediators and the NF-κB signaling pathway. These results are consistent with this compound’s ability to up-induce pro-apoptotic proteins and to down-regulate the anti-apoptotic counterparts. Alone or in combination with TRAIL-mediated immunotherapy or radiotherapy, curcumin is also reported to be a good inducer of prostate cancer cell death by apoptosis. Curcumin appears thus as a non-toxic alternative for prostate cancer prevention, treatment or co-treatment.
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Phase II Trial of Curcumin in Patients with Advanced Pancreatic Cancer
Purpose: Pancreatic cancer is almost always lethal, and the only U.S. Food and Drug Administration–approved therapies for it, gemcitabine and erlotinib, produce objective responses in <10% of patients. We evaluated the clinical biological effects of curcumin (diferuloylmethane), a plant-derived dietary ingredient with potent nuclear factor-κB (NF-κB) and tumor inhibitory properties, against advanced pancreatic cancer.
Experimental Design: Patients received 8 g curcumin by mouth daily until disease progression, with restaging every 2 months. Serum cytokine levels for interleukin (IL)-6, IL-8, IL-10, and IL-1 receptor antagonists and peripheral blood mononuclear cell expression of NF-κB and cyclooxygenase-2 were monitored.
Results: Twenty-five patients were enrolled, with 21 evaluable for response. Circulating curcumin was detectable as drug in glucuronide and sulfate conjugate forms, albeit at low steady-state levels, suggesting poor oral bioavailability. Two patients showed clinical biological activity. One had ongoing stable disease for >18 months; interestingly, one additional patient had a brief, but marked, tumor regression (73%) accompanied by significant increases (4- to 35-fold) in serum cytokine levels (IL-6, IL-8, IL-10, and IL-1 receptor antagonists). No toxicities were observed. Curcumin down-regulated expression of NF-κB, cyclooxygenase-2, and phosphorylated signal transducer and activator of transcription 3 in peripheral blood mononuclear cells from patients (most of whom had baseline levels considerably higher than those found in healthy volunteers). Whereas there was considerable interpatient variation in plasma curcumin levels, drug levels peaked at 22 to 41 ng/mL and remained relatively constant over the first 4 weeks.
Conclusions: Oral curcumin is well tolerated and, despite its limited absorption, has biological activity in some patients with pancreatic cancer.
Source Clinical Cancer Research
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Curcumin Targets FOLFOX-surviving Colon Cancer Cells via Inhibition of EGFRs and IGF-1R
2Karmanos Cancer Center, Wayne State University, Detroit, MI 48201, U.S.A.
3.Department of Internal Medicine, Wayne State University, Detroit, MI 48201, U.S.A.
Curcumin (diferuloylmethane), which has no discernible toxicity, inhibits initiation, promotion and progression of carcinogenesis. 5-Fluorouracil (5-FU) or 5-FU plus oxaliplatin (FOLFOX) remains the backbone of colorectal cancer chemotherapeutics, but produces an incomplete response resulting in survival of cells (chemo-surviving cells) that may lead to cancer recurrence. The present investigation was, therefore, undertaken to examine whether addition of curcumin to FOLFOX is a superior therapeutic strategy for chemo-surviving cells. Forty-eight-hour treatment of colon cancer HCT-116 and HT-29 cells with FOLFOX resulted in 60-70% survival, accompanied by a marked activation of insulin like growth factor-1 receptor (IGF-1R) and minor to moderate increase in epidermal growth factor receptor (EGFR), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (HER-2) as well as v-akt murine thymoma viral oncogene homolog 1 (AKT), cyclooxygenase-2 (COX-2) and cyclin-D1. However, inclusion of curcumin to continued FOLFOX treatment for another 48 h greatly reduced the survival of these cells, accompanied by a concomitant reduction in activation of EGFR, HER-2, IGF-1R and AKT, as well as expression of COX-2 and cyclin-D1. More importantly, EGFR tyrosine kinase inhibitor gefitinib or attenuation of IGF-1R expression by the corresponding si-RNA caused a 30-60% growth inhibition of chemo-surviving HCT-116 cells. However, curcumin alone was found to be more effective than both gefitinib and IGF-1R si-RNA mediated growth inhibition of chemo-surviving HCT-116 cells and addition of FOLFOX to curcumin did not increase the growth inhibitory effect of curcumin. Our data suggest that inclusion of curcumin in conventional chemotherapeutic regimens could be an effective strategy to prevent the emergence of chemoresistant colon cancer cells.
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Chemoprevention of Colon Carcinogenesis by Dietary Curcumin, a Naturally Occurring Plant Phenolic Compound
1 Chinthalapally V. Rao, Abraham Rivenson, Barbara Simi and Bandaru S. Reddy2
Divisions of Nutritional Carcinogenesis [C. V. R., B. S., B. S. R.] Pathology [A. R.], American Health Foundation, Valhalla, New York 10595
Human epidemiological and laboratory animal model studies have suggested that nonsteroidal antiinflammatory drugs reduce the risk of development of colon cancer and that the inhibition of colon carcinogenesis is mediated through the alteration in cyclooxygenase metabolism of arachidonic acid. Curcumin, which is a naturally occurring compound, is present in turmeric, possesses both antiinflammatory and antioxidant properties, and has been tested for its chemopreventive properties in skin and forestomach carcinogenesis. The present study was designed to investigate the chemopreventive action of dietary curcumin on azozymethane induced colon carcinogenesis and also the modulating effect of this agent on the colonic mucosal and tumor phospholipase A2, phospholipaseC1, lipoxygenase, and cyclooxygenase activities in male F344rats. At 5 weeks of age, groups of animals were fed the control(modified AIN-76A) diet or a diet containing 2000 ppm of curcumin.At 7 weeks of age, all animals, except those in the vehicle(normal saline)-treated groups, were given two weekly s.c. injectionsof azoxymethane at a dose rate of 15 mg/kg body weight. All groups were continued on their respective dietary regimen until the termination of the experiment at 52 weeks after the carcinogen treatment. Colonic tumors were evaluated histopathologically.Colonic mucosa and tumors were analyzed for phospholipase A2,phospholipase C1, ex vivo prostaglandin (PG) E2, cyclooxygenase,and lipoxygenase activities. The results indicate that dietary administration of curcumin significantly inhibited incidence of colon adenocarcinomas (P < 0.004) and the multiplicity of invasive (P < 0.015), noninvasive (P < 0.01), and total(invasive plus noninvasive) adenocarcinomas (P < 0.001).Dietary curcumin also significantly suppressed the colon tumor volume by >57% compared to the control diet. Animals fed the curcumin diet showed decreased activities of colonic mucosal and tumor phospholipase A2 (50%) and phospholipase C1 (40%)and levels of PGE2 (>38%). The formation of prostaglandins such as PGE2, PGF2, PGD2, 6-keto PGF1, and thromboxane B2 through the cyclooxygenase system and production of 5(S)-, 8(S)-, 12(S)-,and 15(S)-hydroxyeicosatetraenoic acids via the lipoxygenase pathway from arachidonic acid were reduced in colonic mucosa and tumors of animals fed the curcumin diet as compared to control diet. Although the precise mechanism by which curcumin inhibits colon tumorigenesis remains to be elucidated, it is likely that the chemopreventive action, at least in part, may be related to the modulation of arachidonic acid metabolism
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