title: Cardiotoxicity of the cancer therapeutic agent imatinib mesylate.
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.
authors.affiliation: Center for Translational Medicine, Jefferson Medical College, 1025 Walnut Street, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Risto
authors.initials: R
authors.lastname: Kerkelä
authors.forename: Luanda
authors.initials: L
authors.lastname: Grazette
authors.forename: Rinat
authors.initials: R
authors.lastname: Yacobi
authors.forename: Cezar
authors.initials: C
authors.lastname: Iliescu
authors.forename: Richard
authors.initials: R
authors.lastname: Patten
authors.forename: Cara
authors.initials: C
authors.lastname: Beahm
authors.forename: Brian
authors.initials: B
authors.lastname: Walters
authors.forename: Sergei
authors.initials: S
authors.lastname: Shevtsov
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Pesant
authors.forename: Fred J
authors.initials: FJ
authors.lastname: Clubb
authors.forename: Anthony
authors.initials: A
authors.lastname: Rosenzweig
authors.forename: Robert N
authors.initials: RN
authors.lastname: Salomon
authors.forename: Richard A
authors.initials: RA
authors.lastname: Van Etten
authors.forename: Joseph
authors.initials: J
authors.lastname: Alroy
authors.forename: Jean-Bernard
authors.initials: JB
authors.lastname: Durand
authors.forename: Thomas
authors.initials: T
authors.lastname: Force
mesh_terms: D000251:Adenosine Triphosphatases / Q000032:analysis / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology / Q000633:toxicity*; D001549:Benzamides; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D006333:Heart Failure / Q000139:chemically induced / Q000473:pathology*; D006801:Humans; D000068877:Imatinib Mesylate; D007274:Injections, Intraperitoneal; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology / Q000633:toxicity*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology / Q000633:toxicity*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D012720:Severity of Illness Index; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000503:physiopathology
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D045304:Cytochromes c; D000251:Adenosine Triphosphatases; D002118:Calcium