Journal of Digestive Cancer Research

Korean Society of Gastrointestinal Cancer Research (대한소화기암연구학회)
권호 표지

Prospective Targets for Colon Cancer Prevention: from Basic Research, Epidemiology and Clinical Trial

  • Shingo Miyamoto (Epidemiology and Prevention Division, Center for Public Health Sciences, National Cancer Center) ;
  • Masaru Terasaki (School of Pharmaceutical Sciences, Health Sciences University of Hokkaido) ;
  • Rikako Ishigamori (Central Animal Division, National Cancer Center Research Institute, National Cancer Center) ;
  • Gen Fujii (Carcinogenesis and Cancer Prevention Division, National Cancer Center Research Institute, National Cancer Center) ;
  • Michihiro Mutoh (Epidemiology and Prevention Division, Center for Public Health Sciences, National Cancer Center)
  • Received : 2016.11.28
  • Accepted : 2016.12.22
  • Published : 2016.12.31
Download PDF
⟨ Previous Next ⟩

Abstract

The step-wise process of colorectal carcinogenesis from aberrant crypt foci, adenoma to adenocarcinoma, is relatively suitable for chemopreventive intervention. Accumulated evidences have revealed that maintaining an undifferentiated state (stemness), inflammation, and oxidative stress play important roles in this colon carcinogenesis process. However, appropriate molecular targets that are applicable to chemopreventive intervention regarding those three factors are still unclear. In this review, we summarized appropriate molecular targets by identification and validation of the prospective targets from a comprehensive overview of data that showed colon cancer preventive effects in clinical trials, epidemiological studies and basic research. We first selected a study that used aspirin, statins and metformin from FDA approved drugs, and epigallocatechin-gallate and curcumin from natural compounds as potential chemopreventive agents against colon cancer because these agents are considered to be promising chemopreventive agents. Experimental and observational data revealed that there are common target molecules in these potential chemopreventive agents: T-cell factor/lymphoid enhancer factor (TCF/LEF), nuclear factor-&B (NF-κB) and nuclear factor-erythroid 2-related factor 2(NRF2). Moreover, these targets, TCF/LEF, NF-κB and NRF2, have been also indicated to suppress maintenance of the undifferentiated state, inflammation and oxidative stress, respectively. In the near future, novel promising candidate agents for colon cancer chemoprevention could be identified by integral evaluation of their effects on these three transcriptional activities.

Keywords

Acknowledgement

This work was supported by the grant from the Japan Agency for Medical Research and Development, AMED.

References

  1. Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin 2015;65(2):87-108.
  2. Sporn MB, Suh N. Chemoprevention: an essential approach to controlling cancer. Nature reviews Cancer 2002;2(7):537-543.
  3. Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. The New England Journal of Medicine 1988;319(9):525-532.
  4. Ichii S, Horii A, Nakatsuru S, et al. Inactivation of both APC alleles in an early stage of colon adenomas in a patient with familial adenomatous polyposis (FAP). Human Molecular Genetics 1992;1(6):387-390.
  5. Sieber OM, Tomlinson IP, Lamlum H. The adenomatous polyposis coli (APC) tumour suppressor- -genetics, function and disease. Molecular Medicine Today 2000;6(12):462-469.
  6. Powell SM, Zilz N, Beazer-Barclay Y, et al. APC mutations occur early during colorectal tumorigenesis. Nature 1992;359(6392):235-237.
  7. Smith AJ, Stern HS, Penner M, et al. Somatic APC and K-ras codon 12 mutations in aberrant crypt foci from human colons. Cancer Res 1994;54(21):5527-5530.
  8. Ilyas M. Wnt signalling and the mechanistic basis of tumour development. J Pathol 2005;205(2):130-144.
  9. Fodde R, Smits R, Clevers H. APC, signal transduction and genetic instability in colorectal cancer. Nature Reviews Cancer 2001;1(1):55-67.
  10. Barker N, van Es JH, Kuipers J, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 2007;449(7165):1003-1007.
  11. Clevers H, Nusse R. Wnt/beta-catenin signaling and disease. Cell 2012;149(6):1192-1205.
  12. Dow LE, O'Rourke KP, Simon J, et al. Apc restoration promotes cellular differentiation and reestablishes crypt homeostasis in colorectal cancer. Cell 2015;161(7):1539-1552.
  13. Haggar FA, Boushey RP. Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clinics in Colon and Rectal Surgery 2009;22(4):191-197.
  14. Kumar A, Takada Y, Boriek AM, Aggarwal BB. Nuclear factor-kappaB: its role in health and disease. Journal of molecular medicine (Berlin, Germany) 2004;82(7):434-448.
  15. Agoff SN, Brentnall TA, Crispin DA, et al. The role of cyclooxygenase 2 in ulcerative colitis-associated neoplasia. The American Journal of Pathology 2000;157(3):737-745.
  16. Hussain SP, Amstad P, Raja K, et al. Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: a cancer-prone chronic inflammatory disease. Cancer Res 2000;60(13):3333-3337.
  17. Stallmach A, Giese T, Schmidt C, et al. Cytokine/chemokine transcript profiles reflect mucosal inflammation in Crohn's disease. International Journal of Colorectal Disease 2004;19(4):308-315.
  18. Karin M. Nuclear factor-kappaB in cancer development and progression. Nature 2006;441(7092):431-436.
  19. Khor TO, Huang MT, Kwon KH, et al. Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis. Cancer Res 2006;66(24):11580-11584.
  20. Khor TO, Huang MT, Prawan A, et al. Increased susceptibility of Nrf2 knockout mice to colitis-associated colorectal cancer. Cancer Prevention Research (Philadelphia, Pa) 2008;1(3):187-191.
  21. Rothwell PM, Wilson M, Elwin CE, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet (London, England) 2010;376(9754):1741-1750.
  22. Ishikawa H, Mutoh M, Suzuki S, et al. The preventive effects of low-dose enteric-coated aspirin tablets on the development of colorectal tumours in Asian patients: a randomised trial. Gut 2014;63(11):1755-1759.
  23. Brown K, Gerstberger S, Carlson L, Franzoso G, Siebenlist U. Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation. Science (New York, NY) 1995;267(5203):1485-1488.
  24. Allport VC, Slater DM, Newton R, Bennett PR. NF-κB and AP-1 are required for cyclo-oxygenase 2 gene expression in amnion epithelial cell line (WISH). Molecular Human Reproduction 2000;6(6):561-565.
  25. Yin MJ, Yamamoto Y, Gaynor RB. The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature 1998;396(6706):77-80.
  26. Ratcliffe MJ, Itoh K, Sokol SY. A positive role for the PP2A catalytic subunit in Wnt signal transduction. The Journal of Biological Chemistry 2000;275(46):35680-35683.
  27. Bos CL, Kodach LL, van den Brink GR, et al. Effect of aspirin on the Wnt/beta-catenin pathway is mediated via protein phosphatase 2A. Oncogene 2006;25(49):6447-6456.
  28. Tauseef M, Shahid M, Sharma KK, Fahim M. Antioxidative action of aspirin on endothelial function in hypercholesterolaemic rats. Basic & Clinical Pharmacology & Toxicology 2008;103(4):314-321.
  29. Jian Z, Tang L, Yi X, et al. Aspirin induces Nrf2-mediated transcriptional activation of haem oxygenase-1 in protection of human melanocytes from H2 O2 -induced oxidative stress. Journal of Cellular and Molecular Medicine 2016;20(7):1307-1318.
  30. Lee JS, Surh YJ. Nrf2 as a novel molecular target for chemoprevention. Cancer Lett 2005;224(2):171-184.
  31. Wei Y, Gong J, Xu Z, Duh EJ. Nrf2 promotes reparative angiogenesis through regulation of NADPH oxidase-2 in oxygen-induced retinopathy. Free Radical Biology & Medicine 2016;99:234-243.
  32. Komiya M, Fujii G, Miyamoto S, et al. Suppressive effects of the NADPH oxidase inhibitor apocynin on intestinal tumorigenesis in obese KK-A(y) and Apc mutant Min mice. Cancer Science 2015;106(11):1499-1505.
  33. Gao XR, Adhikari CM, Peng LY, et al. Efficacy of different doses of aspirin in decreasing blood levels of inflammatory markers in patients with cardiovascular metabolic syndrome. The Journal of Pharmacy and Pharmacology 2009;61(11):1505-1510.
  34. Alfonso LF, Srivenugopal KS, Arumugam TV, et al. Aspirin inhibits camptothecin-induced p21CIP1 levels and potentiates apoptosis in human breast cancer cells. International Journal of Oncology 2009;34(3):597-608.
  35. Demierre MF, Higgins PD, Gruber SB, Hawk E, Lippman SM. Statins and cancer prevention. Nature Reviews Cancer 2005;5(12):930-942.
  36. Gronich N, Rennert G. Beyond aspirin-cancer prevention with statins, metformin and bisphosphonates. Nat Rev Clin Oncol 2013;10(11):625-642.
  37. Blais L, Desgagne A, LeLorier J. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and the risk of cancer: a nested case-control study. Archives of Internal Medicine 2000;160(15):2363-2368.
  38. Graaf MR, Beiderbeck AB, Egberts AC, Richel DJ, Guchelaar HJ. The risk of cancer in users of statins. J Clin Oncol 2004;22(12):2388-2394.
  39. Friis S, Poulsen AH, Johnsen SP, et al. Cancer risk among statin users: a population-based cohort study. International Journal of Cancer 2005;114(4):643-647.
  40. Poynter JN, Gruber SB, Higgins PD, et al. Statins and the risk of colorectal cancer. The New England Journal of Medicine 2005;352(21):2184-2192.
  41. Samadder NJ, Mukherjee B, Huang SC, et al. Risk of colorectal cancer in self-reported inflammatory bowel disease and modification of risk by statin and NSAID use. Cancer 2011;117(8):1640-1648.
  42. Hoffmeister M, Chang-Claude J, Brenner H. Individual and joint use of statins and low-dose aspirin and risk of colorectal cancer: a population-based case-control study. International Journal of Cancer 2007;121(6):1325-1330.
  43. Broughton T, Sington J, Beales IL. Statin use is associated with a reduced incidence of colorectal cancer: a colonoscopy-controlled case-control study. BMC Gastroenterology 2012;12:36.
  44. Lakha F, Theodoratou E, Farrington SM, et al. Statin use and association with colorectal cancer survival and risk: case control study with prescription data linkage. BMC Cancer 2012;12:487.
  45. Wei JT, Mott LA, Baron JA, Sandler RS. Reported use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors was not associated with reduced recurrence of colorectal adenomas. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2005;14(4):1026-1027.
  46. Pantan R, Tocharus J, Suksamrarn A, Tocharus C. Synergistic effect of atorvastatin and Cyanidin-3-glucoside on angiotensin II-induced inflammation in vascular smooth muscle cells. Experimental Cell Research 2016;342(2):104-112.
  47. Lee JY, Kim JS, Kim JM, et al. Simvastatin inhibits NF-κB signaling in intestinal epithelial cells and ameliorates acute murine colitis. International I Immunopharmacology 2007;7(2):241-248.
  48. Ehrenstein MR, Jury EC, Mauri C. Statins for atherosclerosis--as good as it gets? The New England Journal of Medicine 2005;352(1):73-75.
  49. Veillard NR, Mach F. Statins: the new aspirin? Cellular and Molecular Life Sciences: CMLS 2002;59(11):1771-1786.
  50. Esteghamati A, Eskandari D, Mirmiranpour H, et al. Effects of metformin on markers of oxidative stress and antioxidant reserve in patients with newly diagnosed type 2 diabetes: a randomized clinical trial. Clinical Nutrition (Edinburgh, Scotland) 2013;32(2):179-185.
  51. Wang J, Kitajima I. Pitavastatin inactivates NF-kappaB and decreases IL-6 production through Rho kinase pathway in MCF7 cells. Oncology Reports 2007;17(5):1149-1154.
  52. Ahn KS, Sethi G, Aggarwal BB. Reversal of chemoresistance and enhancement of apoptosis by statins through down-regulation of the NF-κB pathway. Biochemical Pharmacology 2008;75(4):907-913.
  53. Salins P, Shawesh S, He Y, et al. Lovastatin protects human neurons against Abeta-induced toxicity and causes activation of beta-catenin-TCF/LEF signaling. Neuroscience Letters 2007;412(3):211-216.
  54. Habeos IG, Ziros PG, Chartoumpekis D, et al. Simvastatin activates Keap1/Nrf2 signaling in rat liver. Journal of Molecular Medicine (Berlin, Germany) 2008;86(11):1279-1285.
  55. Jang HJ, Hong EM, Kim M, et al. Simvastatin induces heme oxygenase-1 via NF-E2-related factor 2(Nrf2) activation through ERK and PI3K/Akt pathway in colon cancer. Oncotarget 2016.
  56. Ihoriya C SM, Komai N, Sasaki T and Kashihara N. Nuclear Factor Erythroid 2-Related Factor 2 is Activated by Rosuvastatin via p21cip1 Upregulation in Endothelial Cells. Biochem & Pharmacol 2014;4:1.
  57. Macari ER, Schaeffer EK, West RJ, Lowrey CH. Simvastatin and t-butylhydroquinone suppress KLF1 and BCL11A gene expression and additively increase fetal hemoglobin in primary human erythroid cells. Blood 2013;121(5):830-839.
  58. Marrone G, Maeso-Diaz R, Garcia-Cardena G, et al. KLF2 exerts antifibrotic and vasoprotective effects in cirrhotic rat livers: behind the molecular mechanisms of statins. Gut 2015;64(9):1434-1443.
  59. Crisby M, Nordin-Fredriksson G, Shah PK, et al. Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization. Circulation 2001;103(7):926-933.
  60. Devaraj S, Chan E, Jialal I. Direct demonstration of an antiinflammatory effect of simvastatin in subjects with the metabolic syndrome. The Journal of Clinical Endocrinology and Metabolism 2006;91(11):4489-4496.
  61. van der Meij E, Koning GG, Vriens PW, et al. A clinical evaluation of statin pleiotropy: statins selectively and dose-dependently reduce vascular inflammation. PLoS One 2013;8(1):e53882.
  62. Castro PF, Miranda R, Verdejo HE, et al. Pleiotropic effects of atorvastatin in heart failure: role in oxidative stress, inflammation, endothelial function, and exercise capacity. The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 2008;27(4):435-441.
  63. Liang D, Zhang Q, Yang H, et al. Anti-oxidative stress effect of loading-dose rosuvastatin prior to percutaneous coronary intervention in patients with acute coronary syndrome: a pros-pec tive randomized controlled clinical trial. Clinical Drug Investigation 2014;34(11):773-781.
  64. Kuriyama S, Tsubono Y, Hozawa A, et al. Obesity and risk of cancer in Japan. Int J Cancer 2005;113(1):148-157.
  65. MacInnis R, English D, Hopper J, et al. Body size and composition and colon cancer risk in women. Int J Cancer 2006;118(6):1496-1500.
  66. Russo A, Franceschi S, La Vecchia C, et al. Body size and colorectal-cancer risk. Int J Cancer 1998;78(2):161-165.
  67. Le Marchand L, Wilkens L, Kolonel L, Hankin J, Lyu L. Asso ciations of sedentary lifestyle, obesity, smoking, alcohol use, and diabetes with the risk of colorectal cancer. Cancer Res 1997;57(21):4787-4794.
  68. Giovannucci E. Insulin and colon cancer. Cancer causes & control: CCC 1995;6(2):164-179.
  69. Zhang P, Li H, Tan X, Chen L, Wang S. Association of metformin use with cancer incidence and mortality: a meta-analysis. Cancer epidemiology 2013;37(3):207-218.
  70. Hosono K, Endo H, Takahashi H, et al. Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial. Cancer prevention research (Philadelphia, Pa) 2010;3(9):1077-1083.
  71. Higurashi T, Hosono K, Takahashi H, et al. Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised phase 3 trial. The Lancet Oncology 2016;17(4):475-483.
  72. Nath N, Khan M, Paintlia MK, et al. Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis. Journal of immunology(Baltimore, Md: 1950) 2009;182(12):8005-8014.
  73. Zhao X, Zmijewski JW, Lorne E, et al. Activation of AMPK attenuates neutrophil proinflammatory activity and decreases the severity of acute lung injury. American journal of physiology Lung cellular and molecular physiology 2008;295(3):L497-504.
  74. Myerburg MM, King JD, Jr., Oyster NM, et al. AMPK agonists ameliorate sodium and fluid transport and inflammation in cystic fibrosis airway epithelial cells. American journal of respiratory cell and molecular biology 2010;42(6):676-684.
  75. Bai A, Ma AG, Yong M, et al. AMPK agonist downregulates innate and adaptive immune responses in TNBS-induced murine acute and relapsing colitis. Biochemical pharmacology 2010;80(11):1708-1717.
  76. Koh S-J, Kim JM, Kim I-K, Ko SH, Kim JS. Anti-inflammatory mechanism of metformin and its effects in intestinal inflammation and colitis-associated colon cancer. Journal of Gastroenterology and Hepatology 2014;29(3):502-510.
  77. Takatani T, Minagawa M, Takatani R, Kinoshita K, Kohno Y. AMP-activated protein kinase attenuates Wnt/beta-catenin signaling in human osteoblastic Saos-2 cells. Molecular and cellular endocrinology 2011;339(1-2):114-119.
  78. Algire C, Moiseeva O, Deschenes-Simard X, et al. Metformin reduces endogenous reactive oxygen species and associated DNA damage. Cancer prevention research (Philadelphia, Pa) 2012;5(4):536-543.
  79. Bordini HP, Kremer JL, Fagundes TR, et al. Protective effect of metformin in an aberrant crypt foci model induced by 1,2-dimethylhydrazine: Modulation of oxidative stress and inflammatory process. Molecular carcinogenesis 2016.
  80. Tan BK, Adya R, Chen J, et al. Metformin decreases angiogenesis via NF-kappaB and Erk1/2/Erk5 pathways by increasing the antiangiogenic thrombospondin-1. Cardiovascular Research 2009;83(3):566-574.
  81. Xu W, Deng YY, Yang L, et al. Metformin ameliorates the proinflammatory state in patients with carotid artery atherosclerosis through sirtuin 1 induction. Translational research: The Journal of Laboratory and Clinical Medicine 2015;166(5):451-458.
  82. Chakraborty A, Chowdhury S, Bhattacharyya M. Effect of met formin on oxidative stress, nitrosative stress and inflammatory biomarkers in type 2 diabetes patients. Diabetes Research and Clinical Practice 2011;93(1):56-62.
  83. Tachibana H. Green tea polyphenol sensing. proceedings of the Japan Academy Series B, Physical and Biological Sciences 2011;87(3):66-80.
  84. Ji BT, Chow WH, Hsing AW, et al. Green tea consumption and the risk of pancreatic and colorectal cancers. International Journal of Cancer 1997;70(3):255-258.
  85. Yang G, Shu XO, Li H, et al. Prospective cohort study of green tea consumption and colorectal cancer risk in women. Cancer epidemiology, biomarkers & prevention: a publica tion of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2007;16(6):1219-1223.
  86. Shimizu M, Fukutomi Y, Ninomiya M, et al. Green tea extracts for the prevention of metachronous colorectal adenomas: a pilot study. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2008;17(11):3020-3025.
  87. Lin YL, Lin JK. (-)-Epigallocatechin-3-gallate blocks the induction of nitric oxide synthase by down-regulating lipopolysaccharide-induced activity of transcription factor nuclear factor-kappaB. Molecular Pharmacology 1997;52(3):465-472.
  88. Gupta RA, Dubois RN. Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nature Reviews Cancer 2001;1(1):11-21.
  89. Peng G, Dixon DA, Muga SJ, Smith TJ, Wargovich MJ. Green tea polyphenol (-)-epigallocatechin-3-gallate inhibits cyclooxygenase-2 expression in colon carcinogenesis. Molecular Carcinogenesis 2006;45(5):309-319.
  90. Ran ZH, Chen C, Xiao SD. Epigallocatechin-3-gallate ameliorates rats colitis induced by acetic acid. Biomedicine & Pharma cotherapy=Biomedecine & Pharmacotherapie 2008;62(3):189-196.
  91. Shirakami Y, Shimizu M, Tsurumi H, et al. EGCG and Polyphenon E attenuate inflammation-related mouse colon carcinogenesis induced by AOM plus DDS. Molecular Medicine Reports 2008;1(3):355-361.
  92. Pahlke G, Ngiewih Y, Kern M, et al. Impact of quercetin and EGCG on key elements of the Wnt pathway in human colon carcinoma cells. Journal of Agricultural and Food Chemistry 2006;54(19):7075-7082.
  93. Oh S, Gwak J, Park S, Yang CS. Green tea polyphenol EGCG suppresses Wnt/beta-catenin signaling by promoting GSK-3betaand PP2A-independent beta-catenin phosphorylation/degradation. BioFactors (Oxford, England) 2014;40(6):586-595.
  94. Ju J, Hong J, Zhou JN, et al. Inhibition of intestinal tumorigenesis in Apcmin/+ mice by (-)-epigallocatechin-3-gallate, the major catechin in green tea. Cancer Research 2005;65(22):10623-10631.
  95. Bose M, Hao X, Ju J, et al. Inhibition of tumorigenesis in Apc Min/+ mice by a combination of (-)-epigallocatechin-3-gallate and fish oil. Journal of Agricultural and Food Chemistry 2007;55(19):7695-7700.
  96. Yuan JH, Li YQ, Yang XY. Protective effects of epigallocatechin gallate on colon preneoplastic lesions induced by 2-amino-3-methylimidazo [4,5-f ] quinoline in mice. Molecular Medicine (Cambridge, Mass) 2008;14(9-10):590-598.
  97. Yuan JH, Li YQ, Yang XY. Inhibition of epigallocatechin gallate on orthotopic colon cancer by upregulating the Nrf2-UGT1A signal pathway in nude mice. Pharmacology 2007;80(4):269-278.
  98. August DA, Landau J, Caputo D, et al. Ingestion of green tea rapidly decreases prostaglandin E2 levels in rectal mucosa in humans. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 1999;8(8):709-713.
  99. Hong J, Smith TJ, Ho CT, August DA, Yang CS. Effects of purified green and black tea polyphenols on cyclooxygenase-and lipoxygenase-dependent metabolism of arachidonic acid in human colon mucosa and colon tumor tissues. Biochemical Pharmacology 2001;62(9):1175-1183.
  100. Oyama J, Maeda T, Sasaki M, et al. Green tea catechins improve human forearm vascular function and have potent anti-inflammatory and anti-apoptotic effects in smokers. Internal Medicine (Tokyo, Japan) 2010;49(23):2553-2559.
  101. Sakata R, Nakamura T, Torimura T, Ueno T, Sata M. Green tea with high-density catechins improves liver function and fat infiltration in non-alcoholic fatty liver disease (NAFLD) patients: a double-blind placebo-controlled study. International Journal of Molecular Medicine 2013;32(5):989-994.
  102. Bogdanski P, Suliburska J, Szulinska M, et al. Green tea extract reduces blood pressure, inflammatory biomarkers, and oxidative stress and improves parameters associated with insulin resistance in obese, hypertensive patients. Nutrition Research (New York, NY) 2012;32(6):421-427.
  103. Pulido-Moran M, Moreno-Fernandez J, Ramirez-Tortosa C, Ramirez-Tortosa M. Curcumin and Health. Molecules (Basel, Switzerland) 2016;21(3):264.
  104. Esatbeyoglu T, Huebbe P, Ernst IM, et al. Curcumin- -from molecule to biological function. Angewandte Chemie (International ed in English) 2012;51(22):5308-5332.
  105. Yang KY, Lin LC, Tseng TY, Wang SC, Tsai TH. Oral bioavailability of curcumin in rat and the herbal analysis from Curcuma longa by LC-MS/MS. Journal of Chromatography B, Analytical Technologies in the Biomedical and Life Sciences 2007;853(1-2):183-189.
  106. Sharma RA, Euden SA, Platton SL, et al. Phase I clinical trial of oral curcumin: biomarkers of systemic activity and compliance. Clin Cancer Res 2004;10(20):6847-6854.
  107. He ZY, Shi CB, Wen H, et al. Upregulation of p53 expression in patients with colorectal cancer by administration of curcumin. Cancer Investigation 2011;29(3):208-213.
  108. Carroll RE, Benya RV, Turgeon DK, et al. Phase IIa clinical trial of curcumin for the prevention of colorectal neoplasia. Cancer Prevention Research (Philadelphia, Pa) 2011;4(3):354-364.
  109. Pereira MA, Grubbs CJ, Barnes LH, et al. Effects of the phytochemicals, curcumin and quercetin, upon azoxymethane-induced colon cancer and 7,12-dimethylbenz[a]anthracene-induced mammary cancer in rats. Carcinogenesis 1996;17(6):1305-1311.
  110. Rao CV, Simi B, Reddy BS. Inhibition by dietary curcumin of azoxymethane-induced ornithine decarboxylase, tyrosine protein kinase, arachidonic acid metabolism and aberrant crypt foci formation in the rat colon. Carcinogenesis 1993;14(11):2219-2225.
  111. Kunnumakkara AB, Diagaradjane P, Guha S, et al. Curcumin sensitizes human colorectal cancer xenografts in nude mice to gamma-radiation by targeting nuclear factor-kappaB-regulated gene products. Clin Cancer Res 2008;14(7):2128-2136.
  112. Plummer SM, Holloway KA, Manson MM, et al. Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemo-preventive agent curcumin involves inhibition of NF-kappaB activation via the NIK/IKK signalling complex. Oncogene 1999;18(44):6013-6020.
  113. Sandur SK, Deorukhkar A, Pandey MK, et al. Curcumin modulates the radiosensitivity of colorectal cancer cells by suppressing constitutive and inducible NF-kappaB activity. International Journal of Radiation Oncology, Biology, Physics 2009;75(2):534-542.
  114. Jaiswal AS, Marlow BP, Gupta N, Narayan S. Beta-catenin-mediated transactivation and cell-cell adhesion pathways are important in curcumin (diferuylmethane)-induced growth arrest and apoptosis in colon cancer cells. Oncogene 2002;21(55):8414-8427.
  115. Sharma RA, McLelland HR, Hill KA, et al. Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer. Clin Cancer Res 2001;7(7):1894-1900.
  116. Garcea G, Berry DP, Jones DJ, et al. Consumption of the putative chemopreventive agent curcumin by cancer patients: assessment of curcumin levels in the colorectum and their pharmacodynamic consequences. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2005;14(1):120-125.
  117. Balstad TR, Carlsen H, Myhrstad MC, et al. Coffee, broccoli and spices are strong inducers of electrophile response element-dependent transcription in vitro and in vivo - studies in electrophile response element transgenic mice. Molecular Nutrition & Food Research 2011;55(2):185-197.
  118. Ye SF, Hou ZQ, Zhong LM, Zhang QQ. Effect of curcumin on the induction of glutathione S-transferases and NADP (H):quinone oxidoreductase and its possible mechanism of action. Yao xue xue bao=Acta pharmaceutica Sinica 2007;42(4):376-380.
  119. Dhillon N, Aggarwal BB, Newman RA, et al. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res 2008;14(14):4491-4499.
  120. Yu JJ, Pei LB, Zhang Y, Wen ZY, Yang JL. Chronic Supplementation of Curcumin Enhances the Efficacy of Antidepressants in Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Pilot Study. Journal of Clinical Psychopharmacology 2015;35(4):406-410.
  121. Durgaprasad S, Pai CG, Vasanthkumar, Alvres JF, Namitha S. A pilot study of the antioxidant effect of curcumin in tropical pancreatitis. The Indian Journal of Medical Research 2005;122(4):315-318.
  122. Yang H, Xu W, Zhou Z, et al. Curcumin attenuates urinary excretion of albumin in type II diabetic patients with enhancing nuclear factor erythroid-derived 2-like 2 (Nrf2) system and repressing inflammatory signaling efficacies. Experimental and clinical endocrinology & diabetes: official journal, German Society of Endocrinology [and] German Diabetes Association 2015;123(6):360-367.
  123. Kalpravidh RW, Siritanaratkul N, Insain P, et al. Improvement in oxidative stress and antioxidant parameters in beta-thalassemia/Hb E patients treated with curcuminoids. Clinical Biochemistry 2010;43(4-5):424-429.
  124. Pesson M, Volant A, Uguen A, et al. A gene expression and pre-mRNA splicing signature that marks the adenoma-adenocarcinoma progression in colorectal cancer. PLoS One 2014;9(2):e87761.
  125. Clevers H, Loh KM, Nusse R. Stem cell signaling. An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control. Science (New York, NY) 2014;346(6205):1248012.