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 Wojcik, Maciej Siński, Piotr Abramczyk, Magdalena Winiarska, Anna Da̧browska-Iwanicka, Jerzy Duszyński, Marek Jakóbisiak, Jakub Golab

Research output: Contribution to journalArticle

73 Citations (Scopus)

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 - 2010
Externally publishedYes

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Antineoplastic Agents
Cardiac Myocytes
Therapeutics
Heart Mitochondria
Preexisting Condition Coverage
Endoplasmic Reticulum Stress
Anthracyclines
Autophagy
Left Ventricular Dysfunction
Pharmaceutical Preparations
Heart Ventricles
Echocardiography
Cardiotoxicity
Bortezomib
Electron Microscopy
Mitochondria
Respiration
Cell Culture Techniques
Adenosine Triphosphate

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Medicine(all)

Cite this

Nowis, D., Ma̧czewski, M., Mackiewicz, U., Kujawa, M., Ratajska, A., Wieckowski, M. R., ... 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

Cardiotoxicity of the anticancer therapeutic agent bortezomib. / Nowis, Dominika; Ma̧czewski, Michał; Mackiewicz, Urszula; Kujawa, Marek; Ratajska, Anna; Wieckowski, Mariusz R.; Wilczyński, Grzegorz M.; Malinowska, Monika; Bil, Jacek; Salwa, Paweł; Bugajski, Marek; Wojcik, Cezary; Siński, Maciej; Abramczyk, Piotr; Winiarska, Magdalena; Da̧browska-Iwanicka, Anna; Duszyński, Jerzy; Jakóbisiak, Marek; Golab, Jakub.

In: American Journal of Pathology, Vol. 176, No. 6, 2010, p. 2658-2668.

Research output: Contribution to journalArticle

Nowis, D, Ma̧czewski, M, Mackiewicz, U, Kujawa, M, Ratajska, A, Wieckowski, MR, Wilczyński, GM, Malinowska, M, Bil, J, Salwa, P, Bugajski, M, Wojcik, 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, vol. 176, no. 6, pp. 2658-2668. https://doi.org/10.2353/ajpath.2010.090690
Nowis D, Ma̧czewski M, Mackiewicz U, Kujawa M, Ratajska A, Wieckowski MR et al. Cardiotoxicity of the anticancer therapeutic agent bortezomib. American Journal of Pathology. 2010;176(6):2658-2668. https://doi.org/10.2353/ajpath.2010.090690
Nowis, Dominika ; Ma̧czewski, Michał ; Mackiewicz, Urszula ; Kujawa, Marek ; Ratajska, Anna ; Wieckowski, Mariusz R. ; Wilczyński, Grzegorz M. ; Malinowska, Monika ; Bil, Jacek ; Salwa, Paweł ; Bugajski, Marek ; Wojcik, Cezary ; Siński, Maciej ; Abramczyk, Piotr ; Winiarska, Magdalena ; Da̧browska-Iwanicka, Anna ; Duszyński, Jerzy ; Jakóbisiak, Marek ; Golab, Jakub. / Cardiotoxicity of the anticancer therapeutic agent bortezomib. In: American Journal of Pathology. 2010 ; Vol. 176, No. 6. pp. 2658-2668.
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