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

E. Bonhoure, D. Pchejetski, N. Aouali, H. Morjani, T. Levade, T. Kohama, Olivier Cuvillier*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

155 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)95-102
Number of pages8
JournalLeukemia
Volume20
Issue number1
DOIs
Publication statusPublished - Jan 2006
Externally publishedYes

Keywords

  • Acute myeloid leukemia
  • Apoptosis
  • Chemoresistance
  • Sphingolipids

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