Abstract 4594: Grape seed extract induces apoptosis in human colorectal carcinoma through modulation of death receptors and anti-apoptotic molecules

Abstract

Abstract Colorectal Cancer (CRC) is the second leading cause of cancer related deaths in the US. Diets rich in fruits and vegetables are shown to decrease CRC incidence by 40%, in part due to antioxidant and free radical properties of the polyphenolics present therein; grape seed extract (GSE) is one of the richest sources of these antioxidants. Oncogenic mutations that suppress apoptosis can lead to tumor initiation, progression, and metastasis; a major cause of conventional treatment resistance is due to apoptotic pathway defects. Accordingly, the strategies that target the mechanisms of apoptosis resistance in cancer cells provide the potential opportunities for cancer management. Herein we investigated the apoptotic effects of GSE and defined associated mechanisms in three human CRC cell lines, namely SW480, SW620 and HCT116, representing II-IV stages of CRC. Normal colon epithelial cells namely NCM460 was also included to establish GSE specificity, if any, towards CRC cells. A comparison of GSE activity in three CRC cell lines showed that almost three times higher GSE levels are needed for comparable cell death effect in SW480 versus SW620/HCT116 cells; cell treatments were accordingly adjusted for remainder studies. GSE treatment of SW480 cells at 25-100μg/mL resulted in a maximum of 55% apoptotic death at 48h; however, even 10-30μg/mL GSE treatments produced 53-57% apoptotic cell death in SW620 and HCT116 cell lines. At the molecular level, GSE induced DR4/5 up regulation, caspase-9, -3, -8, and PARP cleavage in all three cell lines indicating the involvement of both extrinsic and intrinsic apoptotic pathways in its efficacy. Furthermore, GSE treatment caused down regulation of anti-apoptotic proteins Bcl-2 and XIAP in SW480 cells only, but increased the levels of pro-apoptotic proteins such as Mcl-1s in all three cell lines. Importantly, GSE also increased the levels of p53 and its associated regulators namely p21, PUMA and Bak, suggesting their possible role in GSE-caused apoptotic death in HCT116 cell line. GSE treatment (25-100μg/mL) of NCM460 cells did not result in significant death compared to what was observed in three different human CRC cell lines, clearly showing its activity selectively in cancer cells. In conclusion, our findings further support the notion that GSE could be an effective chemopreventive and chemotherapeutic agent for colorectal. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4594. doi:10.1158/1538-7445.AM2011-4594