Nature Medicine
- 12, 908 - 916 (2006)
Published online: 23 July 2006; | doi:10.1038/nm1446
Cardiotoxicity of the cancer therapeutic agent imatinib mesylateRisto Kerkelä1, 2, Luanda Grazette3, Rinat Yacobi4, Cezar Iliescu5, Richard Patten2, Cara Beahm1, Brian Walters2, Sergei Shevtsov1, 2, Stéphanie Pesant1, Fred J Clubb6, Anthony Rosenzweig3, Robert N Salomon7, Richard A Van Etten4, Joseph Alroy7, 8, Jean-Bernard Durand5 & Thomas Force1, 21
Center for Translational Medicine, Jefferson Medical College, 1025 Walnut Street, Philadelphia, Pennsylvania 19107, USA. 2
The Molecular Cardiology Research Institute, Tufts–New England Medical Center and Tufts University School of Medicine, 750 Washington Street, Boston, Massachusetts 02111, USA. 3
Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA. 4
Molecular Oncology Research Institute, Tufts–New England Medical Center and Tufts University School of Medicine, 750 Washington Street, Boston, Massachusetts 02111, USA. 5
M.D. Anderson Cancer Center and The University of Texas, 1515 Holcombe Boulevard Houston, Texas 77030, USA. 6
Department of Cardiovascular Pathology, Texas Heart Institute, 6770 Bertner Avenue Houston, Texas 77030, USA. 7
Department of Pathology, Tufts–New England Medical Center and Tufts University School of Medicine, 750 Washington Street, Boston, Massachusetts 02111, USA. 8
Tufts Cummings School of Veterinary Medicine, 200 Westboro Road, North Grafton, Massachusetts 01536, USA.
Correspondence should be addressed to Thomas Force thomas.force@jefferson.edu 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.
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