title: Vesnarinone causes oxidative damage by inhibiting catalase function through ceramide action in myeloid cell apoptosis.
abstract: Vesnarinone is an effective inotropic agent for treating congestive heart failure, but its clinical usage is restricted because of the severe side effect of agranulocytosis. In myeloid HL-60 cells, vesnarinone increased the intracellular content of a proapoptotic lipid mediator, ceramide, in a time- and dose-dependent manner. Vesnarinone-induced apoptosis was significantly enhanced by simultaneous treatment with a cell-permeable N-acetyl sphingosine (C2-ceramide). Treatment with neither vesnarinone, C2-ceramide, nor simultaneously with vesnarinone and C2-ceramide caused a marked increase of reactive oxygen intermediates (ROI) generation measured by the 2',7'-dichlorofluorescin method. However, oxidative damage judged by the production of lipid peroxidates and the nitroblue tetrazolium-reducing ability were enhanced more significantly by simultaneous treatment with vesnarinone and C2-ceramide than by vesnarinone alone. Moreover, vesnarinone inhibited catalase function both at the protein and activity level, and this inhibition was synergistically enhanced by C2-ceramide, and vesnarinone-induced oxidative damage and apoptosis were significantly suppressed by treatment of HL-60 cells with purified catalase. C2-ceramide enhanced vesnarinone-induced inhibition of the ROI-scavenging enzyme catalase at the levels of protein and activity in HL-60 cells; in contrast, however, vesnarinone did not induce ceramide generation, oxidative damage, or catalase depletion in HL-60/ves cells, where vesnarinone could not induce apoptosis. Taken together, the results suggest that vesnarinone induces myeloid cell apoptosis by increasing oxidative damage via ceramide-induced inhibition of catalase function.
authors.affiliation: Department of Hematology and Oncology, Clinical Sciences for Pathological Organs, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Tadakazu
authors.initials: T
authors.lastname: Kondo
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kitano
authors.forename: Kazuya
authors.initials: K
authors.lastname: Iwai
authors.forename: Mitsumasa
authors.initials: M
authors.lastname: Watanabe
authors.forename: Hisanori
authors.initials: H
authors.lastname: Umehara
authors.forename: Naoharu
authors.initials: N
authors.lastname: Daido
authors.forename: Naochika
authors.initials: N
authors.lastname: Domae
authors.forename: Masaro
authors.initials: M
authors.lastname: Tashima
authors.forename: Takashi
authors.initials: T
authors.lastname: Uchiyama
authors.forename: Toshiro
authors.initials: T
authors.lastname: Okazaki
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002374:Catalase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D018384:Oxidative Stress; D011719:Pyrazines; D011804:Quinolines / Q000494:pharmacology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002518:Ceramides; D004791:Enzyme Inhibitors; C064769:N-acetylsphingosine; D011719:Pyrazines; D011804:Quinolines; C041667:vesnarinone; D002374:Catalase; D013110:Sphingosine