Journal Article

Primary Endothelial Damage Is the Mechanism of Cardiotoxicity of Tubulin-Binding Drugs

Igor Mikaelian, Andreas Buness, Maria-Cristina de Vera-Mudry, Charu Kanwal, Denise Coluccio, Erik Rasmussen, Hing W. Char, Valerie Carvajal, Holly Hilton, Juergen Funk, Jean-Christophe Hoflack, Mark Fielden, Frank Herting, Michael Dunn and Laura Suter-Dick

in Toxicological Sciences

Volume 117, issue 1, pages 144-151
Published in print September 2010 | ISSN: 1096-6080
Published online July 2010 | e-ISSN: 1096-0929 | DOI:
Primary Endothelial Damage Is the Mechanism of Cardiotoxicity of Tubulin-Binding Drugs

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The use of tubulin binders (TBs) in the treatment of cancer often is associated with cardiotoxicity, the mechanism of which has not been elucidated. To test the hypothesis that interstitial cells of the myocardium are the primary target of TBs, we evaluated the acute effects of a single iv administration of three reference TBs: colchicine (0.2 and 2 mg/kg), vinblastine (0.5 and 3 mg/kg), and vincristine (0.1 and 1 mg/kg) 6 and 24 h after dosing. Mitotic arrest was identified at 24 h in all high-dose groups based on an increase in the number of mitotic figures in the interstitium coupled with a decrease in the number of Ki67-positive interstitial cells. Analysis of the myocardial transcriptomic data further supported G2/M cell cycle arrest 6 h after dosing with the high-dose groups of all three compounds. Apoptotic figures and an increase in the number of cleaved caspase 3–positive cells were identified at 6 and 24 h at the highest dose of each compound predominantly in interstitial cells, whereas a few cardiomyocytes were affected as well. Transcriptomic profiling of the myocardium further suggested that some of the affected interstitial cells were endothelial cells based on the upregulation of genes typically associated with vascular damage and downregulation of endothelial cell-specific molecule 1 and apelin. Taken together, these data identify endothelial cells of the myocardium as the primary target of the cardiotoxicity of TBs and identify cell cycle arrest as the mechanism of this toxicity.

Keywords: heart; cardiotoxicity; cardiac; endothelium; pathogenesis; microtubule

Journal Article.  4329 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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