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

Leukemia. 2006 Jan;20(1):95-102. doi: 10.1038/sj.leu.2404023.

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-60NP16 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 pre-mitochondrial level. Incubation with cell-permeable ceramide of chemoresistant cells led to a sphingosine kinase-1 inhibition and apoptosis both prevented by sphingosine kinase-1 over-expression. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Apoptosis / drug effects
  • Benzoquinones / pharmacology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Ceramides / biosynthesis
  • Doxorubicin / pharmacology
  • Drug Resistance, Multiple*
  • Drug Resistance, Neoplasm
  • Etoposide / pharmacology
  • HL-60 Cells
  • Humans
  • Leukemia, Myeloid / drug therapy
  • Leukemia, Myeloid / metabolism*
  • Mitochondria / drug effects
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Phosphotransferases (Alcohol Group Acceptor) / pharmacology
  • RNA Interference / physiology
  • Receptors, Lysosphingolipid / metabolism

Substances

  • Benzoquinones
  • Ceramides
  • F 12509A
  • Receptors, Lysosphingolipid
  • Etoposide
  • Doxorubicin
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase