Primary endothelial damage is the mechanism of cardiotoxicity of tubulin-binding drugs

Toxicological Sciences : an Official Journal of the Society of Toxicology
Igor MikaelianLaura Suter-Dick

Abstract

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 v...Continue Reading

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Citations

Jul 22, 2011·Toxicological Sciences : an Official Journal of the Society of Toxicology·Michael E DunnWanping Geng
Feb 12, 2014·Texas Heart Institute Journal·Ambuj RoyNagendra Boopathy Senguttuvan
Dec 19, 2015·Journal of Veterinary Internal Medicine·R Langhorn, J L Willesen
Mar 28, 2013·Toxicology and Applied Pharmacology·Palanivel GajalakshmiSuvro Chatterjee
Nov 8, 2012·Experimental and Toxicologic Pathology : Official Journal of the Gesellschaft Für Toxikologische Pathologie·Ryota TochinaiKimiyuki Kaneko
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May 18, 2016·Current Treatment Options in Cardiovascular Medicine·Umberto Campia, Ana Barac
Aug 26, 2016·Journal of Toxicologic Pathology·Ryota TochinaiMasayoshi Kuwahara
Sep 14, 2016·Journal of Toxicologic Pathology·Brian R BerridgeMonique Y Wells
Apr 29, 2014·Toxicologic Pathology·Kaïdre BendjamaPatrice Cacoub
Apr 30, 2014·Toxicologic Pathology·Igor MikaelianUNKNOWN Vascular Injury Working Group of the Predictive Safety Consortium
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