Article

Kerkelä, R. et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat. Med. 12, 908-916

Center for Translational Medicine, Jefferson Medical College, 1025 Walnut Street, Philadelphia, Pennsylvania 19107, USA.
Nature Medicine (Impact Factor: 27.36). 09/2006; 12(8):908-16. DOI: 10.1038/nm1446
Source: PubMed

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.

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    • "Protein kinases are often classified into different groups or subfamilies, but yet their entire super-family experiences a high degree of structural conservation. Structural similarity often makes them confusing to an inhibitor drug and thus, causes toxic side effects (Kerkela et al., 2006 "
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    • "Numerous heart diseases are related to increases in MPTP activators such as calcium and oxidative stress and reductions in MPTP inhibitors such as ATP/ADP. Several studies have demonstrated that inhibition of the MPTP pore lessens the cardiomyocyte loss that underlies some cardiac pathologies including myocardial ischemia/reperfusion (IR) injury,57,58 calcium-induced cardiomyopathy,59 diabetic cardiomyopathy,60 and the cardiotoxicity of anti-cancer drugs.61 "
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