Mechanisms of Apoptosis Sensitivity and Resistance to the BH3 Mimetic ABT-737 in Acute Myeloid Leukemia

Cancer Cell. 2006 Nov;10(5):375-88. doi: 10.1016/j.ccr.2006.10.006.

Abstract

BCL-2 proteins are critical for cell survival and are overexpressed in many tumors. ABT-737 is a small-molecule BH3 mimetic that exhibits single-agent activity against lymphoma and small-cell lung cancer in preclinical studies. We here report that ABT-737 effectively kills acute myeloid leukemia blast, progenitor, and stem cells without affecting normal hematopoietic cells. ABT-737 induced the disruption of the BCL-2/BAX complex and BAK-dependent but BIM-independent activation of the intrinsic apoptotic pathway. In cells with phosphorylated BCL-2 or increased MCL-1, ABT-737 was inactive. Inhibition of BCL-2 phosphorylation and reduction of MCL-1 expression restored sensitivity to ABT-737. These data suggest that ABT-737 could be a highly effective antileukemia agent when the mechanisms of resistance identified here are considered.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Biphenyl Compounds* / metabolism
  • Biphenyl Compounds* / therapeutic use
  • Cell Line
  • Dimerization
  • Drug Resistance, Neoplasm / physiology*
  • Hematopoietic Stem Cells / physiology
  • Humans
  • Leukemia, Myeloid, Acute* / drug therapy
  • Leukemia, Myeloid, Acute* / metabolism
  • Mice
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins / metabolism
  • Nitrophenols* / metabolism
  • Nitrophenols* / therapeutic use
  • Piperazines / metabolism
  • Piperazines / therapeutic use
  • Protein Conformation
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / chemistry
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Sulfonamides* / metabolism
  • Sulfonamides* / therapeutic use
  • bcl-2 Homologous Antagonist-Killer Protein / genetics
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism
  • bcl-2-Associated X Protein / chemistry
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism

Substances

  • ABT-737
  • Biphenyl Compounds
  • Mcl1 protein, mouse
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Nitrophenols
  • Piperazines
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Small Interfering
  • Recombinant Fusion Proteins
  • Sulfonamides
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein