Abstract 4763: Resveratrol synergizes with recombinant death ligands for potent antitumor activity against human metastatic colon cancers

Abstract

Abstract Despite recent advances in the treatment of metastatic colon cancer (CC), most patients are not curable. Furthermore, whenever patients have exhausted all available standard chemotherapy and biologic agent treatment, patients are left with a very poor performance status. Thus, additional therapy for CC needs to be both active against the most advanced forms of the disease and tolerable for patients. Resveratrol (RV) is a phytoalexin from the skin of grapes that has been shown to have inhibitory effects on the proliferation of human tumors. It can be administered to cancer patients as an oral naturopathic/nutritional supplement. The current study investigated the capacity of RV to modulate apoptotic and immunoregulatory gene expression in CC cells and explored the functional consequences of modulation on in vitro tumor cell proliferation. Gene expression was assessed with a real time PCR assay and in vitro proliferation with a standard MTS assay. The ATCC cell line, T84 as well as cell suspensions prepared from metastatic CC specimens involving the stomach (SM), ovary (OM), and extensive peritoneal carcinomatosis (PC) were tested. Inhibition of proliferation was observed with RV alone in concentrations up to 5 ug/mL and this was enhanced further when RV was combined with the immunologic death ligands, rTNF and rTRAIL. For the T84 cell line, levels of proliferation inhibition were 28.0%, 0.5%, 5.4%, 44.5% and 51.8% with RV, TNF, TRAIL, RV+TNF, and RV+TRAIL respectively. The corresponding values for surgical specimens were SM: 5.6%, 1.0%, 0.3%, 28.3%, and 52.4% respectively; OM: 26.2%, 4.6%, 6.1%, 57.4%, and 75.0% respectively; and PC: 46.9%, 17.1%, 59.6%, 61.8% and 96.7%, respectively. These effects of RV + immunologic death ligands were reflected by changes in expression of apoptotic and immunoregulatory genes. For example, in OM cells some of the genes whose expression was up-regulated by RV, TRAIL, and RV+TRAIL were FAS (4.33, 1.57, & 6.22-fold, respectively), DAPK (3.07, 1.16, 3.68), CARD6 (1.96, -1.09, 3.01), and TRADD (2.05, 1.29, 2.31). Consistently, there was increased gene expression in response to the combination of RV +TNF/TRAIL to levels greater than those elicited by any single agent for the following genes: TNFRSF9; CASP10; BCL2L1; BAK1; and BAX. The results of this study demonstrate that RV, a well tolerated oral naturopathic/nutritional supplement can inhibit the in vitro proliferation of human CC cells and collaborate with the immunologic death ligands TNF and TRAIL to inhibit proliferation further. These effects are correlated with changes in expression of apoptotic and immunoregulatory genes in CC cells. Taken together, the results suggest that RV could be combined with cytokine-based therapy or other forms of immunotherapy which elicit immunologic death ligands for the treatment of metastatic CC in patients. 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 4763. doi:10.1158/1538-7445.AM2011-4763