title: NADPH oxidases participate to doxorubicin-induced cardiac myocyte apoptosis.
abstract: Cumulative doses of doxorubicin, a potent anticancer drug, lead to serious myocardial dysfunction. Numerous mechanisms including apoptosis have been proposed to account for its cardiotoxicity. Cardiac apoptosis induced by doxorubicin has been related to excessive reactive oxygen species production by the mitochondrial NADH dehydrogenase. Here, we explored whether doxorubicin treatment activates other superoxide anion generating systems such as the NADPH oxidases, membrane-embedded flavin-containing enzymes, and whether the subsequent oxidative stress contributes to apoptosis. We showed that doxorubicin treatment of rat cardiomyoblasts H9c2 triggers increases in caspase-3 like activity and hypoploid cells, both common features of apoptosis. Doxorubicin exposure also leads to a rapid superoxide production through NADPH oxidase activation. Inhibition of these enzymes using diphenyliodonium and apocynin reduces doxorubicin-induced reactive oxygen species production, caspase-3 like activity and sub-G1 cell population. In conclusion, NADPH oxidases participate to doxorubicin-induced cardiac apoptosis.
authors.affiliation: EA 2689, CHRU and Université de Lille 2, IFR 114 IMPRT, Lille 59045, France.
authors.forename: Mylène
authors.initials: M
authors.lastname: Gilleron
authors.forename: Xavier
authors.initials: X
authors.lastname: Marechal
authors.forename: David
authors.initials: D
authors.lastname: Montaigne
authors.forename: Jessica
authors.initials: J
authors.lastname: Franczak
authors.forename: Remi
authors.initials: R
authors.lastname: Neviere
authors.forename: Steve
authors.initials: S
authors.lastname: Lancel
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D004317:Doxorubicin / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D032386:Myoblasts, Cardiac / Q000187:drug effects / Q000201:enzymology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology; D019255:NADPH Oxidases / Q000096:biosynthesis*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D019255:NADPH Oxidases