Cardiotoxicity of the anticancer therapeutic agent bortezomib.
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, Ca(2+) 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.
Nowis
Dominika
D
Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, 1A Banacha Str., F Building, 02-097 Warsaw, Poland.
Maczewski
Michał
M
Mackiewicz
Urszula
U
Kujawa
Marek
M
Ratajska
Anna
A
Wieckowski
Mariusz R
MR
Wilczyński
Grzegorz M
GM
Malinowska
Monika
M
Bil
Jacek
J
Salwa
Pawel
P
Bugajski
Marek
M
Wójcik
Cezary
C
Siński
Maciej
M
Abramczyk
Piotr
P
Winiarska
Magdalena
M
Dabrowska-Iwanicka
Anna
A
Duszyński
Jerzy
J
Jakóbisiak
Marek
M
Golab
Jakub
J
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000633:toxicity*; D001897:Boronic Acids / Q000494:pharmacology / Q000633:toxicity*; D000069286:Bortezomib; D002460:Cell Line; D019069:Cell Respiration / Q000187:drug effects; D004452:Echocardiography; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006331:Heart Diseases / Q000139:chemically induced*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology / Q000633:toxicity; D011719:Pyrazines / Q000494:pharmacology / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib