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Caspase activation is accelerated by the inhibition of arsenite-induced, membrane rafts-dependent Akt activation.
Hossain, Khaled; Akhand, Anwarul A; Kawamoto, Yoshiyuki; Du, Jun; Takeda, Kozue; Wu, Jianghong; Yoshihara, Motoi; Tsuboi, Hideo; Kato, Masashi; Suzuki, Haruhiko; Nakashima, Izumi.
Afiliación
  • Hossain K; Department of Immunology, Graduate School of Medicine, Nagoya University, Nagoya, Japan.
Free Radic Biol Med ; 34(5): 598-606, 2003 Mar 01.
Article en En | MEDLINE | ID: mdl-12614848
ABSTRACT
Renewed interest in arsenic has been shown recently due to its dual nature of being a potent toxin and a drug for treatment of acute promyelocytic leukemia (APL) because of its ability to trigger caspase activation. Here, we found that sodium arsenite (NaAsO(2)) also triggers the signal for activation of Akt and downstream glycogen synthase 3beta (GSK3beta). Such Akt/GSK3beta activation was abrogated completely by wortmannin, an inhibitor of PI-3 kinase, and greatly by pertussis toxin, a G-protein inhibitor. Arsenite-induced Akt phosphorylation also was inhibited by sequestrating membrane cholesterol with beta cyclodextrin. Reducing reagents/reactive oxygen species (ROS) scavengers reduced arsenite-induced Akt phosphorylation and beta cyclodextrin reduced arsenite-mediated ROS production, suggesting that arsenite-induced G-protein/Akt/GSK3beta pathway is membrane raft dependent and redox linked. We also found that a combination of a low concentration (1 microM) of arsenite and wortmannin triggers the signal for caspase activation, whereas neither of these elements alone did so. These results suggested that selective blockade of the arsenite-provoked PI-3 kinase/Akt pathway can promote the arsenite-triggered pathway for caspase activation, and this may open a new study area for wider applications of arsenic as a drug for treating various kinds of leukemia.
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Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Proteínas Proto-Oncogénicas / Proteínas Serina-Treonina Quinasas / Apoptosis / Compuestos de Sodio / Arsenitos / Caspasas / Microdominios de Membrana / Beta-Ciclodextrinas / Inhibidores Enzimáticos Límite: Humans Idioma: En Revista: Free Radic Biol Med Asunto de la revista: BIOQUIMICA / MEDICINA Año: 2003 Tipo del documento: Article País de afiliación: Japón
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Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Proteínas Proto-Oncogénicas / Proteínas Serina-Treonina Quinasas / Apoptosis / Compuestos de Sodio / Arsenitos / Caspasas / Microdominios de Membrana / Beta-Ciclodextrinas / Inhibidores Enzimáticos Límite: Humans Idioma: En Revista: Free Radic Biol Med Asunto de la revista: BIOQUIMICA / MEDICINA Año: 2003 Tipo del documento: Article País de afiliación: Japón