Resistance of acute myeloid leukemic cells to the triterpenoid CDDO-Imidazolide is associated with low caspase-8 and FADD levels

Leuk Res. 2008 Aug;32(8):1244-58. doi: 10.1016/j.leukres.2007.12.008. Epub 2008 Mar 4.

Abstract

The synthetic triterpenoid CDDO-Im-induced apoptosis of patient-derived AML blasts: 11/25 AMLs were highly sensitive, while the remaining were moderately sensitive to CDDO-Im. The addition of TRAIL significantly potentiated the cytotoxic effect of CDDO-Im, through mechanisms involving the induction of TRAIL-R1/TRAIL-R2 and downmodulation of TRAIL-R3/TRAIL-R4. Biochemical studies showed that CDDO-Im: induced a rapid and marked GSH depletion and antioxidants (GSH or NAC) completely inhibited its pro-apoptotic effect; sequentially activated caspase-8, -9 and -3; caspase inhibitors partially protected AML blasts from CDDO-Im-induced apoptosis; resistance of AML blasts to CDDO-Im-induced apoptosis correlated with low caspase-8/FADD and high Bcl-X(L) expression in leukemic blasts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Caspase 8 / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm
  • Enzyme Activation
  • Fas-Associated Death Domain Protein / metabolism*
  • Humans
  • Imidazoles / pharmacology*
  • Leukemia, Myeloid, Acute / drug therapy*
  • Oleanolic Acid / analogs & derivatives*
  • Oleanolic Acid / pharmacology
  • TNF-Related Apoptosis-Inducing Ligand / analysis
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology
  • Tumor Cells, Cultured

Substances

  • 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole
  • Fas-Associated Death Domain Protein
  • Imidazoles
  • TNF-Related Apoptosis-Inducing Ligand
  • Oleanolic Acid
  • Caspase 8