Abstract A26: Colon cancer prevention through combinations of dietary or pharmacological agents

Our studies aim at developing combinations of dietary or pharmacological agents that lower the risk for colorectal cancer (CRC). In vitrostudies have demonstrated that histone deacetylase inhibitors (HDACis) induce programmed death (apoptosis) in CRC cells with mutations in the WNT/beta-catenin pathway, and the apoptotic levels depend upon the hyperactivation of WNT signaling. Since mutations in the WNT/catenin pathway are present in almost 80% of all sporadic CRCs, dietary and synthetic HDACis are promising anti-CRC agents. However, HDACi-initiated apoptosis of CRC cells is counteracted by induction of compensatory proliferation supported by the AKT and JAK/STAT cell survival pathways. Therefore, we ascertained whether agents that suppress cell survival signaling augment the apoptotic effect of HDACis. We utilized apoptotic assays and immunoblotting analyses to ascertain the ability of compensatory pathway inhibitors to augment the apoptosis induced by dietary and pharmacological HDACis in colorectal neoplastic cells. The effects of the agents were assessed in HDACi-resistant colorectal cancer (HCT-R) and early colonic adenoma (LT97) cells. A combination treatment of CRC cells with a synthetic HDACi (LBH589), an AKT inhibitor (MK2206), and a JAK/STAT inhibitor (pyridone 6) validated the concept that the apoptotic effect of a HDACi is augmented by inhibitors of compensatory proliferation. Such pharmacological approach to CRC prevention might be applicable for populations at high risk for colon cancer (e.g., CRC patients with partial colonic resection, chronic inflammatory bowel disease, history of colonic polyps). Interestingly, diet-derived modulators of compensatory survival pathways affect differently HDACi-induced apoptosis in colonic carcinoma and early adenoma cells. Thus, caffeic acid phenethyl ester (CAPE, an AKT inhibitor contained in some honeybee propolis), and gallotannin (a JAK/STAT inhibitor derived from some fruit and wine) augment the apoptotic effect of the dietary HDACi butyrate in colonic carcinoma HCT-R cells, but not in adenoma LT97 cells. Resveratrol and pterostilbene (phenols found in grapes and blueberries) both suppress butyrate-induced apoptosis in colorectal carcinoma HCT-R cells, and augment butyrate-induced apoptosis in early adenoma cells in the presence of CAPE. Since at physiologically achievable concentrations CAPE, gallotannin, resveratrol, and pterostilbene alone or in combination do not induce apoptosis, the signaling pathways targeted by these compounds in butyrate-treated colonic neoplastic cells are true apoptosis-induced compensatory proliferation pathways. Our data suggest that different compensatory proliferation pathways are activated in colonic adenoma and carcinoma cells in response to the diet-derived HDACi butyrate. Further analyses should ascertain the identity of these cell survival signaling pathways. In conclusion, the rationale of combining inducers of apoptosis (e.g., HDACis) with inhibitors of compensatory proliferation may result in the design of supplements with a powerful CRC-protective effect. The next step in the development of such dietary supplements is ascertaining their effect in animal models of intestinal cancer. Citation Format: Eric Drago, Michael Bordonaro, Jeffrey Marteslo, Patricia Melvin, Wafa Atamna, Darina Lazarova. Colon cancer prevention through combinations of dietary or pharmacological agents. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr A26.