title: Doxorubicin-induced apoptosis: implications in cardiotoxicity.
abstract: In this review, we discuss the role of nitric oxide synthase in doxorubicin (DOX)-induced cardiomyopathy, a prominent side effect of DOX chemotherapy in cancer patients. It is becoming increasingly clear that apoptosis of myocardial cells plays a critical role in the onset of cardiomyopathy. DOX exposure to endothelial cells and cardiomyocytes caused apoptotic cell death at sub-micromolar concentrations. DOX-induced generation of H2O2 has been shown to be responsible for this drug's toxicity and apoptosis. H2O2 in turn enhanced endothelial nitric oxide synthase (eNOS) transcription in endothelial cells and myocytes. Antisense eNOS depressed DOX-induced oxidative stress and apoptosis. Redox-metal chelators inhibited DOX-induced apoptosis, clearly suggesting a role for reactive oxygen species in DOX-induced apoptosis. Here, we will focus on the role of eNOS expression, iron chelation, and iron signaling on DOX-mediated apoptosis.
authors.affiliation: Biophysics Research Institute and Free Radical Research Center, Medical College of Wisconsin, Milwaukee 53226, USA. balarama@mcw.edu
authors.forename: B
authors.initials: B
authors.lastname: Kalyanaraman
authors.forename: Joy
authors.initials: J
authors.lastname: Joseph
authors.forename: Shashi
authors.initials: S
authors.lastname: Kalivendi
authors.forename: Suwei
authors.initials: S
authors.lastname: Wang
authors.forename: Eugene
authors.initials: E
authors.lastname: Konorev
authors.forename: Srigiridhar
authors.initials: S
authors.lastname: Kotamraju
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000473:pathology*; D004317:Doxorubicin / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D017382:Reactive Oxygen Species; D004317:Doxorubicin; D006861:Hydrogen Peroxide; D007501:Iron; D019001:Nitric Oxide Synthase