Abstract
Imatinib mesylate (Gleevec) is a small-molecule inhibitor of the fusion protein Bcr-Abl, the causal agent in chronic myelogenous leukemia. Here we report ten individuals who developed severe congestive heart failure while on imatinib and we show that imatinib-treated mice develop left ventricular contractile dysfunction. Transmission electron micrographs from humans and mice treated with imatinib show mitochondrial abnormalities and accumulation of membrane whorls in both vacuoles and the sarco- (endo-) plasmic reticulum, findings suggestive of a toxic myopathy. With imatinib treatment, cardiomyocytes in culture show activation of the endoplasmic reticulum (ER) stress response, collapse of the mitochondrial membrane potential, release of cytochrome c into the cytosol, reduction in cellular ATP content and cell death. Retroviral gene transfer of an imatinib-resistant mutant of c-Abl, alleviation of ER stress or inhibition of Jun amino-terminal kinases, which are activated as a consequence of ER stress, largely rescues cardiomyocytes from imatinib-induced death. Thus, cardiotoxicity is an unanticipated side effect of inhibition of c-Abl by imatinib.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphatases / analysis
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Adenosine Triphosphatases / metabolism
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / adverse effects*
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / toxicity*
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Benzamides
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Calcium / metabolism
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Cell Death / drug effects
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Cell Membrane Permeability / drug effects
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Cells, Cultured
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Cytochromes c / metabolism
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Dose-Response Relationship, Drug
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Echocardiography
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Heart Failure / chemically induced
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Heart Failure / pathology*
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Humans
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Imatinib Mesylate
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Injections, Intraperitoneal
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Membrane Potentials / drug effects
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Mice
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Mice, Inbred C57BL
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Mitochondria, Heart / drug effects
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Mitochondria, Heart / pathology
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Mitochondria, Heart / ultrastructure
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Mitochondrial Membranes / drug effects
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Myocytes, Cardiac / drug effects
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Myocytes, Cardiac / pathology
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Myocytes, Cardiac / ultrastructure
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Piperazines / administration & dosage
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Piperazines / adverse effects*
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Piperazines / pharmacology
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Piperazines / toxicity*
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Pyrimidines / administration & dosage
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Pyrimidines / adverse effects*
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Pyrimidines / pharmacology
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Pyrimidines / toxicity*
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Sarcoplasmic Reticulum / drug effects
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Sarcoplasmic Reticulum / pathology
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Sarcoplasmic Reticulum / ultrastructure
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Severity of Illness Index
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Time Factors
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Ventricular Dysfunction, Left / chemically induced
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Ventricular Dysfunction, Left / physiopathology
Substances
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Antineoplastic Agents
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Benzamides
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Piperazines
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Pyrimidines
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Imatinib Mesylate
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Cytochromes c
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Adenosine Triphosphatases
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Calcium