Abstract 2866: Targeting autophagy in pancreatic cancer

Abstract

Abstract Autophagy is a cell survival pathway that has been shown to be activated in a variety of cancers including pancreatic cancer. It has been suggested that cancer cells activate autophagy to survive microenvironmental stresses such as depletion of nutrients, hypoxia and chemotherapeutic agents. Studies have shown that inhibition of autophagy can sensitize cancer cells to the treatment of therapeutic agents. Chloroquine (CQ) is a well established pharmacological inhibitor of autophagy and has been shown to enhance the sensitivity of cancer cells to treatment of cytotoxic agents. Dexamethasone (DEX), a synthetic gluococorticoid, which has been reported to sensitize pancreatic cancer cells to the treatment of gemcitabine (GEM) and carboplatin, is known to induce autophagy. In addition, activation of glucocorticoid receptor (GR) by DEX inhibits NF-kB and AP-1, two activators of survival pathways in many tumors. Whether DEX increases the cytotoxic effects of GEM through autophagy, NF-kB signaling, or a combo of both is unclear. Our preliminary studies show that DEX dramatically enhances the anti-tumor activity of CQ, indicating that the inhibition of autophagy may increase cell sensitivity to drug treatment. Therefore, we hypothesize that a combination pretreatment with CQ and DEX will significantly enhance the anti-tumor activity of GEM in pancreatic cancer, and that such enhancement in GEM activity is induced by the synergistic inhibition of autophagy by CQ and DEX. In vitro cell growth assay results showed that addition of CQ and DEX significantly increase the antitumor activity of GEM in MIA PaCa-2 and SU.86.86 pancreatic cancer cells. Interestingly, combination treatment of DEX+GEM or CQ+GEM did not show significant synergistic effect. A correlation between autophagy inhibition and cell death was evident when levels of LC3B-II protein, a common indicator of autophagy induction, were compared in cells exposed to single or combination drug treatments. In MIA PaCa-2 cells, CQ+DEX with 100nM GEM reduced LC3B-II levels by at least 50%. Animal studies are underway to determine the efficacy of the triple drug combination in vivo. Our results indicate pancreatic cells use autophagy as a cell survival mechanism in response to gemcitabine, and the drug combination dexamethasone and chloroquine are able to inhibit authophagy, thus rendering the pancreatic cancer cells more sensitive to gemcitabine. 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 2866. doi:10.1158/1538-7445.AM2011-2866