Overcoming MDR-associated chemoresistance in HL-60 acute myeloid leukemia cells by targeting shingosine kinase-1

被引：0
作者：
E Bonhoure
D Pchejetski
N Aouali
H Morjani
T Levade
T Kohama
O Cuvillier
机构：
[1] Inserm,Department of Cancer Genetics
[2] U466,undefined
[3] CNRS,undefined
[4] UMR 6142,undefined
[5] Université de Reims Champagne-Ardennes,undefined
[6] UFR de Pharmacie,undefined
[7] IFR33,undefined
[8] Université de Reims Champagne-Andrennes,undefined
[9] UFR de Pharmacie,undefined
[10] IFR33,undefined
[11] JE2428 Onco-Pharamcologie,undefined
[12] Sankyo Co. Ltd,undefined
[13] Pharmacology and Molecular Biology Research Laboratories,undefined
[14] Research Group I,undefined
[15] Roswell Park Center Institute,undefined
来源：
Leukemia | 2006年 / 20卷
关键词：
acute myeloid leukemia; sphingolipids; chemoresistance; apoptosis;
D O I：
暂无
中图分类号：
学科分类号：
摘要：
We examined the involvement of sphingosine kinase-1, a critical regulator of the sphingolipid balance, in susceptibility to antineoplastic agents of either sensitive or multidrug-resistant acute myeloid leukemia cells. Contrary to parental HL-60 cells, doxorubicin and etoposide failed to trigger apoptosis in chemoresistant HL-60/Doxo and HL-60/VP16 cells overexpressing MRP1 and MDR1, respectively. Chemosensitive HL-60 cells displayed sphingosine kinase-1 inhibition coupled with ceramide generation. In contrast, chemoresistant HL-60/Doxo and HL-60/VP16 had sustained sphingosine kinase-1 activity and did not produce ceramide during treatment. Enforced expression of sphingosine kinase-1 in chemosensitive HL-60 cells resulted in marked inhibition of apoptosis that was mediated by blockade of mitochondrial cytochrome c efflux hence suggesting a control of apoptosis at the premitochondrial level. Incubation with cell-permeable ceramide of chemoresistant cells led to a sphingosine kinase-1 inhibition and apoptosis both prevented by sphingosine kinase-1 overexpression. Furthermore, F-12509a, a new sphingosine kinase inhibitor, led to ceramide accumulation, decrease in sphingosine 1-phosphate content and caused apoptosis equally in chemosensitive and chemoresistant cell lines that is inhibited by adding sphingosine 1-phosphate or overexpressing sphingosine kinase-1. F-12509a induced classical apoptosis hallmarks namely nuclear fragmentation, caspase-3 cleavage as well as downregulation of antiapoptotic XIAP, and release of cytochrome c and SMAC/Diablo.
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页码：95 / 102
页数：7
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