title: Mitochondrial translocator protein (TSPO) ligands prevent doxorubicin-induced mechanical dysfunction and cell death in isolated cardiomyocytes.
abstract: Contractile dysfunction and subsequent development of cardiomyopathies are well known limiting factors in the treatment of cancer with doxorubicin and have been linked to mitochondrial dysfunction. Here, using adult isolated paced cardiomyocytes, we have demonstrated that ligands of translocator protein (TSPO) 4'-chlorodiazepam and TRO40303 prevented the doxorubicin-induced alterations in contractility and improved cardiomyocyte viability. This cardioprotective effect was closely associated with both a potent reduction in reactive oxygen species production and inhibition of mitochondrial permeability transition pore opening. Thus, preventive administration of TSPO ligands may represent a novel pharmacological strategy to protect the heart during doxorubicin treatment.
authors.affiliation: INSERM U955, équipe 3, Créteil F-94010, France; Université Paris-Est, Faculté de Médecine, Créteil F-94010, France; Institut Supérieur des BioSciences, Faculté de Médecine, Créteil F-94010, France.
authors.forename: Alexandra d'Anglemont
authors.initials: Ad
authors.lastname: de Tassigny
authors.forename: Rana
authors.initials: R
authors.lastname: Assaly
authors.forename: Sophie
authors.initials: S
authors.lastname: Schaller
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Pruss
authors.forename: Alain
authors.initials: A
authors.lastname: Berdeaux
authors.forename: Didier
authors.initials: D
authors.lastname: Morin
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects*; D004317:Doxorubicin / Q000494:pharmacology*; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D008024:Ligands; D017382:Reactive Oxygen Species; D004317:Doxorubicin
keywords: 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid; 2,7-dichlorodihydrofluorescein-diacetate; 4′-chlorodiazepam; BAPTA; CDZ; Cardiomyocytes; CoCl(2); CsA; DCF; DCFH-DA; Doxorubicin; IMAC; Mitochondria; OH; PI; Permeability transition pore; ROS; TSPO; TSPO ligands; cobalt chloride; cyclosporin A; dichlorofluorescein; hydroxyl radical; inner membrane anion channel; mPTP; mitochondrial permeability transition pore; propidium iodide; reactive oxygen species; translocator protein