Abstract
Abstract We have previously shown that the grape bioactive compound resveratrol (RSV) potentiates grape seed extract (GSE)-induced colon cancer cell apoptosis at physiologically relevant concentrations. However, RSV-GSE combination efficacy against colon cancer stem cells (CSCs), which play a key role in chemotherapy and radiation resistance, is not known. Hence, we tested the anti-cancer efficacy of the RSV-GSE in an azoxymethane-induced mouse model of colon carcinogenesis. RSV-GSE suppressed tumor incidence similar to sulindac, without any gastrointestinal toxicity. Additionally, RSV-GSE treatment reduced the number of crypts containing cells with nuclear β-catenin (an indicator of colon CSCs) via induction of apoptosis. In in vitro mechanistic studies, RSV-GSE suppressed proliferation and sphere formation properties of colon CSCs (positive for CD44, CD133 and ALDH1b1), suppressed pGSK3β and nuclear translocation of β-catenin, a critical regulator of CSC proliferation, similar to sulindac. RSV-GSE, but not sulindac, suppressed nuclear levels of downstream proteins of Wnt/β-catenin pathway, c-Myc and cyclin D1. RSV-GSE also induced mitochondrial-mediated apoptosis in colon CSCs characterized by elevated p53, Bax/Bcl-2 ratio and cleaved PARP. Furthermore, shRNA-mediated knockdown of p53, a tumor suppressor gene that is mutated in advanced stages of colon cancer, in the colon CSCs did not alter efficacy of RSV-GSE. The suppression of Wnt/β-catenin signaling and elevated mitochondrial-mediated apoptosis in colon CSCs support potential clinical testing/application of grape bioactives for colon cancer prevention and/or therapy. Citation Format: Lavanya Reddivari, Venkata Charepalli, Ramakrishna Vadde, Sridhar Radhakrishnan, Joshua D. Lambert, Ryan J. Elias, Jairam KP Vanamala. Grape compounds suppress colon cancer stem cells in vitro and in a rodent model of colon carcinogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2500.
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