Caspase-dependent and -independent cell death of Jurkat human leukemia cells induced by novel synthetic ceramide analogs

被引:40
作者
Granot, T
Milhas, D
Carpentier, S
Dagan, A
Ségui, B
Gatt, S
Levade, T
机构
[1] Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Biochem, IL-91010 Jerusalem, Israel
[2] CHU Rangueil, INSERM, U466, F-31054 Toulouse, France
[3] CHU Rangueil, Biochim Lab, F-31054 Toulouse, France
基金
以色列科学基金会;
关键词
ceramide; apoptosis; sphingolipid; Bcl-xL; leukemia; anticancer drug;
D O I
10.1038/sj.leu.2404084
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Ceramide metabolism has emerged as a potential target for anticancer therapy. Here, the potential usefulness of two novel synthetic ceramide analogs as anti-leukemic drugs was investigated. Compounds AD2646 and AD2687 were able to dose-and time-dependently decrease the viability of Jurkat leukemic cells. This was accompanied by an accumulation of endogenous ceramide owing to perturbed ceramide metabolism. Cytotoxicity involved caspase activation but also necrotic-like features, as evidenced by phosphatidylserine externalization, membrane permeability, hypodiploidy, caspase processing and only partial protection from cell death by a pan-caspase inhibitor. Ceramide analogs also induced cell death in Jurkat mutants that are deficient in cell death signaling proteins, including FADD, caspase-8 and 10, and RIP. While overexpression of Bcl-xL did not suppress ceramide accumulation, it conferred robust protection from caspase activation and cell death. Altogether, these novel ceramide analogs are able to kill leukemic cells through distinct pathways implicating caspase activation and mitochondrial events, and represent a new group of bioactive molecules with potential applications in anticancer therapy.
引用
收藏
页码:392 / 399
页数:8
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