Cardiotoxicity of the anticancer therapeutic agent bortezomib

Dominika Nowis, Michał Ma̧czewski, Urszula Mackiewicz, Marek Kujawa, Anna Ratajska, Mariusz R. Wieckowski, Grzegorz M. Wilczyński, Monika Malinowska, Jacek Bil, Paweł Salwa, Marek Bugajski, Cezary Wójcik, Maciej Siński, Piotr Abramczyk, Magdalena Winiarska, Anna Da̧browska-Iwanicka, Jerzy Duszyński, Marek Jakóbisiak, Jakub Golab

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

Recent case reports provided alarming signals that treatment with bortezomib might be associated with cardiac events. In all reported cases, patients experiencing cardiac problems were previously or concomitantly treated with other chemotherapeutics including cardiotoxic anthracyclines. Therefore, it is difficult to distinguish which components of the therapeutic regimens contribute to cardiotoxicity. Here, we addressed the influence of bortezomib on cardiac function in rats that were not treated with other drugs. Rats were treated with bortezomib at a dose of 0.2 mg/kg thrice weekly. Echocardiography, histopathology, and electron microscopy were used to evaluate cardiac function and structural changes. Respiration of the rat heart mitochondria was measured polarographically. Cell culture experiments were used to determine the influence of bortezomib on cardiomyocyte survival, contractility, Ca2+ fluxes, induction of endoplasmic reticulum stress, and autophagy. Our findings indicate that bortezomib treatment leads to left ventricular contractile dysfunction manifested by a significant drop in left ventricle ejection fraction. Dramatic ultrastructural abnormalities of cardiomyocytes, especially within mitochondria, were accompanied by decreased ATP synthesis and decreased cardiomyocyte contractility. Monitoring of cardiac function in bortezomib-treated patients should be implemented to evaluate how frequently cardiotoxicity develops especially in patients with pre-existing cardiac conditions, as well as when using additional cardiotoxic drugs.

Original languageEnglish (US)
Pages (from-to)2658-2668
Number of pages11
JournalAmerican Journal of Pathology
Volume176
Issue number6
DOIs
StatePublished - Jun 2010

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Nowis, D., Ma̧czewski, M., Mackiewicz, U., Kujawa, M., Ratajska, A., Wieckowski, M. R., Wilczyński, G. M., Malinowska, M., Bil, J., Salwa, P., Bugajski, M., Wójcik, C., Siński, M., Abramczyk, P., Winiarska, M., Da̧browska-Iwanicka, A., Duszyński, J., Jakóbisiak, M., & Golab, J. (2010). Cardiotoxicity of the anticancer therapeutic agent bortezomib. American Journal of Pathology, 176(6), 2658-2668. https://doi.org/10.2353/ajpath.2010.090690