Abstract 2933: The apoptotic mechanism of action of SKI-178, a novel Sphingosine kinase 1 selective inhibitor

Abstract

Abstract We previously developed SKI-178 as a novel Sphingosine kinase 1 (SphK1) selective inhibitor that is cytotoxic toward a broad panel of cancer types. Herein, we sought to determine the mechanism-of-action of SKI-178-induced cell death. We present evidence that SKI-178 induces prolonged mitosis followed by apoptotic cell death through the intrinsic apoptotic cascade. Further examination of the mechanism-of-action (MOA) of SKI-178 implicated c-Jun NH2-terminal kinase (JNK) and cyclin-dependent protein kinase 1 (CDK1) as critical factors required for SKI-178-induced apoptosis. In cell cycle synchronized human AML cell lines, we demonstrate that entry into mitosis is required for apoptotic induction by SKI-178 and that CDK1, not JNK, is required for SKI-178-induced apoptosis. We further demonstrate that the sustained activation of CDK1 during prolonged mitosis, mediated by SKI-178, leads to the simultaneous phosphorylation of the pro-survival Bcl-2 family members, Bcl-2 and Bcl-xl, as well as the phosphorylation and subsequent degradation of Mcl-1. Moreover, multi-drug resistance mediated by MDR-1 and/or pro-survival Bcl-2 family member over-expression did not affect the sensitivity of AML cells to SKI-178. In addition to AML, we extend the MOA of SKI-178 to include various solid tumor cell lines, including pancreatic cancer and glioblastoma. Taken together, we provide evidence that SKI-178 induces apoptosis in a CDK1-dependent manner and is not a substrate for MDR1, making it a promising chemotherapeutic candidate for the treatment of various cancer types, including those known to be drug resistant. Citation Format: Taryn E. Dick, Jeremy Hengst, Vijay Kale, Ashley Colledge, Jong K. Yun. The apoptotic mechanism of action of SKI-178, a novel Sphingosine kinase 1 selective inhibitor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2933. doi:10.1158/1538-7445.AM2015-2933