Abstract 767: CXL017 re-sensitizes multidrug resistant leukemia cells to chemotherapy via modulating Bcl-2 family proteins and SERCA proteins

Abstract

Abstract Multidrug resistance (MDR) is a major hurdle in the treatment of cancer and there is a pressing need for new therapies. We have recently developed CXL017, derived from a Bcl-2 and SERCA dual inhibitor, with selective cytotoxicity towards MDR cancer cells. In this study, we present new evidence for its therapeutic potential in treatment of MDR cancers and offer mechanistic insights. CXL017 significantly and selectively suppresses the growth of tumors derived from the MDR cancer cell line, HL60/MX2, in vivo. In addition, HL60/MX2 failed to develop stable resistance to CXL017 upon prolonged exposure. In comparison, HL60/MX2 acquired greater than 2000-fold resistance to cytarabine (Ara-C). Remarkably, instead of acquiring cross-resistance, HL60/MX2 cells exposed to CXL017 were re-sensitized to standard therapies (10 to 100-fold). Western blotting analyses revealed that HL60/MX2 has significantly elevated levels of Mcl-1, Bax and Bak relative to HL60. HL60/MX2 also over-expresses SERCA2 and SERCA3 with elevated endoplasmic reticulum (ER) calcium content. CXL017 exposure significantly down-regulates Mcl-1 and Bax but causes up-regulation of Bcl-XL, SERCA2, and SERCA3 proteins, along with a reduction in ER calcium content. Given the well-established functions of Bcl-2 family proteins and ER calcium in drug resistance, our results suggest that the reduction in Mcl-1 and the decrease in ER calcium content are responsible for CXL017 induced chemosensitization of MDR cancer cells. These results support the strategy to develop dual inhibitors of anti-apoptotic Bcl-2 proteins and SERCA to treat MDR cancers. 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 767. doi:1538-7445.AM2012-767