title: Primary endothelial damage is the mechanism of cardiotoxicity of tubulin-binding drugs.
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 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.
authors.affiliation: Non-Clinical Safety, Bldg 100/310, Hoffmann-La Roche, Inc., Nutley, New Jersey 07110, USA. igor.mikaelian@roche.com
authors.forename: Igor
authors.initials: I
authors.lastname: Mikaelian
authors.forename: Andreas
authors.initials: A
authors.lastname: Buness
authors.forename: Maria-Cristina
authors.initials: MC
authors.lastname: de Vera-Mudry
authors.forename: Charu
authors.initials: C
authors.lastname: Kanwal
authors.forename: Denise
authors.initials: D
authors.lastname: Coluccio
authors.forename: Erik
authors.initials: E
authors.lastname: Rasmussen
authors.forename: Hing W
authors.initials: HW
authors.lastname: Char
authors.forename: Valerie
authors.initials: V
authors.lastname: Carvajal
authors.forename: Holly
authors.initials: H
authors.lastname: Hilton
authors.forename: Juergen
authors.initials: J
authors.lastname: Funk
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Hoflack
authors.forename: Mark
authors.initials: M
authors.lastname: Fielden
authors.forename: Frank
authors.initials: F
authors.lastname: Herting
authors.forename: Michael
authors.initials: M
authors.lastname: Dunn
authors.forename: Laura
authors.initials: L
authors.lastname: Suter-Dick
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000633:toxicity*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D020869:Gene Expression Profiling; D006321:Heart / Q000187:drug effects*; D007150:Immunohistochemistry; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014404:Tubulin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D014404:Tubulin