Brewers' rice induces apoptosis in azoxymethane-induced colon carcinogenesis in rats via suppression of cell proliferation and the Wnt signaling pathway Tan Bee Ling, NorhaizanMohd Esa, HeshuSulaiman Rahman, Hazilawati Hamzah andRoselina Karim
Abstract Background Brewers' rice is locally known as temukut, is a byproduct of the rice milling process, and consists of broken rice, rice bran, and rice germ. Unlike rice bran, the health benefit of brewers' rice has yet to be fully studied. Our present study aimed to identify the chemopreventive potential of brewers' rice with colonic tumor formation and to examine further the mechanistic action of brewers' rice during colon carcinogenesis.
Methods Male Sprague-Dawley rats were randomly divided into five groups: (G1) normal; (G2) azoxymethane (AOM) alone; and (G3), (G4), and (G5), which were AOM fed with 10%, 20%, and 40% (w/w) of brewers' rice, respectively. Rats in group 2 to 5 were injected intraperitoneally with AOM (15 mg/kg body weight) once weekly for two weeks. Colon tumor incidence and multiplicity was assessed by hematoxylin and eosin (H&E) staining. The expression of beta-catenin, cyclooxygenase-2 (COX-2), and Ki-67 was evaluated by immunohistochemical staining. The apoptosis-inducing activity was analyzed using a TUNEL assay. The data were analyzed using a one-way analysis of variance (ANOVA) with P-value < 0.05 was considered significant.
Results Overall analyses revealed that brewers' rice reduced colon tumor incidence and multiplicity. The results from immunohistochemistry analysis also showed that brewers' rice decreased the expression of beta-catenin, COX-2, and Ki-67 in a dose-dependent manner. Furthermore, TUNEL analysis demonstrated that administration of brewers' rice in AOM-induced rat colorectal cancer resulted in a dose-dependent increase in cell apoptosis.
Conclusions Taken together, our data suggested that brewers' rice can inhibit cell proliferation, induce apoptosis, and suppress COX-2 and beta-catenin expression via the Wnt signaling pathway and holds great promise in the field of chemoprevention as a dietary agent.
Omega 3 fatty acids chemosensitize multidrug resistant colon cancer cells by down-regulating cholesterol synthesis and altering detergent resistant membranes composition
Giada Gelsomino (firstname.lastname@example.org) Paola A Corsetto (email@example.com) Ivana Campia (firstname.lastname@example.org) Gigliola Montorfano (email@example.com) Joanna Kopecka (firstname.lastname@example.org) Barbara Castella (email@example.com) Elena Gazzano (firstname.lastname@example.org) Dario Ghigo (email@example.com) Angela M Rizzo (firstname.lastname@example.org) Chiara Riganti
Abstract Background The activity of P-glycoprotein (Pgp) and multidrug resistance related protein 1 (MRP1), two membrane transporters involved in multidrug resistance of colon cancer, is increased by high amounts of cholesterol in plasma membrane and detergent resistant membranes (DRMs). It has never been investigated whether omega 3 polyunsatured fatty acids (PUFAs), which modulate cholesterol homeostasis in dyslipidemic syndromes and have chemopreventive effects in colon cancer, may affect the response to chemotherapy in multidrug resistant (MDR) tumors.
Methods We studied the effect of omega 3 PUFAs docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in human chemosensitive colon cancer HT29 cells and in their MDR counterpart, HT29-dx cells.
Results MDR cells, which overexpressed Pgp and MRP1, had a dysregulated cholesterol metabolism, due to the lower expression of ubiquitin E3 ligase Trc8: this produced lower ubiquitination rate of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGC oAR), higher cholesterol synthesis, higher cholesterol content in MDR cells. We found that DHA and EPA re-activated Trc8 E3 ligase in MDR cells, restored the ubiquitination rate of HMGCoAR to levels comparable with chemosensitive cells, reduced the cholesterol synthesis and incorporation in DRMs. Omega 3 PUFAs were incorporated in whole lipids as well as in DRMs of MDR cells, and altered the lipid composition of these compartments. They reduced the amount of Pgp and MRP1 contained in DRMs, decreased the transporters activity, restored the antitumor effects of different chemotherapeutic drugs, restored a proper tumor-immune system recognition in response to chemotherapy in MDR cells.
Conclusions Our work describes a new biochemical effect of omega 3 PUFAs, which can be useful to overcome chemoresistance in MDR colon cancer cells.
Abstract We previously reported that oral administration of black raspberry powder decreased promoter methylation of tumor suppressor genes in tumors from patients with colorectal cancer. The anthocyanins (ACs) in black raspberries are responsible, at least in part, for their cancer-inhibitory effects. In the present study, we asked if ACs are responsible for the demethylation effects observed in colorectal cancers. Three days of treatment of ACs at 0.5, 5, and 25 μg/ml suppressed activity and protein expression of DNMT1 and DNMT3B in HCT116, Caco2 and SW480 cells. Promoters of CDKN2A, and SFRP2, SFRP5, and WIF1, upstream of Wnt pathway, were demethylated by ACs. mRNA expression of some of these genes was increased. mRNA expression of β-catenin and c-Myc, downstream of Wnt pathway, and cell proliferation were decreased; apoptosis was increased. ACs were taken up into HCT116 cells and were differentially localized with DNMT1 and DNMT3B in the same cells visualized using confocal laser scanning microscopy. Although it was reported that DNMT3B is regulated by c-Myc in mouse lymphoma, DNMT3B did not bind with c-Myc in HCT116 cells. In conclusion, our results suggest that ACs are responsible, at least in part, for the demethylation effects of whole black raspberries in colorectal cancers.
Conclusion .In conclusion, we found that anthocyanins derived from BRBs are taken up into the cytoplasm and nucleus of cultured human colon cancer cells. They demethylate tumor suppressor genes through inhibition of DNMT1 and DNMT3B. Based on the fluorescence staining results, ACs may inhibit DNMTs through direct as well as indirect target(s). Future studies aimed on identifying these targets are warranted.
Eupalitin from Asparagus falcatus (Linn.) has anti-cancer activity and induces activation of caspases 3/7 in human colorectal tumor cells Raza Murad Ghalib1*, Sayed Hasan Mehdi2, Rokiah Hashim2, Othman Sulaiman2, Fiona How Ni Foong1, B. M. Khadeer Ahamed3, Amin Malik Shah Abdul Majid3 and Faiyaz Ahmed4
1Department of Chemistry, Kulliyaah of Science, IIUM, Kuantan, Malaysia. 2School of Industrial Technology, Universiti Sains Malaysia, Minden–11800, Pulau Pinang, Malaysia. 3Department of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden–11800, Pulau Pinang, Malaysia. 4Indian Institute of Crop Processing Technology, Ministry of Food Processing Industries, Govt of India, Pudukkottai Road, Thanjavur 613 005, Tamil Nadu, India.
3,5,4′-Trihydroxy-6,7-dimethoxy-flavone (Eupalitin) has been isolated from the leaves of Asparagus falcatus (Linn.). Anti-proliferation and apoptosis studies were conducted on eupalitin. Results showed that eupalitin exhibited significant cytotoxicity against human colorectal tumor cells. It is found that eupalitin induces the activation of caspases 3/7, a hallmark of apoptosis. The study suggests that the anti-proliferative property of eupalitin towards the human colorectal tumor cells may be probably due to its capability to induce apoptosis in cells.
In the present study, we report for the first time that eupalitin has significant ability to inhibit the proliferation of human colorectal cancer cells by activating the caspase 3/7 cascade......
Combination of Selenium and Green Tea Improves the Efficacy of Chemoprevention in a Rat Colorectal Cancer Model by Modulating Genetic and Epigenetic Biomarkers Ying Hu mail, Graeme H. McIntosh, Richard K. Le Leu, Laura S. Nyskohus, Richard J. Woodman,Graeme P. Young
Abstract Dietary supplementation of selenium and green tea holds promise in cancer prevention. In this study, we evaluated the efficacies of selenium and green tea administered individually and in combination against colorectal cancer in an azoxymethane (AOM)-induced rat colonic carcinogenesis model and determined the underlying mechanisms of the protection. Four-week old Sprague-Dawley male rats were fed with diets containing 0.5% green tea extract, 1ppm selenium as selenium-enriched milk protein, or combination of 1ppm selenium and 0.5% green tea extract. Animals received 2 AOM (15 mg/kg) treatments to induce colonic oncogenesis. Rats were killed 8 or 30 wk later after the last AOM to examine the effect of dietary intervention on aberrant crypt foci (ACF) formation or tumor development. On sacrifice, colons were examined for ACF and tumors, the mRNA levels of SFRP5 and Cyclin D1, and the proteins levels of ß-catenin, COX-2, Ki-67, DNMT1 and acetyl histone H3. The combination of selenium and green tea resulted in a significant additive inhibition of large ACF formation, this effect was greater than either selenium or green tea alone, P<0.01; the combination also had a significant additive inhibition effect on all tumor endpoints, the effect of the combination diet on tumor incidence, multiplicity and size was greater than selenium or green tea alone, P<0.01. Rats fed the combination diet showed marked reduction of DNMT1 expression and induction of histone H3 acetylation, which were accompanied by restoration of SFRP5 mRNA in normal-appearing colonic crypts. The combination diet also significantly reduced ß-catenin nuclear translocation, Cyclin D1 expression and cell proliferation. These data show, for the first time, that combination of selenium and green tea is more effective in suppressing colorectal oncogenesis than either agent alone. The preventive effect is associated with regulation of genetic and epigenetic biomarkers implicated in colonic carcinogenesis.
Model Selection Approach Suggests Causal Association between 25-Hydroxyvitamin D and Colorectal Cancer
Lina Zgaga equal contributor mail, Felix Agakov equal contributor, Evropi Theodoratou, Susan M. Farrington, Albert Tenesa, Malcolm G. Dunlop,Paul McKeigue,Harry Campbell
Introduction Vitamin D deficiency has been associated with increased risk of colorectal cancer (CRC), but causal relationship has not yet been confirmed. We investigate the direction of causation between vitamin D and CRC by extending the conventional approaches to allow pleiotropic relationships and by explicitly modelling unmeasured confounders.
Methods Plasma 25-hydroxyvitamin D (25-OHD), genetic variants associated with 25-OHD and CRC, and other relevant information was available for 2645 individuals (1057 CRC cases and 1588 controls) and included in the model. We investigate whether 25-OHD is likely to be causally associated with CRC, or vice versa, by selecting the best modelling hypothesis according to Bayesian predictive scores. We examine consistency for a range of prior assumptions.
Results Model comparison showed preference for the causal association between low 25-OHD and CRC over the reverse causal hypothesis. This was confirmed for posterior mean deviances obtained for both models (11.5 natural log units in favour of the causal model), and also for deviance information criteria (DIC) computed for a range of prior distributions. Overall, models ignoring hidden confounding or pleiotropy had significantly poorer DIC scores.
Conclusion Results suggest causal association between 25-OHD and colorectal cancer, and support the need for randomised clinical trials for further confirmations.
Lowering the Risk of Rectal Cancer among Habitual Beer Drinkers by Dietary Means Gabriel Kune1 and Lyndsey Watson2
1Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, 41 Power Street, Toorak, VIC 3142, Australia 2Mother and Child Health Research, La Trobe University, Melbourne, VIC 3000, Australia
Abstract Whole-life beer consumption and a quantitative measurement of several dietary micronutrients consumed in adult life were obtained from the dietary and alcohol data of the case-control arm of the population-based Melbourne Colorectal Cancer Study. There was a statistically significant risk, adjusted for other established risk factors, among habitual beer drinkers (AOR 1.75, 95% CI 1.28–2.41) with a significant positive dose-response effect (AOR trend 1.34, 95% CI 1.16–1.55). Among beer consumers the data were interpreted as showing an attenuation of this risk with consumption of the four micronutrients involved in methylation: folate, methionine, vitamins B6 and B12, and the four micronutrients examined with antioxidant properties: selenium, vitamins E, C, and lycopene. The strongest effects were noted with vitamins E, C, and lycopene, and the weakest with methionine and selenium. Whilst not condoning excessive beer drinking, the regular consumption of foods rich in these micronutrients may provide a simple and harmless preventative strategy among persistent habitual beer drinkers and deserves further study with larger study numbers.
Conclusion Habitual longstanding beer drinking was associated with a statistically significant risk for rectal cancer, and there was a significant positive dose-response effect. As measured in this study, the regular consumption of foods containing the micronutrients involved with methylation, folate, methionine, vitamins B6 and B12, and the four micronutrients examined with antioxidant properties, selenium, vitamins E, C, and lycopene, all attenuated this risk among beer drinkers. The strongest effects were noted for vitamins E, C and lycopene, and the weakest for methionine and selenium containing foods. Whilst certainly not encouraging excessive beer drinking, the results support the proposition that the regular consumption of foods containing some of the micronutrients involved in one-carbon metabolism, particularly folate, vitamins B6, B12, and some with antioxidant properties, namely, vitamins E, C, lycopene and selenium, micronutrients that are plentiful in many vegetables, fruits, grains, nuts, and fish, may provide a relatively simple and harmless means of counteracting the excess risk of rectal cancer in habitual and persistent beer drinkers. This conclusion in our view deserves further investigation with larger study numbers and therefore greater statistical power.
Source : Advances in Preventive Medicine Volume 2011 (2011), Article ID 874048, 5 pages doi:10.4061/2011/874048 Link to Full Article
Pien Tze Huang inhibits the proliferation of human colon carcinoma cells by arresting G1/S cell cycle progression ALING SHEN,1,2 FEI HONG,3 LIYA LIU,1,2 JIUMAO LIN,1,2 LIHUI WEI,1 QIAOYAN CAI,1,2 ZHENFENG HONG,1 and JUN PENG1,
Abstract Pien Tze Huang (PZH), a well-known traditional Chinese formula prescribed 450 years ago in the Ming Dynasty, has been used in China and Southeast Asia for centuries as a folk remedy for various types of cancer, including colorectal cancer (CRC). Recently, we reported that PZH is capable of inhibiting colon cancer growth both in vivo and in vitro via the promotion of apoptosis and inhibition of tumor angiogenesis. To elucidate the mechanism of the tumoricidal activity of PZH, its effect on the proliferation of human colon carcinoma Caco-2 cells was evaluated and the underlying molecular mechanism was investigated. Results showed that PZH inhibited Caco-2 cell viability and survival in a dose- and/or time-dependent manner. In addition, PZH treatment was found to block the G1/S cell cycle progression. Moreover, PZH suppressed the mRNA and protein expression of pro-proliferative Cyclin D1 and CDK4. Findings of the present study suggest that inhibition of cell proliferation via the G1/S cell cycle arrest is a potential mechanism by which PZH can be effective in the treatment of cancer.
Source : Oncol Lett. 2012 October; 4(4): 767–770. Published online 2012 July 19. doi: 10.3892/ol.2012.811 Link to Full Article
Anticancer activity of botanical compounds in ancient fermented beverages (Review) P.E. McGOVERN1, M. CHRISTOFIDOU-SOLOMIDOU2,3, W. WANG4, F. DUKES2, T. DAVIDSON1 and W.S. EL-DEIRY4
1Biomolecular Archaeology Laboratory, University of Pennsylvania Museum of Archaeology and Anthropology; 2Pulmonary, Allergy and Critical Care Division, 3Center of Excellence in Environmental Toxicology (CEET), and 4Division of Hematology and Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
Abstract Humans around the globe probably discovered natural remedies against disease and cancer by trial and error over the millennia. Biomolecular archaeological analyses of ancient organics, especially plants dissolved or decocted as fermented beverages, have begun to reveal the preliterate histories of traditional pharmacopeias, which often date back thousands of years earlier than ancient textual, ethnohistorical, and ethnological evidence. In this new approach to drug discovery, two case studies from ancient Egypt and China illustrate how ancient medicines can be reconstructed from chemical and archaeological data and their active compounds delimited for testing their anticancer and other medicinal effects. Specifically, isoscopoletin from Artemisia argyi, artemisinin from Artemisia annua, and the latter's more easily assimilated semi-synthethic derivative, artesunate, showed the greatest activity in vitro against lung and colon cancers. In vivo tests of these compounds previously unscreened against lung and pancreatic cancers are planned for the future.
Conclusion ..These data show that both artesunate and artemisinin treatments resulted in a concentration-dependent inhibition of cell growth in Lewis lung carcinoma cells, but that artesunate was >30 times as effective ... ...The active compounds detected by the p53 studies included artemisinin, artesunate, borneol, isoscopoletin, and ursolic acid, with inhibition effects on tumor growth ranging in concentration from micromolar to millimolar amounts. Although artesunate, and to a lesser extent artemisinin, are most active against HCT116 colon adenocarcinoma... ...ursolic acid, found in species of thyme, is much more effective against colon cancer under low-oxygen conditions (hypoxia) than normal atmospheric conditions (normoxia). This compound inhibits tumor growth at a concentration of around 50 μM under normoxia; much lower concentrations of 1-10 μM are sufficient to achieve the same result under hypoxia. Tumor cells, especially those which are solid and dense, survive and proliferate under hypoxia. A strategy in anticancer therapy is to counteract this property of tumor cells. It may be hypothesized that the anticancer potency of ursolic acid is related to mechanisms operating under hypoxia... ...Based on these results, we propose in vivo and clinical studies of one derivative compound from A. annua in particular: artesunate. As already known from in vivo mouse studies of other cancers, we plan to test this compound for its clinical efficacy against lung and pancreatic cancer. To date, the effectiveness of artesunate against these specific cancers has not been determined...
Anti-Cancer Effects of Chinese Red Yeast Rice beyond Monacolin K alone in Colon Cancer Cells Mee Young Hong,* Navindra P. Seeram, Yanjun Zhang, and David Heber Center For Human Nutrition, David Geffen School of Medicine, University of California, Los Angeles, 90095, USA
Chinese Red Yeast Rice (RYR) is a food herb made by fermenting Monascus purpureus Went yeast on white rice. RYR contains a mixture of monacolins, one of which, Monacolin K (MK), is identical to lovastatin. Epidemiological studies show that individuals taking statins have a reduced risk of colon cancer. In the present study, lovastatin decreased cellular proliferation (P<.001) and induced apoptosis (P <.05) in HCT-116 and HT-29 human colon cancer cells. RYR inhibited both tumor cell growth (P <.001) and enhanced apoptosis (P <.05) in HCT-116. The inhibition of proliferation was reversed by mevalonate in lovastatin-treated cells, since lovastatin is a 3-hydroxy-3-methyl-glutaryl CoA reductase (HMGCR) inhibitor. However, RYR with mevalonate did not reverse the observed inhibition of growth. MK-free RYR did not reverse the observed lovastatin-mediated inhibition of cancer cell growth These observations suggest that other components in RYR, including other monacolins, pigments, or the combined matrix effects of multiple constituents may affect intracellular signaling pathways differently than purified crystallized lovastatin in colon cancer cells. RYR was purified into two fractions: pigment-rich (PF-RYR) and monacolin-rich (MF-RYR) fractions. The effect of MF-RYR was similar to that of lovastatin, while the effect of PF-RYR was similar to that of the whole RYR extract in proliferation, apoptosis and mRNA level of HMGCR and sterol response element binding protein-2. These results suggest that matrix effects of RYR beyond MK alone may be active in inhibiting colon cancer growth. RYR with/without MK may be a botanical approach to colon cancer chemoprevention worthy of further investigation.
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
Anti-tumor effect of Archidendron lucidum (Benth.) against esophageal cancer, colorectal cancer and hepatoma Chia-Yuan Liu1,2,3#, Yuen-Liang Lai4,5#, Chin-Ping Lin1, Yu-Tse Wu3, Tung-Hu Tsai3## and Yu-Jen Chen1,3,4*
1Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan. 2Division of Gastroenterology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan. 3Institute of Traditional Medicine, National Yang-Ming University, Taipei, Taiwan. 4Department of Radiation Oncology, Mackay Memorial Hospital, Taipei, Taiwan. 5Taipei Medical University- Shuang Ho Hospital, Taipei, Taiwan. 6Department of Education and Research, Taipei City Hospital, Taipei, Taiwan.
Abstract Archidenron lucidum is an indigenous medicinal plant in Taiwan used for treatment of inflammatory diseases and cancer. This study was aimed to investigate its anti-cancer effect against gastrointestinal and hepatic malignancy. We found that the 50% effective concentrations of its methanol extract (MEAL) against human esophageal cancer CE81T/VGH, hepatoma HA22T/VGH and murine colorectal cancer CT26 cells were less than 5.0 μg/mL in vitro whereas those of water extract were greater than 30 μg/mL. Cell cycle arrest at G2/M phase was observed in all three cell lines treated with MEAL. Development of hypodiploidy cells suggests that apoptosis might be one of the cell death pathways of CE81T/VGH cells. Intraperitoneal injection with 1.25 mg/kg MEAL significantly inhibited syngeneic CT26 tumor growth in BALB/c mice without obvious toxicity in terms of changes in body weight, leukocyte count and plasma creatinine and alanine aminotransferase (ALT) levels. Higher dose (2.5 mg/kg) MEAL did not further increase the anti-tumor effect, but resulted in elevation of plasma ALT level. Our results indicate that optimal dose of MEAL might possess the anti-tumor effects against esophageal, hepatocellular and colorectal cancers with a relative safety profile. Accordingly, we are purifying effective and less toxic compounds from MEAL.
Source : Journal of Medicinal Plants Research Vol. 5(21), pp. 5221-5229, 9 October, 2011 Link to Full Article
Thymoquinone rich fraction from Nigella sativa and thymoquinone are cytotoxic towards colon and leukemic carcinoma cell lines Ismail Norsharina1,2, Ismail Maznah1,2*, Al-Absi Aied1 and Al-Naqeeb Ghanya1,2
1Nutrigenomics and Nutricosmeceuticals Programme, Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, UPM 43400 Serdang, Selangor Darul Ehsan, Malaysia. 2Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, UPM 43400 Serdang, Selangor Darul Ehsan, Malaysia.
Nigella sativa has been used for centuries in Asia, Middle East and Africa to promote health and fight diseases. In this study, the anti-cancer effects of thymoquinone rich fraction (TQRF) extracted from N.sativa seeds using supercritical fluid extraction (SFE) system and commercially available thymoquinone (TQ) on colon cancer (HT29), lymphoblastic leukemia (CEMSS) and promyelocytic leukemia (HL60) cells lines were investigated. The concentration that gave 50% inhibition of cell viability (IC50) of HT29, CEMSS and HL60 cells treated with TQRF were 400, 350 and 250 μg/ml, respectively. Meanwhile, the IC50 of TQ was 8, 5 and 3 μg/ml, respectively. Cell cycle analysis shows the increment of apoptosis in a time-dependent manner. However, both TQRF and TQ were not able to arrest the cell cycle phases of the cells. Apoptosis was the main mode of HT29, CEMSS and HL60 cells death induced by both TQRF and TQ. Our findings support the potential use of TQRF and TQ for the treatment of colon cancer and leukemia.
....In conclusion, this study indicates that TQRF and TQ possess cytotoxic properties against colorectal cancer and showed more prominent cytotoxic effects on leukemic cell lines. In spite of TQ, TQRF was also has potential to be used as anti-cancer treatment. Therefore, TQRF from N. sativa does have the potential to be developed as a nutraceuticals for preventing the progression of cancer.
Source : Journal of Medicinal Plants Research Vol. 5(15), pp. 3359-3366, 4 August, 2011 Link to Full Article
Effects of Triterpenoid Glycosides from Fresh Ginseng Berry on SW480 Human Colorectal Cancer Cell Line Jing-Tian Xie, MD,1,2 Guang-Jian Du, PhD,1,2 Eryn McEntee, MS,1,2 Han H. Aung, MD,1,2 Hui He, MD,1 Sangeeta R. Mehendale, MD, PhD,1,2 Chong-Zhi Wang, PhD,1,2 and Chun-Su Yuan, MD, PhD1,2,31 Tang Center for Herbal Medicine Research, University of Chicago, Chicago, IL, USA. 2Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL, USA. 3Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, IL, USA.
Purpose The pharmacological activities, notably the anticancer properties, of bioactive constituents fromfresh American ginseng berry have not yet been well studied. In this study, we investigated the antiproliferative effects of fresh American ginseng berry extract (AGBE) and its representative triterpenoid glycosides using the human colorectal cancer cell line SW480.
Materials and Methods Using high performance liquid chromatography (HPLC), the contents of 8 ginsenosides in AGBE were determined. The cell growth inhibitory effects of AGBE and three triterpenoid glycosides (ginsenosides Rb3, Re, and Rg3) were evaluated by proliferation assay and 3H-thymidine incorporation assay. Cell cycle and apoptotic effects were analyzed by using flow cytometry after staining with propidium iodide and annexin V
.Results HPLC analysis data showed that AGBE has a distinct ginsenoside profile. AGBE inhibited SW480 cell growth significantly in a time-dependent (24-96 hours) and concentration-dependent (0.1-1.0 mg/mL) manner. Ginsenosides Rb3, Re, and Rg3 also possess significant antiproliferative activities on SW480 cells. 3H-thymidine incorporation assay indicated that AGBE and ginsenosides Rb3, Re, and Rg3 might inhibit the transferring and duplication of DNA in SW480 cells. Flow cytometric assay data suggested that AGBE arrested SW480 cells in S and G2/M phases, and significantly induced cell apoptosis.
Conclusion AGBE and ginsenosides Rb3, Re, and Rg3 possessed significant antiproliferative effects and induced changes of morphological appearance on SW480 cells. The mechanisms of the antiproliferation of AGBE and tested ginsenosides involved could be cell cycle arrest and induction of apoptosis.
Inhibition of Anchorage-Independent Proliferation and G0/G1 Cell-Cycle Regulation in Human Colorectal Carcinoma Cells by 4,7-Dimethoxy-5-Methyl-l,3-Benzodioxole Isolated from the Fruiting Body of Antrodia camphorate
1Department of Chemistry, Tunghai University, Taichung, Taiwan 2Graduate Institute of Biomedical Technology, Taipei Medical University, Taipei 110, Taiwan 3Department of Environmental and Occupational Health, National Cheng Kung University Medical College, Tainan, Taiwan 4Graduate Institute of Neuroscience, Taipei Medical University, Taipei, Taiwan 5Department of Applied Chemistry, Chung Shan Medical University, Taichung 402, Taiwan
In this study, 4,7-dimethoxy-5-methyl-l,3-benzodioxole (SY-1) was isolated from three different sources of dried fruiting bodies of Antrodia camphorate (AC). AC is a medicinal mushroom that grows on the inner heartwood wall of Cinnamomum kanehirai Hay (Lauraceae), an endemic species that is used in Chinese medicine for its anti-tumor and immunomodulatory properties. In this study, we demonstrated that SY-1 profoundly decreased the proliferation of human colon cancer cells (COLO 205) through G0/G1 cell-cycle arrest (50–150 μM) and induction of apoptosis (>150 μM). Cell-cycle arrest induced by SY-1 was associated with a significant increase in levels of p53, p21/Cip1 and p27/Kip1, and a decrease in cyclins D1, D3 and A. In contrast, SY-1 treatment did not induce significant changes in G0/G1 phase cell-cycle regulatory proteins in normal human colonic epithelial cells (FHC). The cells were cultured in soft agar to evaluate anchorage-independent colony formation, and we found that the number of transformed colonies was significantly reduced in the SY-1-treated COLO 205 cells. These findings demonstrate for the first time that SY-1 inhibits human colon cancer cell proliferation through inhibition of cell growth and anchorage-independent colony formation in soft agar. However, the detailed mechanisms of these processes remain unclear and will require further investigation.
Source : Evidence-Based Complementary and Alternative Medicine Volume 2011 (2011), Article ID 984027, 10 pages doi:10.1093/ecam/nep020 Link to Full Article
Apoptosis Induction in Primary Human Colorectal Cancer Cell Lines and Retarded Tumor Growth in SCID Mice by Sulforaphane
1Division of Traumatology, Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan 2Graduate Institute of Medical Science, College of Health Sciences, Chang Jung Christian University, No. 396, Sec. 1, Changrong Road, Gueiren District, Tainan City 71101, Taiwan 3Department of Nutrition and Health Sciences, College of Health Sciences, Chang Jung Christian University, No. 396, Sec. 1, Changrong Road, Gueiren District, Tainan City 71101, Taiwan 4Department of Obstetrics and Gynecology, Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan 5Innovative Research Center of Medicine, College of Health Sciences, Chang Jung Christian University, No. 396, Sec. 1, Changrong Road, Gueiren District, Tainan City 71101, Taiwan
.Abstract We have investigated the anticancer effects of the dietary isothiocyanate sulforaphane (SFN) on colorectal cancer (CRC), using primary cancer cells lines isolated from five Taiwanese colorectal cancer patients as the model for colorectal cancer. SFN-treated cells accumulated in metaphase (SFN 6.25 μM) and subG1 (SFN 12.5 and 25 μM) as determined by flow cytometry. In addition, treated cells showed nuclear apoptotic morphology that coincided with an activation of caspase-3, and loss of mitochondrial membrane potential (ΔΨm). Incubations at higher SFN doses (12.5 and 25 μM) resulted in cleavage of procaspase-3 and elevated caspase-2, -3, -8, and -9 activity, suggesting that the induction of apoptosis and the sulforaphane-induced mitosis delay at the lower dose are independently regulated. Daily SFN s.c. injections (400 micromol/kg/d for 3 weeks) in severe combined immunodeficient mice with primary human CRC (CP1 to CP5) s.c. tumors resulted in a decrease of mean tumor weight by 70% compared with vehicle-treated controls. Our findings suggest that, in addition to the known effects on cancer prevention, sulforaphane may have antitumor activity in established colorectal cancer.
Source:Evidence-Based Complementary and Alternative Medicine Volume 2012 (2012), Article ID 415231, 13 pages doi:10.1155/2012/415231 Link to Full Article
NB Sulforaphane (SFN), a potent cancer preventive agent, is a dietary isothiocyanate compound found as a precursor glucosinolate in cruciferous vegetables such as Brussels sprouts, cauliflower, and broccoli. For more information on Sulforaphane visit Linus Pauling Institute
Role of cyclin inhibitor protein p21 in the inhibition of HCT116 human colon cancer cell proliferation by American ginseng (Panax quinquefolius) and its constituents M.L. King* and L.L. Murphy Southern Illinois University, School of Medicine, Department of Physiology, Carbondale, IL 62901
American ginseng and its ginsenoside constituents have been shown to exert anti-cancer effects although the mechanism of action remains unclear. The present study determined the effects of water-extracted ginseng (GE) or its ginsenoside (GF) and polysaccharide (PS) fractions on the proliferation of human colon cancer cells and examined the role of p21 in mediating these effects using wild-type and p21−/− HCT116 human colon carcinoma cells. Proliferation was inhibited by GE, GF, and PS in wild-type and p21−/− cells, and the p21−/− cells were more sensitive to these treatments. Wild type cells treated with GE were arrested in the G0/G1 phase of the cell cycle and the expression of p53 and p21 proteins was increased while phospho-MEK levels decreased. In contrast, cells deficient in p21 displayed reduced cell viability, elevated number of dead cells, and increased expression of Bax and cleaved caspase-3 proteins. Both polysaccharides and ginsenosides appear to be responsible for the anti-proliferative and proapoptotic effects of GE. This study suggests that p21 functions to arrest HCT116 wild-type cells treated with GE, while p21-deficient cells undergo cell death in a ginseng constituent-dependent manner.
Apoptotic Cell Death and Inhibition of Wnt/β-Catenin Signaling Pathway in Human Colon Cancer Cells by an Active Fraction (HS7) from Taiwanofungus camphoratus Chi-Tai Yeh,1,2,3 Chih-Jung Yao,2,4 Jiann-Long Yan,5 Shuang-En Chuang,5 Liang-Ming Lee,4 Chien-Ming Chen,1 Chuan-Feng Yeh,5 Chi-Han Li,5 and Gi-Ming Lai1,2,4,5
1Cancer Center, Shuang Ho Hospital, Taipei Medical University, Taipei 235, Taiwan 2Center of Excellence for Cancer Research, Taipei Medical University, Taipei 110, Taiwan 3Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei 110, Taiwan 4Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan 5National Institute of Cancer Research, National Health Research Institutes, Miaoli 350, Taiwan
Aberrant activation of Wnt/β-catenin signaling plays an important role in the development of colon cancer. HS7 is an active fraction extracted from Taiwanofungus camphoratus, which had been widely used as complementary medicine for Taiwan cancer patients in the past decades. In this study, we demonstrated the effects of HS7 on the growth inhibition, apoptosis induction, and Wnt/β-catenin signaling suppression in human colon cancer cells. HS7 significantly inhibited proliferation of HT29, HCT116, and SW480 colon cancer cells in a dose- and time-dependent manner. The apoptosis induction was evidenced by DNA fragmentation and subG1 accumulation, which was associated with increased Bax/Bcl-2 ratio, activation of caspase-3 and cleavage of PARP. By using Tcf-dependent luciferase activity assay, HS7 was found to inhibit the β-catenin/Tcf transcriptional activities. In addition, HS7 strongly suppressed the binding of Tcf complexes to its DNA-binding site shown in electrophoretic mobility shift assay. This inhibition was further confirmed by the decreased protein levels of Tcf-4 and β-catenin. The β-catenin/Tcf downstream target genes, such as survivin, c-myc, cyclin D1, MMP7, and MT1-MMP involved in apoptosis, invasion, and angiogenesis were also diminished as well. These results indicate that Taiwanofungus camphoratus may provide a benefit as integrative medicine for the treatment of colon cancer.
Purpose: 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.
Experimental Design: 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
shift assay and immunohistochemistry. Markers of
proliferation, angiogenesis, and invasion were monitored by
and Western blot analysis.
Results: 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
growth factor), many of which were induced by
radiation therapy and mediate radioresistance. The combination of
radiation therapy also suppressed angiogenesis, as
indicated by a decrease in vascular endothelial growth factor and
density (P = 0.002 versus radiation alone).
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
Efficacy of Goshajinkigan for Peripheral Neurotoxicity of Oxaliplatin in Patients with Advanced or Recurrent Colorectal Cancer Toru Kono,1 Noriaki Mamiya,1,2 Naoyuki Chisato,1 Yosiaki Ebisawa,1 Hirotaka Yamazaki,3 Jiro Watari,4 Yasuhiro Yamamoto,5 Shigetaka Suzuki,5 Toshiyuki Asama,1 and Kazunori Kamiya6
1Division of Gastroenterologic and General Surgery, Department of Surgery, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510, Japan 2Division of Cancer Chemotherapy Center, Higashiasahikawa Hospital, Asahikawa, Japan 3Department of Surgery, Kushiro City Medical Association Hospital, Kushiro, Japan 4Deptartment of Gastroenterology, Kushiro City Medical Association Hospital, Kushiro, Japan 5Department of Surgery, Kobayashi Hospital, Kitami, Japan 6Department of Surgery, Karasawa Hospital, Asahikawa, Japan
Peripheral neurotoxicity is the major limiting factor for oxaliplatin therapy. Goshajinkigan (GJG), a traditional Japanese herbal medicine, was recently shown to be effective in protecting against the neurotoxicity of taxanes in Japan. We retrospectively investigated the effect of GJG on peripheral neurotoxicity associated with oxaliplatin therapy. Ninety patients with metastatic colorectal cancer that received FOLFOX4 or modified FOLFOX6 therapy were assigned to receive one of the following adjuncts: oral GJG at 7.5 g day−1 (Gr oup , 𝑛 = 11) intravenous supplementation of calcium gluconate and magnesium sulfate (1 g each before and after FOLFOX) (Group B, 𝑛=14) a combined GJG and calcium gluconate and magnesium sulfate therapies (Group C, 𝑛=21), or no concomitant therapy (Group D, 𝑛=44) the incidence of peripheral neurotoxicity was investigated when the cumulative dose of oxaliplatin exceeded 500 mg m−2. When the cumulative dose of oxaliplatin exceeded 500 mg m−2, the incidence of neuropathy (all grades) in Groups A–D was 50.0%, 100%, 78.9%, and 91.7%, respectively. It was lowest in the group that received GJG alone. Concomitant administration of GJG reduced the neurotoxicity of oxaliplatin in patients that received chemotherapy for colorectal cancer.
In recent years, the standard chemotherapy for advanced/recurrent colorectal cancer is a continuous intravenous infusion of 5-fluorouracil (5-FU) combined with either oxaliplatin (FOLFOX, FOLFOX4 or modified FOLFOX6) or irinotecan (FOLFIRI) [1–3]. Acute and persistent peripheral neuropathy is the characteristic of oxaliplatin therapy , and the oxaliplatin dose must be limited to avoid toxicity. The prevalence of peripheral neurotoxicity increases with the total accumulated dose of oxaliplatin, and often interferes with the continuation of FOLFOX therapy . Gamelin et al. [6, 7] reported that administration of calcium gluconate and magnesium sulfate (Ca/Mg) before and after oxaliplatin therapy could alleviate peripheral neurotoxicity. Other similar treatments have been described, including carbamazepine [8–10] or glutathione , but an effective remedy for peripheral neurotoxicity related to oxaliplatin therapy has not yet been established.
Goshajinkigan (GJG) is an extracted traditional Japanese herbal medicine (Kampo) that is mainly used for the improvement of symptoms like numbness, cold sensation and limb pain associated with diabetic neuropathy [12–15]. Moreover, Mamiya et al.  and Shindo et al.  recently reported that peripheral neurotoxicity due to oxaliplatin was relieved by administration of GJG in patients with advanced colorectal cancer that were receiving FOLFOX therapy.
We conducted the present retrospective study to compare the efficacy of GJG with that of Ca/Mg for alleviation of peripheral neurotoxicity in patients with advanced or recurrent colorectal cancer that received either FOLFOX4 therapy or modified FOLFOX6 (mFOLFOX6) therapy at our hospital and affiliated institutions in Japan.
Source : Evidence-Based Complementary and Alternative Medicine Volume 2011 (2011), Article ID 418481, 8 pages doi:10.1093/ecam/nep200 LINK TO FULL ARTICLE
Natural products and colon cancer: current status and future prospects Subapriya Rajamanickam1 and Rajesh Agarwal1,2 1Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, Denver, Colorado, USA 2University of Colorado Cancer Center, University of Colorado Denver, Denver, Colorado, USA
Abstract Carcinogenesis is a multistage process consisting of initiation, promotion and progression phases. Thus, the multistage sequence of events has many phases for prevention and intervention. Chemoprevention, a novel approach for controlling cancer, involves the use of specific natural products or synthetic chemical agents to reverse, suppress or prevent premalignancy before the development of invasive cancer. Several natural products, such as, grains, nuts, cereals, spices, fruits, vegetables, beverages, medicinal plants and herbs and their various phytochemical constituents including, phenolics, flavonoids, carotenoids, alkaloids, nitrogen containing as well as organosulfur compounds confer protective effects against wide range of cancers including colon cancer. Since diet has an important role in the etiology of colon cancer, dietary chemoprevention received attention for colon cancer prevention. However, identification of an agent with chemopreventive potential requires in vitro studies, efficacy and toxicity studies in animal models before embarking on human clinical trials. A brief introduction about colon cancer and the role of some recent natural products in colon cancer chemoprevention with respect to multiple molecular mechanisms in various in vitro, in vivo and clinical studies are described in this review.
Conclusion This review summarized chemopreventive efficacy of natural products and their constituent phytochemicals in various in vitro and in vivo colon cancer models. All these results strengthen the fact that natural products can modulate various molecular pathways involved in cancer initiation and progression. Studies described here and elsewhere clearly highlight the use of natural products as novel chemopreventive agents for colon cancer intervention. It is expected that future studies with natural products will define various molecular mechanisms and targets for tumor growth inhibition, apoptosis, and especially angioprevention. To date, chemoprevention clinical trials with natural products conducted in colon cancer are very limited. Extensive clinical research is warranted to evaluate further safety and chemopreventive efficacy of natural products either alone or in combination with chemotherapeutic agents against colon cancer.
Bee products prevent VEGF-induced angiogenesis in human umbilical vein endothelial cells
Hiroshi Izuta,1 Masamitsu Shimazawa,1 Kazuhiro Tsuruma,1 Yoko Araki,2 Satoshi Mishima,2 and Hideaki Hara11 Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585, Japan2Nagaragawa Research Center, Api Co. Ltd., 692-3 Nagara, Gifu 502-0071, Japan
Background Vascular endothelial growth factor (VEGF) is a key regulator of pathogenic angiogenesis in diseases such as cancer and diabetic retinopathy. Bee products [royal jelly (RJ), bee pollen, and Chinese red propolis] from the honeybee, Apis mellifera, have been used as traditional health foods for centuries. The aim of this study was to investigate the anti-angiogenic effects of bee products using human umbilical vein endothelial cells (HUVECs).
Methods In an in vitro tube formation assay, HUVECs and fibroblast cells were incubated for 14 days with VEGF and various concentrations of bee products [RJ, ethanol extract of bee pollen, ethanol extract of Chinese red propolis and its constituent, caffeic acid phenethyl ester (CAPE)]. To clarify the mechanism of in vitro angiogenesis, HUVEC proliferation and migration were induced by VEGF with or without various concentrations of RJ, bee pollen, Chinese red propolis, and CAPE.
Results RJ, bee pollen, Chinese red propolis, and CAPE significantly suppressed VEGF-induced in vitro tube formation in the descending order: CAPE > Chinese red propolis >> bee pollen > RJ. RJ and Chinese red propolis suppressed both VEGF-induced HUVEC proliferation and migration. In contrast, bee pollen and CAPE suppressed only the proliferation.
Conclusion Among the bee products, Chinese red propolis and CAPE in particular showed strong suppressive effects against VEGF-induced angiogenesis. These findings indicate that Chinese red propolis and CAPE may have potential as preventive and therapeutic agents against angiogenesis-related human diseases.
More ..... In a previous study, we found that Brazilian green propolis and its constituent caffeoylquinic acid derivatives suppressed VEGF-induced cell proliferation, migration, and in vitro tube formation in HUVECs . In the present study, Chinese red propolis and its chemical constituent, CAPE, suppressed VEGF-induced in vitro tube formation. Caffeic acid is a known suppressor of tumor angiogenesis that acts in human retinal carcinoma cells by blocking STAT3-mediated VEGF expression . These studies indicate that caffeoyl groups included in propolis may be important components responsible for its anti-angiogenic activities.The pharmacological effects of bee products have been reported in many different diseases. In particular, there are many reports about the anti-tumor effects of propolis and CAPE. Our previous studies indicate that baccharin and drupanin, constituents of Brazilian propolis, inhibit tumor growth both in vitro and in vivo . Likewise, CAPE induces growth arrest and apoptosis of colon cancer cells via the beta-catenin/T-cell factor signaling pathway . Tumor angiogenesis is a very important step in the growth and metastasis of tumor development. Combined with these findings in the present study, Chinese propolis and its CAPE constituent suppressed VEGF-induced angiogenesis in HUVECs indicates that the anti-tumor effects of propolis and CAPE may be dependent both on direct inhibition of tumor cell growth and on angiostatic effects on the vessels supplying nutrients to the neoplasm.
Blechnum Orientale Linn - a fern with potential as antioxidant, anticancer and antibacterial agent How Y Lai,1 Yau Y Lim,1 and Kah H Kim2
1School of Science, Monash University Sunway Campus, Bandar Sunway, 46150 Petaling Jaya, Selangor, Malaysia2Department of Physiology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
Abstract Blechnum orientale Linn. (Blechnaceae) is used ethnomedicinally for the treatment of various skin diseases, stomach pain, urinary bladder complaints and sterilization of women. The aim of the study was to evaluate antioxidant, anticancer and antibacterial activity of five solvent fractions obtained from the methanol extract of the leaves of Blechnum orientale Linn.
Methods Five solvent fractions were obtained from the methanol extract of B. orientale through successive partitioning with petroleum ether, chloroform, ethyl acetate, butanol and water. Total phenolic content was assessed using Folin-Ciocalteu's method. The antioxidant activity was determined by measuring the scavenging activity of DPPH radicals. Cytotoxic activity was tested against four cancer cell lines and a non-malignant cell using MTT assay. Antibacterial activity was assessed using the disc diffusion and broth microdilution assays. Standard phytochemical screening tests for saponins, tannins, terpenoids, flavonoids and alkaloids were also conducted.
Results The ethyl acetate, butanol and water fractions possessed strong radical scavenging activity (IC50 8.6-13.0 μg/ml) and cytotoxic activity towards human colon cancer cell HT-29 (IC50 27.5-42.8 μg/ml). The three extracts were also effective against all Gram-positive bacteria tested: Bacillus cereus, Micrococcus luteus, methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA) and Stapylococcus epidermidis(minimum inhibitory concentration MIC 15.6-250 μg/ml; minimum bactericidal concentration MBC 15.6-250 μg/ml). Phytochemical analysis revealed the presence of flavonoids, terpenoids and tannins. Ethyl acetate and butanol fractions showed highest total phenolic content (675-804 mg gallic acid equivalent/g).
Conclusions The results indicate that this fern is a potential candidate to be used as an antioxidant agent, for colon cancer therapy and for treatment of MRSA infections and other MSSA/Gram-positive bacterial infectious diseases.
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
Cinnamon extract induces tumor cell death through inhibition of NFκB and AP1
1 School of Life Sciences and Immune Synapse Research Center, Gwangju Institute of Science and Technology (GIST), 1 Oryong-dong, Puk-ku, Gwangju 500-712, Republic of Korea 2 Korea Institute of Oriental Medicine, Daejeon 305-811, Republic of Korea 3 Global leader program, Bugil Academy, Cheonan, Gyeonggido 330-941, Republic of Korea 4 Chosun University School of Medicine, Gwangju 501-759, Republic of Korea
Background Cinnamomum cassia bark is the outer skin of an evergreen tall tree belonging to the family Lauraceae containing several active components such as essential oils (cinnamic aldehyde and cinnamyl aldehyde), tannin, mucus and carbohydrate. They have various biological functions including anti-oxidant, anti-microbial, anti-inflammation, anti-diabetic and anti-tumor activity. Previously, we have reported that anti-cancer effect of cinnamon extracts is associated with modulation of angiogenesis and effector function of CD8+ T cells. In this study, we further identified that anti-tumor effect of cinnamon extracts is also link with enhanced pro-apoptotic activity by inhibiting the activities NFκB and AP1 in mouse melanoma model.
Methods Water soluble cinnamon extract was obtained and quality of cinnamon extract was evaluated by HPLC (High Performance Liquid Chromatography) analysis. In this study, we tested anti-tumor activity and elucidated action mechanism of cinnamon extract using various types of tumor cell lines including lymphoma, melanoma, cervix cancer and colorectal cancer in vitro and in vivo mouse melanoma model.
Results Cinnamon extract strongly inhibited tumor cell proliferation in vitro and induced active cell death of tumor cells by up-regulating pro-apoptotic molecules while inhibiting NFκB and AP1 activity and their target genes such as Bcl-2, BcL-xL and survivin. Oral administration of cinnamon extract in melanoma transplantation model significantly inhibited tumor growth with the same mechanism of action observed in vitro.
Conclusion Our study suggests that anti-tumor effect of cinnamon extracts is directly linked with enhanced pro-apoptotic activity and inhibition of NFκB and AP1 activities and their target genes in vitro and in vivo mouse melanoma model. Hence, further elucidation of active components of cinnamon extract could lead to development of potent anti-tumor agent or complementary and alternative medicine for the treatment of diverse cancers.
Germinated brown rice (GBR) reduces the incidence of aberrant crypt foci with the involvement of β-catenin and COX-2 in azoxymethane-induced colon cancer in rats
Saiful Yazan Latifah1,4 ,Nurdin Armania1, Tan Hern Tze1 ,Yaacob Azhar1 , Abdul Hadi Nordiana4 , Saad Norazalina2 , Ithnin Hairuszah3 , Moin Saidi1 and Ismail Maznah1,4
1 Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor Malaysia 2 Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor Malaysia 3 Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor Malaysia 4 Laboratory of Molecular Biomedicine, Institutes of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor Malaysia
Abstract Chemoprevention has become an important area in cancer research due to the failure of current therapeutic modalities. Epidemiological and preclinical studies have demonstrated that nutrition plays a vital role in the etiology of cancer. This study was conducted to determine the chemopreventive effects of germinated brown rice (GBR) in rats induced with colon cancer. GBR is brown rice that has been claimed to be richer in nutrients compared to the common white rice. The male Sprague Dawley rats (6 weeks of age) were randomly divided into 5 groups: (G1) positive control (with colon cancer, unfed with GBR), (G2) fed with 2.5 g/kg of GBR (GBR (g)/weight of rat (kg)), (G3) fed with 5 g/kg of GBR, (G4) fed with 10 g/kg of GBR and (G5) negative control (without colon cancer, unfed with GBR). GBR was administered orally once daily via gavage after injection of 15 mg/kg of body weight of azoxymethane (AOM) once a week for two weeks, intraperitonially. After 8 weeks of treatment, animals were sacrificed and colons were removed. Colonic aberrant crypt foci (ACF) were evaluated histopathologically. Total number of ACF and AC, and multicrypt of ACF, and the expression of β-catenin and COX-2 reduced significantly (p < 0.05) in all the groups treated with GBR (G2, G3 and G4) compared to the control group (G1). Spearman rank correlation test showed significant positive linear relationship between total β-catenin and COX-2 score (Spearman's rho = 0.616, p = 0.0001). It is demonstrated that GBR inhibits the development of total number of ACF and AC, and multicrypt of ACF, reduces the expression of β-catenin and COX-2, and thus can be a promising dietary supplement in prevention of colon cancer.......This study indicates that GBR possesses good chemopreventive effects, more likely due to the nutritional components that are increasing in content following the process of germination such as phytic acid (IP6), ferulic acid, inositol and dietary fiber . It has been reported that inositol hexaphosphate (IP6) reduced the carcinogen-induced large bowel cancer and inhibited growth of transplanted tumors . However, the mechanism by which IP6 exerts chemopreventive is not completely understood
Background Tian Xian Liquid (TXL) is a Chinese medicine decoction and has been used as an anticancer dietary supplement. The present study aims to investigate the effects of TXL on the apoptosis of HT-29 cells and tumor growth in vivo.
Method HT-29 colon cancer cells were treated with gradient dilution of TXL. The mitochondrial membrane potential was measured by JC-1 assay. The release of cytochrome c from mitochondrial and apoptosis-related proteins Bax, Bcl-2, cleaved caspase-3, 9 were examined by Western blot analysis. HT-29 cells were implanted in nude mice to examine the effects of TXL on tumor growth.
Results TXL inhibited HT-29 xenografted model and showed a strong and dose-dependent inhibitory effect on the proliferation of HT-29 cells. Mitochondrial membrane potential was reduced by TXL at the concentration of 0.5% above. For Western blot analysis, an increase in Bax expression and a decrease in Bcl-2 expression were observed in TXL-treated cells. TXL treatment increased the protein level of cleaved casepase-3 and caspase-9, and the release of cytochrome c in cytoplasm was up-regulated as well.
Conclusion TXL significantly inhibits cell proliferation in the HT-29 cells and HT-29 xenografted model via the mitochondrial cell death pathway.
Chemopreventive potential of β-Sitosterol in experimental colon cancer model - an In vitro and In vivo study Albert A Baskar1,2 ,Savarimuthu Ignacimuthu1 , Gabriel M Paulraj1and Khalid S Al Numair2
1 Division of Ethnopharmacology, Entomology Research Institute, Loyola College, Chennai - 600 034, Tamil Nadu, India 2 Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh, 11433, Kingdom of Saudi Arabia
Abstract Background Asclepias curassavica Linn. is a traditional medicinal plant used by tribal people in the western ghats, India, to treat piles, gonorrhoea, roundworm infestation and abdominal tumours. We have determined the protective effect of β-sitosterol isolated from A. curassavica in colon cancer, using in vitro and in vivo models.
Methods The active molecule was isolated, based upon bioassay guided fractionation, and identified as β-sitosterol on spectral evidence. The ability to induce apoptosis was determined by its in vitro antiradical activity, cytotoxic studies using human colon adenocarcinoma and normal monkey kidney cell lines, and the expression of β-catenin and proliferating cell nuclear antigen (PCNA) in human colon cancer cell lines (COLO 320 DM). The chemopreventive potential of β-sitosterol in colon carcinogenesis was assessed by injecting 1,2-dimethylhydrazine (DMH, 20 mg/kg b.w.) into male Wistar rats and supplementing this with β-sitosterol throughout the experimental period of 16 weeks at 5, 10, and 20 mg/kg b.w.
Results β-sitosterol induced significant dose-dependent growth inhibition of COLO 320 DM cells (IC50 266.2 μM), induced apoptosis by scavenging reactive oxygen species, and suppressed the expression of β-catenin and PCNA antigens in human colon cancer cells. β-sitosterol supplementation reduced the number of aberrant crypt and crypt multiplicity in DMH-initiated rats in a dose-dependent manner with no toxic effects.
Conclusion We found doses of 10-20 mg/kg b.w. β-sitosterol to be effective for future in vivo studies. β-sitosterol had chemopreventive potential by virtue of its radical quenching ability in vitro, with minimal toxicity to normal cells. It also attenuated β-catenin and PCNA expression, making it a potential anticancer drug for colon carcinogenesis.
Source : BMC Complementary and Alternative Medicine 2010, 10:24doi:10.1186/1472-6882-10-24 LINK TO FULL ARTICLE
NB β-sitosterol is widely distributed in the plant kingdom and found in Nigella sativa, pecans, Serenoa repens (saw palmetto), avocados, Cucurbita pepo (pumpkin seed), Pygeum africanum, cashew fruit, rice bran, wheat germ, corn oils, soybeans, sea-buckthorn, wolfberries, and Wrightia tinctoria.
Anti-cancer Effects of Protein Extracts from Calvatia lilacina, Pleurotus ostreatus and Volvariella volvaceaJin-Yi Wu1, Chi-Hung Chen2, Wen-Huei Chang3, King-Thom Chung4, Yi-Wen Liu1, Fung-Jou Lu5 and Ching-Hsein Chen1,* 1Graduate Institute of Biomedical and
Biopharmaceutical Sciences, College of Life Sciences, 2Graduate Institute of Food Science and Biopharmaceutics, National Chiayi University, Chiayi, 3Department of Chemical Biology, National Pingtung University of Education, Pingtung, Taiwan, 4Department of Biology, The University of Memphis, Memphis, TN, USA and 5Department of Applied Chemistry, Chung Shan Medical University, Taichung, Taiwan
Calvatia lilacina (CL), Pleurotus ostreatus (PO) and Volvariella volvacea (VV) are widely distributed worldwide and commonly eaten as mushrooms. In this study, cell viabilities were evaluated for a human colorectal adenocarcinoma cell line (SW480 cells)and a human monocytic leukemia cell line (THP-1 cells). Apoptotic mechanisms induced by the protein extracts of PO and VV were evaluated for SW480 cells. The viabilities of THP-1 and SW480cells decreased in a concentration-dependent manner after 24h of treatment with the protein extracts of CL, PO or VV. Apoptosis analysis revealed that the percentage of SW480 cells in theSubG1 phase (a marker of apoptosis) was increased upon PO andVV protein-extract treatments, indicating that oligonucleosomal DNA fragmentation existed concomitantly with cellular death.The PO and VV protein extracts induced reactive oxygen species(ROS) production, glutathione (GSH) depletion and mitochondrial transmembrane potential (m) loss in SW480 cells. Pretreatment with N-acetylcysteine, GSH or cyclosporine A partially prevented the apoptosis induced by PO protein extracts, but not that induced by VV extracts, in SW480 cells. The protein extracts of CL,PO and VV exhibited therapeutic efficacy against human colorectal adenocarcinoma cells and human monocytic leukemia cells. The PO protein extracts induced apoptosis in SW480 cells partially through ROS production, GSH depletion and mitochondrial dysfunction.Therefore, the protein extracts of these mushrooms could be considered an important source of new anti-cancer drugs.
Source: eCAM Advance Access published online on May 18, 2010 eCAM, doi:10.1093/ecam/neq05 LINK TO FULL ARTICLE
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.
Prospective Cohort Study of Green Tea Consumption and Colorectal Cancer Risk in Women Gong Yang, Xiao-Ou Shu, Honglan Li, Wong-Ho Chow, Bu-Tian Ji, Xianglan Zhang, Yu-Tang Gao, Wei Zheng
1Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; 2Shanghai Cancer Institute, Shanghai, China; and 3Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, Maryland
Abstract Teaand its constituents have shown anticarcinogenic activities in in vitroand animal studies. Epidemiologic studies, however, have been inconsistent. We prospectively evaluated the association between greentea consumption andcolorectalcancer (CRC) risk in a cohort of 69,710 Chinese women aged 40 to 70 years. Information on tea consumption was assessed through in-person interviews at baseline and reassessed 2 to 3 years later in a follow-up survey. During 6 years of follow-up, 256 incident cases of CRC were identified. The multivariate relative risk of CRC was 0.63 (95% confidence interval, 0.45-0.88) for women who reported drinking greentea regularly at baseline compared with nonregular tea drinkers. A significant dose-response relationship was found for both the amount of tea consumed (P trend = 0.01) and duration in years of lifetime tea consumption (P trend = 0.006). The reduction in risk was most evident among those who consistently reported to drink tea regularly at both the baseline and follow-up surveys (relative risk, 0.43; 95% confidence interval, 0.24-0.77). The inverse association with regular tea drinking was observed for both colon and rectal cancers. This study suggests that regular consumption of green tea may reduce CRC risk in women.
Grape Seed Extract Inhibits In vitro and In vivo Growth of Human Colorectal Carcinoma Cells Manjinder Kaur,1Rana P. Singh,1Mallikarjuna Gu,1Rajesh Agarwal,1,2 and Chapla Agarwal1,2
Abstract Purpose: Accumulating evidences suggest the beneficial effects of fruit-and-vegetable consumptioninlowering the riskof various cancers, including colorectal cancer.Herein,we investigated the in vitro and in vivo anticancer effects and associated mechanisms of grape seed extract (GSE), a rich source of proanthocyanidins, against colorectal cancer. Experimental Design: Effects of GSE were examined on human colorectal cancer HT29 and LoVo cells in culture for proliferation, cell cycle progression, and apoptosis. The in vivo effect of oral GSE was examined on HT29 tumor xenograft growth in athymic nude mice. Xenografts were analyzed by immunohistochemistry for proliferation and apoptosis. The molecular changes associated with the biological effects of GSE were analyzed by Western blot analysis.
Results: GSE (25-100 Ag/mL) causes a significant dose- and time-dependent inhibition of cell growth with concomitant increase in cell death. GSE inducedG1phase cell cycle arrest alongwith a marked increase in Cip1/p21protein level and a decrease in G1phase ^ associated cyclins and cyclin-dependent kinases.GSE-induced cell deathwas apoptotic and accompanied bycaspase-3 activation. GSE feeding to mice at 200 mg/kg dose showed time-dependent inhibition of tumor growth without any toxicity and accounted for 44% decrease in tumor volume per mouse after 8weeks of treatment. GSE inhibited cell proliferation but increased apoptotic cell death in tumors.GSE-treated tumors also showed enhanced Cip1/p21protein levels and poly(ADP-ribose) polymerase cleavage.
Conclusions: In summary, our results show that GSE inhibits cell growth and induces cell cycle arrest and apoptosis in human colorectal cancer cells and modulates cell cycle regulators with a strong effect for Cip1/p21 up-regulation. Usually, p53 plays a regulatory role in Cip1/p21 induction; however, in our studies, GSE up-regulates Cip1/p21 independent of p53 because HT29 cells showing a robust increase in Cip1/p21 harbor nonfunctional p53, although LoVo cells carry wild-type p53. Therefore, it would be of significance to investigate in future studies the p53-independent mechanisms of Cip1/p21 induction by GSE that might have a wide implication in cancer chemoprevention as p53 inactivation is one of the primary events in initiation, growth and progression of many types of cancers, including colorectal cancer. Furthermore, findings in xenograft study translate the anticancer effects and associated mechanisms of GSE observed in cell culture experiments in to an in vivo preclinical colorectal cancer model. However, a dose-dependent in vivo study with GSE is needed in future that would provide additional information regarding the lowest effective as well as highest nontoxic doses of GSE, which would be useful for the translational studies.GSE may be an effective chemopreventive agent against colorectal cancer, and that growth inhibitory and apoptotic effects of GSE against colorectal cancer could be mediated via an up-regulation of Cip1/p21.
Prospective cohort study of soy food intake and colorectal cancer risk in women Gong Yang1,2,3, Xiao-Ou Shu1,2,3, Honglan Li1,2,3, Wong-Ho Chow1,2,3, Hui Cai1,2,3, Xianglan Zhang1,2,3, Yu-Tang Gao1,2,3 and Wei Zheng1,2,31
From the Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203 (GY, X-OS, HC, XZ, and WZ);the Shanghai Cancer Institute, Shanghai, China (HL and Y-TG);and the Division of Cancer Epidemiology and Genetics, NationalCancer Institute, NIH, DHHS, Bethesda, MD (W-HC).
Abstract Background: Soy and some of its constituents, such as isoflavones,have been shown to have cancer-inhibitory activities in experimental studies. Data from epidemiologic studies linking usual soy food intake with colorectal cancer are limited and inconsistent.
Objective: The objective was to investigate whether soy food intake is associated with colorectal cancer risk.
Design: We prospectively examined 68,412 women aged 40–70y and free of cancer and diabetes at enrollment. Usual soy food intake was assessed at baseline (1997–2000) and reassessed during the first follow-up (2000–2002) through in-person interviews with a validated food-frequency questionnaire. We excluded the first year of observation to minimize lifestyle changes related to preclinical disease.
Results: During a mean follow-up of 6.4 y, 321 incident colorectal cancer cases were identified. After adjustment for potential confounding factors, total soy food intake was inversely associated with colorectal cancer risk. Each 5-g/d increment in intake of soy foods as assessed by dry weight [equivalent to 1 oz (28.35g) tofu/d] was associated with an 8% reduction in risk (95%CI: 3%, 14%). Women in the highest tertile of intake had a multivariaterelative risk of 0.67 (95% CI: 0.49, 0.90) compared with those in the lowest tertile (P for trend = 0.008). This inverse association was primarily confined to postmenopausal women. Similar results were also found for intakes of soy protein and isoflavones.
Conclusion:This prospective study suggests that consumption of soy foods may reduce the risk of colorectal cancer in postmenopausal women.
Source:American Journal of Clinical Nutrition, doi:10.3945/ajcn.2008.26742 Vol. 89, No. 2, 577-583, February 2009 LINK TO FULL ARTICLE
Roles of Probiotics and Prebiotics in Colon Cancer Prevention: Postulated Mechanisms and In-vivo Evidence
Min-Tze Liong Food Technology Division, School of Industrial Technology, Universiti Sains Malaysia, 11800 Minden,
Abstract: Probiotics are live bacteria that could exert health beneficial effects upon consumption. In additional to their conventional use as gut modulators, probiotics are investigated for their role to prevent cancer. In-vivo and molecular studies have demonstrated encouraging outcomes, mainly attributed to its antimicrobial effects against carcinogen-producing microorganisms, antimutagenic properties, and alteration of the tumor differentiation processes. Prebiotics are indigestible food components that could promote the growth of beneficial bacteria including probiotics. Present studies have suggested that prebiotics also possess protective effect against colon carcinogenesis, mainly attributed to the production of short chain fatty acids upon its fermentation by gut microflora, and alteration of gene-expressions in tumor cells. Synbiotic (combination of probiotic and prebiotic) has been found to exert a synergistic effect in improving colon carcinogenesis compared to when both were used individually. This paper highlights the colon cancer preventive effects by probiotics, prebiotics and synbiotics. In addition, the controversial outcomes on the insignificant effect of these food adjuncts will be discussed.
1Department of Veterans Affairs Medical Center, Wayne State University, Detroit, MI 48201, U.S.A. 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.
Abstract 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.
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
Abstract 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
Folate intake and the risk of colorectal cancer in a Korean population
J Kim1, D H Kim2, B H Lee3, S H Kang4, H J Lee5, S Y Lim1, Y K Suh2 and Y O Ahn6
1Cancer Epidemiology Branch, National Cancer Research Institute, National Cancer Center, Goyang, South Korea
2Department of Social and Preventive Medicine, Hallym University College of Medicine, Chunchon, Kangwon-do, South Korea
3Department of General Surgery, Hallym University Sacred Heart Hospital, Anyang, South Korea
4Department of Statistics, Seoul National University, Seoul, South Korea
5Department of Social and Preventive Medicine, Inha University College of Medicine, Incheon, South Korea
6Department of Preventive Medicine, Seoul, Seoul National University College of Medicine, Seoul, South Korea
Background: Folate, a water-soluble B vitamin and one of the major micronutrients in vegetables, is known as an essential factor for the de novo biosynthesis of purines and thymidylate, and it plays an important role in DNA synthesis and replication. Thus, folate deficiency results in ineffective DNA synthesis, and has been shown to induce the initiation and progression of colorectal cancer (CRC). Recently, the incidence of CRC in Korea has increased markedly in both men and women; this trend may be related to the adoption of a more 'westernized' lifestyle, including dietary habits.
Objective: A hospital-based case–control study was conducted to examine the relationship between folate intake and the risk of CRC within a Korean population.
Methods: A total of 596 cases and 509 controls, aged 30-79 years, were recruited from two university hospitals. Site- and sex-specific odds ratios (ORs) were estimated using logistic regression models.
Results: Cases were more frequently found to have a family history of CRC among first-degree relatives, to consume more alcohol, to be more likely current smokers and less likely to participate in vigorous physical activity than the controls. In the overall data for men and women combined, multivariate ORs (95% confidence interval (CI), P for trend) comparing the highest vs the lowest quartile of dietary folate intake were: 0.47 (0.32–0.69, <0.001) for CRC, 0.42 (0.26–0.69, <0.001) for colon cancer and 0.48 (0.28–0.81, 0.007) for rectal cancer. An inverse association was also found in women with dietary folate intake: 0.36 (0.20–0.64, <0.001) for CRC, 0.34 (0.16–0.70, 0.001) for colon cancer and 0.30 (0.12–0.74, 0.026) for rectal cancer, but not in men. In addition, the total folate intake of women was strongly associated with a reduced risk of rectal cancer (OR, 0.38; 95% CI, 0.17–0.88; P for trend=0.04).
Conclusion: We found a statistically significant relationship between higher dietary folate intake and reduced risk of CRC, colon cancer and rectal cancer in women. A significant association is indicated between higher total folate intake and reduced risk of rectal cancer in women.
Cancer Chemopreventive Potential of Apples, Apple Juice, and Apple Components
Author Clarissa Gerhauser
Affiliation Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany Review Abstract
Apples (Malus sp., Rosaceae) are a rich source of nutrient as well as non-nutrient components and contain high levels of polyphenols and other phytochemicals. Main structural classes of apple constituents include hydroxycinnamic acids, dihydrochalcones,flavonols (quercetin glycosides), catechins and oligomeric procyanidins, as well as triterpenoids in apple peel and anthocyanins in red apples. Several lines of evidence suggest that apples and apple products possess a wide range of biological activities which may contribute to health beneficial effects against cardiovascular disease, asthma and pulmonary dysfunction, diabetes, obesity, and cancer (reviewed by Boyer and Liu, Nutr J 2004). The present review will summarize the current knowledge on potential cancer preventive effects of apples, apple juice and apple extracts (jointly designated as apple products). In brief, apple extracts and components, especially oligomeric procyanidins, have been shown to influence multiple mechanisms relevant for cancer prevention in in vitro studies. These include antimutagenic activity, modulation of carcinogen metabolism, antioxidant activity, anti-inflammatory mechanisms, modulation of signal transduction pathways, antiproliferative and apoptosis-inducing activity, as well as novel mechanisms on epigenetic events and innate immunity. Apple products have been shown to prevent skin, mammary and colon carcinogenesis in animal models. Epidemiological observations indicate that regular consumption of one or moreapples a day may reduce the risk for lungand colon cancer.
Biological/Chemopreventive Activity of Stilbenes and their Effect on Colon Cancer Author Agnes M. Rimando1, Nanjoo Suh2, 3
1 United States Department of Agriculture, Agricultural Research Service, Natural Products Utilization Research Unit, University, MS, USA 2 Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA 3 The Cancer Institute of New Jersey, New Brunswick, NJ, USA
Abstract Colon cancer is one of the leading causes of cancer death in men and women in Western countries. Epidemiological studies have linked the consumption of fruits and vegetables to a reduced risk of colon cancer, and small fruits are particularly rich sources of many active phytochemical stilbenes, such as resveratrol and pterostilbene. Recent advances in the prevention of colon cancer have stimulated an interest in diet and lifestyle as an effective means of intervention. As constituents of small fruits such as grapes, beries and their products, stilbenes are under intense investigation as cancer chemopreventive agents. One of the best-characterized stilbenes, resveratrol, has been known as an antioxidant and an anti-aging compound as well as an anti-inflammatory agent. Stilbenes have diverse pharmacological activities, which include cancer prevention, a cholesterol-lowering effect, enhanced insulin sensitivity, and increased lifespan. This review summarizes results related to the potential use of various stilbenes as cancer chemopreventive agents, their mechanisms of action, as well as their pharmacokinetics and efficacy for the prevention of colon cancer in animals and humans. As constituents of grapes, red wine and small fruits, resveratrol and related stilbenes are under intense investigation as cancer chemopreventive agents. After the landmark studies on prevention of cancer and protection against the detrimental health effects associated with a high-calorie diet in experimental animals, including resveratrol's ability to mimic caloric restriction, the potential impact of stilbenes on human health have elicited considerable public attention. In vitro cell culture experiments as well as preclinical animal studies with resveratrol and relatedstilbenes suggest a multitude of mechanisms for the pharmacological activity of this group of compounds. Elucidation of mechanisms of action and in vivo efficacy of stilbenes may lead to new approaches for the treatment and prevention of various neoplasias, including colon cancer.
Conclusion As constituents of grapes, red wine and small fruits, resveratrol and related stilbenes are under intense investigation as cancer chemopreventive agents. After the landmark studies on prevention of cancer and protection against the detrimental health effects associated with a high-calorie diet in experimental animals, including resveratrol's ability to mimic caloric restriction, the potential impact of stilbenes on human health have elicited considerable public attention. In vitro cell culture experiments as well as preclinical animal studies with resveratrol and related stilbenes suggest a multitude of mechanisms for the pharmacological activity of this group of compounds. Elucidation of mechanisms of action and in vivo efficacy of stilbenes may lead to new approaches for the treatment and prevention of various neoplasias, including colon cancer.