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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.

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Figure 1: Imatinib is cardiotoxic in humans.
Figure 2: Imatinib is cardiotoxic in mice.
Figure 3: Effect of imatinib treatment on mitochondrial function and on mediators and markers of apoptosis.
Figure 4: Effect of imatinib on characteristics of necrotic cell death.
Figure 5: Signaling pathways regulating imatinib-induced cell death.

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Acknowledgements

We thank J. Molkentin, C. Baines and M. Venkatachalam for advice. This work was supported by a grant from the National Heart Lung and Blood Institute (HL67371 to T.F.) and a Specialized Center of Research grant from the Leukemia and Lymphoma Society (to R.A.V.) and grants from the Finnish Heart Foundation and the Paavo Nurmi Foundation (to R.K.).

Author information

Authors and Affiliations

Authors

Contributions

R.K. performed cell-culture studies, animal studies, generated figures, and helped design the study and write the manuscript. L.G. performed ATP and ADP assays, caspase 3/7 activity assays, Bax translocation and multimerization studies. R.Y. generated retroviruses. C.I. collected patient data. R.P. assisted with performance and analysis of echocardiographic studies. C.B., B.W. and S.S. assisted with cell-culture studies. S.P. assisted with histological studies. F.J.C. analyzed electron micrographs of patient biopsies. A.R. provided expertise for apoptosis studies. R.N.S. provided expertise for histological studies. R.A.V. generated retroviruses, provided expertise on c-Abl, and helped write and edit the manuscript. J.A. analyzed electron micrographs of mouse hearts. J.-B.D. enrolled participants, analyzed patient data and contributed to study design. T.F. (principal investigator) designed studies, interpretated and analyzed data, and drafted and edited the manuscript.

Note: Supplementary information is available on the Nature Medicine website.

Corresponding author

Correspondence to Thomas Force.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Imatinib leads to the upregulation and cleavage of PKCδ. (PDF 2764 kb)

Supplementary Fig. 2

Imatinib activates JNK pathway in vivo. (PDF 1302 kb)

Supplementary Fig. 3

Inhibition of JNKs does not reduce activation of the ER stress response. (PDF 892 kb)

Supplementary Table 1

Clinical characteristics of patients with imatinib-associated heart failure. (PDF 25 kb)

Supplementary Methods (PDF 48 kb)

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Kerkelä, R., Grazette, L., Yacobi, R. et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 12, 908–916 (2006). https://doi.org/10.1038/nm1446

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