title: Oestrogen enhances cardiotoxicity induced by Sunitinib by regulation of drug transport and metabolism.
abstract: OBJECTIVE
  To define the molecular mechanisms of cardiotoxicity induced by Sunitinib and to identify the role of biological sex in modulating toxicity.
  
  
  RESULTS
  Exposure of isolated cardiomyocytes to plasma-relevant concentrations of Sunitinib and other tyrosine kinase inhibitors produces a broad spectrum of abnormalities and cell death via apoptosis downstream of sexually dimorphic kinase inhibition. Phosphorylation of protein kinase C and phospholipase γ abrogates these effects for most tyrosine kinase inhibitors tested. Female sex and estradiol cause increased cardiotoxicity, which is mediated by reduced expression of a drug efflux transporter and a metabolic enzyme. Female but not male mice exposed to a 28-day course of oral Sunitinib exhibit similar abnormalities as well as functional deficits and their hearts exhibit differential expression of genes responsible for transport and metabolism of Sunitinib.
  
  
  CONCLUSIONS
  We identify the specific pathways affected by tyrosine kinase inhibitors in mammalian cardiomyocytes, interactions with biological sex, and a role for oestrogen in modulating drug efflux and metabolism. These findings represent a critical step toward reducing the incidence of cardiotoxicity with tyrosine kinase inhibitor chemotherapeutics.
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology & BioFrontiers Institute, University of Colorado at Boulder, Boulder, CO 80309, USA.
authors.forename: Pamela Ann
authors.initials: PA
authors.lastname: Harvey
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology & BioFrontiers Institute, University of Colorado at Boulder, Boulder, CO 80309, USA leslie.leinwand@colorado.edu.
authors.forename: Leslie Anne
authors.initials: LA
authors.lastname: Leinwand
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D066126:Cardiotoxicity; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D007211:Indoles / Q000633:toxicity*; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects*; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation; D011758:Pyrroles / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D000077210:Sunitinib; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004967:Estrogens; D007211:Indoles; D011758:Pyrroles; D010656:Phenylephrine; D019363:Cytochrome P-450 CYP1A1; D010738:Type C Phospholipases; D000077210:Sunitinib
keywords: Cardiotoxicity; Cytochrome P450; Multidrug-resistance-1; Oestrogen; Sunitinib