Abstract 1552: Resveratrol increases sensitivity of human peritoneal cancer cells to macrophage-mediated cytolysis

Abstract

Abstract The peritoneal cavity contains numerous cells of the immune system capable of mediating antitumor effects. The persistence of cancer in this environment is thought to be due, in part, to the capacity of these cells to circumvent immunologic detection and destruction. Nevertheless, the presence of an immune system within the peritoneal cavity provides the opportunity to elicit tumor cytolysis by resident and/or circulating immune cells mobilized from the peripheral blood. One strategy that may be applicable in this setting is the introduction of compounds into the peritoneal cavity that enhance the sensitivity of malignant cells to activated immune cells. Ideally, these compounds would be tolerated by normal tissues while exerting clinical effects on tumor tissues. In the current investigation, we explored the capacity of the natural product, resveratrol, to modulate sensitivity of human peritoneal cancer cells to the lytic effects of activated human peripheral blood monocytes (PBM). PBM were primed with gamma interferon (IFN) followed by lipopolysaccharide (LPS) as a second signal. Target cells consisted of newly established cells lines from surgical specimens of patients with peritoneal carcinaomatosis (PC) or metastatic colorectal cancer (CRC). Cytolysis was determined following activation with a 24 hour 51Chromium release assay. Control activation of PBM with medium elicted 25 lytic units (LU) and < 5 LU against untreated CRC and PC cells respectively. These values were not changed significantly when resveratrol-pretreated tumor cells were used as targets. In contrast, PBM fully activated with IFN/LPS elicted 224 and 118 LU against untreated CRC and PC respectively and 316 and 199 LU against resveratrol-pretreated CRC and PC respectively. These results were investigated further to determine the effects of resveratrol pretreatment on expression of genes associated with immunologic sensitivity. A real time PCR assay indicated significantly increased expression of death receptors of the TNF superfamily as a consequence of resveratrol pretreatment. Subsequent studies demonstrated that recombinant TNF and TRAIL ligands could significantly inhibit proliferation of resveratrol-pretreated CRC and PC greater than media-pretreated cells. The results of this study demonstrate that human peritoneal cancer cells can be rendered significantly more sensitive to the cytolytic effects of activated human monocytes and macrophages when exposed to the natural product, resveratrol. Given the substantial quantity of macrophages in the peritoneal cavitry of humans, and the influence of malignant tissues on increasing these numbers further, modalities designed to exploit the tumor cytolytic effects of peritoneal macrophages for the treatment of human peritoneal cancers should be explored. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1552. doi:1538-7445.AM2012-1552