Abstract 5609: Resveratrol as a modulator of human tumor proliferation and immunologic sensitivity

Abstract

Abstract Integrative cancer treatment employing natural products (NPs) in conjunction with conventional therapeutic modalities (Tx) is attractive for tumors that are difficult to control clinically. In this context, pluripotent activities of NPs have the potential of affecting multiple processes relevant to cancer growth. Unfortunately, there is little empiric evidence to elucidate clinically useful effects of NPs making it difficult to optimize Tx regimens. This challenge justifies translational studies to characterize NP effects on processes relevant to tumor control. In the current study, we assessed the action of Resveratrol (RV), a phytoalexin present in the skin of red grapes on the sensitivity of human tumors to proliferation inhibition and antitumor immunity. Proliferation was assessed with MTS assay; immune-mediated lysis with 51Chromium release assay; and gene expression with real time PCR. Using the following ATCC cell lines: malignant melanoma (MM); renal (RC); ovarian (OC); non-small cell lung (NSCLC); pancreatic (PC); breast (BC); and bladder (BLC) cancer, significant dose-dependent proliferation inhibition (paired, 2-tail t tests) in RV-treated cells was demonstrated for all tumors with rank order of sensitivity being: MM > RC > OC > NSCLC > BC > BLC > PC. Significant inhibition (p < 0.05) was also observed with tumor cells from surgical specimens from patients with colon, RC, PC, and OC. The substantial proliferation inhibitory effects of RV on MM (> 80% at 10μg/mL; p = 0.005) and RC (> 65% at 10μg/mL; p = 0.02) was associated with significant chanages in quantitative expression of various pro and anti-apoptotic regulatory genes. For example, RV-treated MM showed > 8 fold down-regulation of anti-apoptotic BCL2 in association with > 13 fold increase in the death associated kinase, DPK1 and RV-treated RC showed 2-3 fold up-regulation of caspases 1, 5, 7, 10, and 14. Moreover, these studies also revealed significantly increased (2-4 fold) expression of different TNF and TRAIL-related death receptors in RV-treated RC and MM cells. Subsequently, testing the effects of RV-pretreated RC and MM to different forms of antitumor immunity showed: 1)RV pre-treated RC are significantly more sensitive to lysis by IL2-activated human lymphocytes compared to control cells (270 vs 121 lytic units respectively, p=0.04); and, 2) proliferation of MM is inhibited significantly (p<0.05) in an additive fashion by the combination of RV + rTNF or RV + rTRAIL. This study demonstrates that RV can favorably modulate tumor cell proliferation and sensitivity to tumor immune mechanisms in some of the most difficult to treat human cancer histologies. These sorts of studies should facilitate development of integrative treatment modalities to exploit the pluripotent activities of NPs such as RV in specific oncologic settings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5609.