Mcl-1 down-regulation potentiates ABT-737 lethality by cooperatively inducing Bak activation and Bax translocation

Cancer Res. 2007 Jan 15;67(2):782-91. doi: 10.1158/0008-5472.CAN-06-3964.


The Bcl-2 antagonist ABT-737 targets Bcl-2/Bcl-xL but not Mcl-1, which may confer resistance to this novel agent. Here, we show that Mcl-1 down-regulation by the cyclin-dependent kinase (CDK) inhibitor roscovitine or Mcl-1-shRNA dramatically increases ABT-737 lethality in human leukemia cells. ABT-737 induces Bax conformational change but fails to activate Bak or trigger Bax translocation. Coadministration of roscovitine and ABT-737 untethers Bak from Mcl-1 and Bcl-xL, respectively, triggering Bak activation and Bax translocation. Studies employing Bax and/or Bak knockout mouse embryonic fibroblasts (MEFs) confirm that Bax is required for ABT-737+/-roscovitine lethality, whereas Bak is primarily involved in potentiation of ABT-737-induced apoptosis by Mcl-1 down-regulation. Ectopic Mcl-1 expression attenuates Bak activation and apoptosis by ABT-737+roscovitine, whereas cells overexpressing Bcl-2 or Bcl-xL remain fully sensitive. Finally, Mcl-1 knockout MEFs are extremely sensitive to Bak conformational change and apoptosis induced by ABT-737, effects that are not potentiated by roscovitine. Collectively, these findings suggest down-regulation of Mcl-1 by either CDK inhibitors or genetic approaches dramatically potentiate ABT-737 lethality through cooperative interactions at two distinct levels: unleashing of Bak from both Bcl-xL and Mcl-1 and simultaneous induction of Bak activation and Bax translocation. These findings provide a mechanistic basis for simultaneously targeting Mcl-1 and Bcl-2/Bcl-xL in leukemia.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis / drug effects
  • Biphenyl Compounds / administration & dosage
  • Biphenyl Compounds / pharmacology*
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • Down-Regulation / drug effects
  • Drug Synergism
  • HL-60 Cells
  • Humans
  • Jurkat Cells
  • Leukemia / drug therapy*
  • Leukemia / genetics
  • Leukemia / metabolism
  • Mice
  • Mice, Knockout
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Nitrophenols / administration & dosage
  • Nitrophenols / pharmacology*
  • Piperazines / administration & dosage
  • Piperazines / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Purines / administration & dosage
  • Purines / pharmacology*
  • RNA Interference
  • Roscovitine
  • Sulfonamides / administration & dosage
  • Sulfonamides / pharmacology*
  • U937 Cells
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism*
  • bcl-2-Associated X Protein / metabolism*
  • bcl-X Protein / metabolism


  • ABT-737
  • BAK1 protein, human
  • BAX protein, human
  • BCL2L1 protein, human
  • Biphenyl Compounds
  • Mcl1 protein, mouse
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Nitrophenols
  • Piperazines
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • Purines
  • Sulfonamides
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • bcl-X Protein
  • Roscovitine
  • Cyclin-Dependent Kinases