Cardiotoxicity of the cancer therapeutic agent imatinib mesylate.
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.
Kerkelä
Risto
R
Center for Translational Medicine, Jefferson Medical College, 1025 Walnut Street, Philadelphia, Pennsylvania 19107, USA.
Grazette
Luanda
L
Yacobi
Rinat
R
Iliescu
Cezar
C
Patten
Richard
R
Beahm
Cara
C
Walters
Brian
B
Shevtsov
Sergei
S
Pesant
Stéphanie
S
Clubb
Fred J
FJ
Rosenzweig
Anthony
A
Salomon
Robert N
RN
Van Etten
Richard A
RA
Alroy
Joseph
J
Durand
Jean-Bernard
JB
Force
Thomas
T
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
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D045304:Cytochromes c; D000251:Adenosine Triphosphatases; D002118:Calcium