Yang Li, Weng Wei, Sun Zhi-Xin, Fu Xian-Jie, Ma Jun, Zhuang Wen-Fang
Department of Hematology, Shanghai Tongren Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Hematology, Shanghai Tongren Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Biochem Biophys Res Commun. 2015 May 15;460(4):903-8. doi: 10.1016/j.bbrc.2015.03.114. Epub 2015 Mar 28.
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.
先前的研究已确定鞘氨醇激酶1（SphK1）是治疗急性髓性白血病（AML）的潜在药物靶点。在本研究中，我们调查了一种新型特异性SphK1抑制剂SKI-II的潜在抗白血病活性。我们证明SKI-II可抑制人AML细胞系（HL-60和U937细胞）的生长和存活。在抑制AML细胞方面，SKI-II比两种已知的SphK1抑制剂SK1-I和FTY720更有效。同时，它可诱导上述AML细胞发生显著凋亡，而一般的半胱天冬酶抑制剂z-VAD-fmk几乎可逆转SKI-II的细胞毒性。SKI-II处理可抑制SphK1激活，并同时提高AML细胞中鞘氨醇-1-磷酸（S1P）前体神经酰胺的水平。相反，外源性添加的S1P可保护细胞免受SKI-II诱导的细胞毒性，而细胞可渗透的短链神经酰胺（C6）则会加重SKI-II对AML细胞的致死性。值得注意的是，SKI-II可诱导原代人AML细胞发生强效凋亡性死亡，但对从健康供体分离的人外周血单个核细胞（PBMC）通常是安全的。在体内，给予SKI-II可抑制严重联合免疫缺陷（SCID）小鼠中U937白血病异种移植肿瘤的生长。这些结果表明，SKI-II可能作为一种有前景的抗AML药物进一步研究。
