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SphK1 Inhibitor II (SKI-II) Inhibits Acute Myelogenous Leukemia Cell Growth in Vitro and in Vivo

SphK1 Inhibitor II (SKI-II) Inhibits Acute Myelogenous Leukemia Cell Growth in Vitro and in Vivo

Li Yang, Wei Weng, Zhi-Xin Sun, Xian-Jie Fu, Jun Ma, Wen-Fang Zhuang

Biochem Biophys Res Commun. 2015 May 15;460(4):903-8.

PMID: 25824043

Abstract:

Previous studies have identified sphingosine kinase 1 (SphK1) as a potential drug target for treatment of acute myeloid leukemia (AML). In the current study, we investigated the potential anti-leukemic activity of a novel and specific SphK1 inhibitor, SKI-II. We demonstrated that SKI-II inhibited growth and survival of human AML cell lines (HL-60 and U937 cells). SKI-II was more efficient than two known SphK1 inhibitors SK1-I and FTY720 in inhibiting AML cells. Meanwhile, it induced dramatic apoptosis in above AML cells, and the cytotoxicity by SKI-II was almost reversed by the general caspase inhibitor z-VAD-fmk. SKI-II treatment inhibited SphK1 activation, and concomitantly increased level of sphingosine-1-phosphate (S1P) precursor ceramide in AML cells. Conversely, exogenously-added S1P protected against SKI-II-induced cytotoxicity, while cell permeable short-chain ceramide (C6) aggravated SKI-II's lethality against AML cells. Notably, SKI-II induced potent apoptotic death in primary human AML cells, but was generally safe to the human peripheral blood mononuclear cells (PBMCs) isolated from healthy donors. In vivo, SKI-II administration suppressed growth of U937 leukemic xenograft tumors in severe combined immunodeficient (SCID) mice. These results suggest that SKI-II might be further investigated as a promising anti-AML agent.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP312636161	SKI II		312636-16-1	Price
IAR42415307	Caspase Inhibitor II, Cell-Permeable			Price

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