Abstract
Cell killing is a critical pharmacological activity of imatinib to eradicate Bcr/Abl+ leukemias. We found that imatinib kills Bcr/Abl+ leukemic cells by triggering the Bcl-2-regulated apoptotic pathway. Imatinib activated several proapoptotic BH3-only proteins: bim and bmf transcription was increased, and both Bim and Bad were activated posttranslationally. Studies using RNAi and cells from gene-targeted mice revealed that Bim plays a major role in imatinib-induced apoptosis of Bcr/Abl+ leukemic cells and that the combined loss of Bim and Bad abrogates this killing. Loss of Bmf or Puma had no effect. Resistance to imatinib caused by Bcl-2 overexpression or loss of Bim (plus Bad) could be overcome by cotreatment with the BH3 mimetic ABT-737. These results demonstrate that Bim and Bad account for most, perhaps all, imatinib-induced killing of Bcr/Abl+ leukemic cells and suggest previously undescribed drug combination strategies for cancer therapy.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antineoplastic Agents / pharmacology
-
Apoptosis / drug effects
-
Apoptosis Regulatory Proteins / genetics
-
Apoptosis Regulatory Proteins / metabolism*
-
Bcl-2-Like Protein 11
-
Benzamides
-
Biphenyl Compounds / pharmacology*
-
Cell Line, Tumor
-
Cell Transformation, Neoplastic
-
Cytotoxicity, Immunologic / drug effects*
-
Drug Resistance, Neoplasm*
-
Fetus / cytology
-
Fusion Proteins, bcr-abl
-
Humans
-
Imatinib Mesylate
-
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
-
Liver / cytology
-
Membrane Proteins / genetics
-
Membrane Proteins / metabolism*
-
Mice
-
Myeloid Progenitor Cells / cytology
-
Nitrophenols
-
Piperazines / pharmacology*
-
Protein-Tyrosine Kinases / metabolism*
-
Proto-Oncogene Proteins / genetics
-
Proto-Oncogene Proteins / metabolism*
-
Proto-Oncogene Proteins c-bcl-2 / metabolism
-
Pyrimidines / pharmacology*
-
Sulfonamides
-
bcl-Associated Death Protein / metabolism*
Substances
-
ABT-737
-
Antineoplastic Agents
-
Apoptosis Regulatory Proteins
-
BCL2L11 protein, human
-
Bcl-2-Like Protein 11
-
Bcl2l11 protein, mouse
-
Benzamides
-
Biphenyl Compounds
-
Membrane Proteins
-
Nitrophenols
-
Piperazines
-
Proto-Oncogene Proteins
-
Proto-Oncogene Proteins c-bcl-2
-
Pyrimidines
-
Sulfonamides
-
bcl-Associated Death Protein
-
Imatinib Mesylate
-
Protein-Tyrosine Kinases
-
Fusion Proteins, bcr-abl