TY - JOUR
T1 - Cardiotoxicity of the anticancer therapeutic agent bortezomib
AU - Nowis, Dominika
AU - Ma̧czewski, Michał
AU - Mackiewicz, Urszula
AU - Kujawa, Marek
AU - Ratajska, Anna
AU - Wieckowski, Mariusz R.
AU - Wilczyński, Grzegorz M.
AU - Malinowska, Monika
AU - Bil, Jacek
AU - Salwa, Paweł
AU - Bugajski, Marek
AU - Wójcik, Cezary
AU - Siński, Maciej
AU - Abramczyk, Piotr
AU - Winiarska, Magdalena
AU - Da̧browska-Iwanicka, Anna
AU - Duszyński, Jerzy
AU - Jakóbisiak, Marek
AU - Golab, Jakub
N1 - Funding Information:
Supported by grants from the Ministry of Science and Higher Education in Poland [N401 3240 33 to D.N., N301 092 32/3407 to M.W., and N40112331/2736 to J.G], the Medical University of Warsaw [1M19/N and 1M19/WB1/07 to M.J.], and an institutional appropriation of the American Cancer Society grant [IRG-84–002-22 to C.W.]. M.W., is also supported by the Polish Mitochondrial Network. J.G., J.B., and M.B. are recipients of the Mistrz Award from the Foundation for Polish Science. M.W. is a recipient of the START Award from the Foundation for Polish Science.
PY - 2010/6
Y1 - 2010/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=77953217057&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77953217057&partnerID=8YFLogxK
U2 - 10.2353/ajpath.2010.090690
DO - 10.2353/ajpath.2010.090690
M3 - Article
C2 - 20519734
AN - SCOPUS:77953217057
SN - 0002-9440
VL - 176
SP - 2658
EP - 2668
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 6
ER -