Abstract 221: C6-ceramide sensitizes the aggressive L3-6 pancreatic cancer cell line to paclitaxel-mediated antitumor effects in vivo and in vitro

Abstract

Abstract Key words: C6 Ceramide, Taxol, Gemcitabine, AMPK, AKT/mTOR, chemotherapy, pancreatic cancer Background: Survival after therapy of pancreatic cancer is about <5% with a strong need for new chemotherapy enhancing strategies. Our previous in vivo studies have demonstrated that C6 Ceramide has synergistic anti tumor effects on agents (Taxol, Oxaliplatin, Gemcitabine) against the aggressive pancreatic cancer cell line L3.6 in scid mice. The molecular mechanisms of this synergistic effect are our current focus. Methods: The synergistic effects of C6 ceramide on Paclitaxel and Gemcitabine were studied both in vivo (by monitoring survival, tumor size, tumor growth rate, in heterografted L3-6 pancreatic cancer cells in scid mice) and in vitro (by MTT assay and apoptosis assays-(Caspase dependent/independent), and Western blot assays of signal transduction pathways to determine molecular mechanisms involved in the C6 Ceramide synergistic effects. Results: In vivo and in vitro data confirmed significant C6 Ceramide synergistic enhancement of Paclitaxel (P) and Gemcitabine (G) in the L3-6 model. Basic findings: Paclitaxel alone activates pro-survival pathway PI3K/AKT/mTOR in L3.6 cells. C6 ceramide induces pharmacological and genetic inhibition of the PI3K/AKT/mTOR pathway sensitizing L3.6 cells to Paclitaxel induced cell death and apoptosis. C6 Ceramide also dramatically enhanced Paclitaxel induced AMPK activation, a key energy switch enzyme that is responsible for cell apoptosis in stress. PI3K/AKT/mTOR inhibition and AMPK induction may be major mechanisms of C6 synergistic effect on paclitaxel induced cell death. We also found that C6 Ceramide also promotes Paclitaxel induced activation of the mitochondrial mediated apoptosis pathway sensitizing L3.6 to chemotherapeutic induced cell death. Conclusion: Our data suggests that combining C6 Ceramide with traditional chemotherapy drugs illustrated by paclitaxel may have potential as a new biologic therapeutic intervention against pancreatic cancer and merits continued study. 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 221.