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University of Minho, Braga, Portugal 5th European Nutrition and Dietetics Conference Rome, 2016 Should the diet of colon cancer patients be personalized based on gene mutation profiles of tumor cells? Cristina Pereira-Wilson Cristina Xavier Dept. of Bioloy, University of Minho, Braga, Portugal 5th European Nutrition and Dietetics Conference June 17, 2016 Rome University of Minho, Braga, Portugal 5th European Nutrition and Dietetics Conference Rome, 2016 Colorectal cancer (CRC) is the third most common cause of cancer related death in western countries. Hereditary and environmental factors are involved. Hereditary predisposition corresponds to only about 20% of total cases of CRC, the remainder are sporadic. Diet may constitute a risk factor but may also have cancer preventive effects. Mutations accumulate in Oncogenes and Tumor suppressor genes University of Minho, Braga, Portugal 5th European Nutrition and Dietetics Conference Rome, 2016 Colorectal cancer Sporadic CRC refers to those cases that occur in individuals over age 50 years without any identifiable predisposing factors. Familial cases are those with a family history of CRC but exclusive of FAP, HNPCC, and the hamartomatous polyposis syndromes. The approximate percentage of distribution for each condition is as follows: sporadic, 75%; familial, 15%; HNPCC, 5%; FAP, 1%; IBD, 1%; MAP, 1%; hamartomas, < 1%. IBD = inflammatory bowel disease; MAP = MYHassociated polyposis University of Minho, Braga, Portugal 5th European Nutrition and Dietetics Conference Rome, 2016 Genetic prognostic and predictive markers in colorectal cancer Axel Walther, Elaine Johnstone, Charles Swanton, Rachel Midgley, Ian Tomlinson & David Kerr Nature Reviews Cancer 9, 489-499 (July 2009) University of Minho, Braga, Portugal 5th European Nutrition and Dietetics Conference Rome, 2016 Barbaro et al, INTERNATIONAL JOURNAL OF ONCOLOGY, 2014 5th European Nutrition and Dietetics Conference Rome, 2016 University of Minho, Braga, Portugal Personalized Medicine… the discovery that KRAS mutation is a marker of probable failure of epidermal growth factor receptor (EGFR)-targeted therapy was the first step in the tailoring of treatment to the individual. Prholifer ation University of Minho, Braga, Portugal 5th European Nutrition and Dietetics Conference Rome, 2016 Personalized Medicine… Alterations in the tumor suppressor p53 are known to cause apoptosis evasion and treatment resistance University of Minho, Braga, Portugal 5th European Nutrition and Dietetics Conference Rome, 2016 Treatment efficacy depends on patient’s genetic information A person’s genetic information will also affect the response to dietary constituents 5th European Nutrition and Dietetics Conference Rome, 2016 University of Minho, Braga, Portugal Cell lines dereived from tumors with well characterized genetic backgounds are useful in the study of effects of dietary constituents Mutations Kras Braf p53 HCT15 CO115 + wt wt + + wt HCT116 p53 wt HCT116 p53 null + + wt wt wt null 5th European Nutrition and Dietetics Conference Rome, 2016 University of Minho, Braga, Portugal Xavier C and Pereira-Wilson C (2016) PharmaNutrition 4: 112-122 Rosmarinic acid Luteolin Ursolic acid Quercetin University of Minho, Braga, Portugal 5th European Nutrition and Dietetics Conference Rome, 2016 Compounds dose dependently decrease cell proliferation in cells with KRas (HCT15) or BRaf (CO115) mutations quercetin (Q), luteolin (L), ursolic acid (UA) and reference compounds, wortmannin (W) and PD-98059 (PD) Xavier,C et al., (2009) Cancer Letters 281, 162-170 University of Minho, Braga, Portugal 5th European Nutrition and Dietetics Conference Rome, 2016 Compounds dose dependently increase cell death by apoptosis in cells with KRas (HCT15) or Braf (CO115) mutations Quercetin (Q), luteolin (L) and ursolic acid (UA) and reference compounds, wortmannin (W) and PD-98059 (PD) Xavier,C et al., (2009) Cancer Letters 281, 162-170 University of Minho, Braga, Portugal 5th European Nutrition and Dietetics Conference Rome, 2016 5-FU is a chemotherapeutic drug widely used in the treatment of CRC Tumor cells with p53 mutation are resistant to 5-FU Q + 5-FU increases cell death particularly in CO115 Xavier,C et al. (2011) Cancer Chemother Pharmacol 68: 1449-1457 University of Minho, Braga, Portugal 5th European Nutrition and Dietetics Conference Rome, 2016 Apoptosis induced by 5-FU and by Q is linked to an increase p53 and caspase activation Is this a p53 dependent effect?... Xavier,C et al. (2011) Cancer Chemother Pharmacol 68: 1449-1457 University of Minho, Braga, Portugal 5th European Nutrition and Dietetics Conference Rome, 2016 Apoptosis induction by Q, 5-FU and Q + 5-FU is p53 dependent Therefore, quercetin may increase 5-FU treatment efficacy in tumors expressing wild type (wt) p53 but will most likely not benefit patients whose tumors do not express wt p53 or express a mutated p53 Xavier,C et al. (2011) Cancer Chemother Pharmacol 68: 1449-1457 University of Minho, Braga, Portugal 5th European Nutrition and Dietetics Conference Rome, 2016 Concluding Remarks In order to use dietary compounds to enhance the efficacy cancer chemotherapy, a detailed characterization of their molecular targets and interactions with the pharmaceutical drugs is needed so as to sellect the patients that will benefit from the combination! 5th European Nutrition and Dietetics Conference Rome, 2016 University of Minho, Braga, Portugal Poster NUTC 15 Our data shows that the studied legumes have the capacity to reduce proliferation by keeping the cells differentiated in cell cycle phase G0-G1. The cell cycle arrest activity is enhanced by boiling and pressure cooking. Importantly, back bean and cowpea demonstrated to be effective independently of tumor p53 status, contrarily to soybean. Taken together, the data suggests that cowpea and black bean have great potential in the nutritional management of colorectal cancer patients. 5th European Nutrition and Dietetics Conference Rome, 2016 University of Minho, Braga, Portugal Thank you for your attention! Cristina Pereira-Wilson Molecular Nutrition Group Department of Biology, University of Minho, Braga Portugal Contact: [email protected] [email protected] Collaborations - M. Rohde Apoptosis Department, Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark - R. Seruca Institute of Molecular Pathology and Immunology (IPATIMUP) University of Porto, Porto, Portugal Aknowledgments University of Minho, Braga, Portugal 5th European Nutrition and Dietetics Conference Rome, 2016 Compounds dose dependently decrease cell proliferation in cells with KRas or BRaf mutations Effect on BrdU incorporation of different concentrations of quercetin (Q), luteolin (L), ursolic acid (UA) and reference compounds, wortmannin (W) and PD-98059 (PD), in HCT15 (a) and CO115 (b) cells. Xavier,C et al., (2009) Cancer Letters 281, 162-170 University of Minho, Braga, Portugal 5th European Nutrition and Dietetics Conference Rome, 2016 The ratio total ERK/p-ERK reflects MAPKinase pathway activity In KRas mutated cells HCT15 Luteolin (L) and quercetin (Q) decrease MAPKinase pathway activity In Braf mutated cells the compounds do not change MAPKinase pathway activity Xavier,C et al., (2009) Cancer Letters 281, 162-170 University of Minho, Braga, Portugal 5th European Nutrition and Dietetics Conference Rome, 2016 The ratio p-AKT/Total AKT reflect the level of activation of the PI3K/AKT pathway In CO115 cells the compounds decrease PI3K/AKT activity In HCT15 cells p-AKT was not detected Xavier,C et al., (2009) Cancer Letters 281, 162-170 University of Minho, Braga, Portugal 5th European Nutrition and Dietetics Conference Rome, 2016 Quercetin decreased activity in MAPKinase pathway in HCT15 cells that express a mutated Kras but not in CO115 that has a Braf mutation in CO115 Q acts on PI3K/AKT Q acts on several molecular targets and as a result it inhibits proliferation in both genetic backgrounds Xavier,C et al., (2009) Cancer Letters 281, 162-170