The apoptotic mechanism of action of the sphingosine kinase 1 selective inhibitor SKI-178 in human acute myeloid leukemia cell lines

Taryn E. Dick, Jeremy A. Hengst, Todd E. Fox, Ashley L. Colledge, Vijay P. Kale, Shen Shu Sung, Arun Sharma, Shantu Amin, Thomas P. Loughran, Mark Kester, Hong Gang Wang, Jong K. Yun

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Abstract

We previously developed SKI-178 (N'-[(1E)-1-(3,4-dimethoxyphenyl) ethylidene]-3-(4-methoxxyphenyl)-1H-pyrazole-5-carbohydrazide) as a novel sphingosine kinase-1 (SphK1) selective inhibitor and, herein, sought to determine the mechanism-of-action of SKI-178-induced cell death. Using human acute myeloid leukemia (AML) cell lines as a model, 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 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 prosurvival Bcl-2 family members, Bcl-2 and Bcl-xl, as well as the phosphorylation and subsequent degradation of Mcl-1. Moreover, multidrug resistance mediated by multidrug-resistant protein1 and/or prosurvival Bcl-2 family member overexpression did not affect the sensitivity of AML cells to SKI-178. Taken together, these findings highlight the therapeutic potential of SKI-178 targeting SphK1 as a novel therapeutic agent for the treatment of AML, including multidrug-resistant/recurrent AML subtypes.

Original languageEnglish (US)
Pages (from-to)494-508
Number of pages15
JournalJournal of Pharmacology and Experimental Therapeutics
Volume352
Issue number3
DOIs
StatePublished - Mar 1 2015

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All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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