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LY294002 and LY303511 Sensitize Tumor Cells to Drug-Induced Apoptosis via Intracellular Hydrogen Peroxide Production Independent of the Phosphoinositide 3-Kinase-Akt Pathway

¹ Department of Physiology, ² Oncology Research Institute, National University Medical Institute, Faculty of Medicine, and ³ Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore

Requests for reprints: Shazib Pervaiz, Department of Physiology, MD902-05, Faculty of Medicine, National University of Singapore, Singapore, Singapore 117597. Fax: 65-67788161; E-mail: phssp{at}nus.edu.sg.

The phosphoinositide 3-kinase (PI3K)-Akt pathway is constitutively active in many tumors, and inhibitors of this prosurvival network, such as LY294002, have been shown to sensitize tumor cells to death stimuli. Here, we report a novel, PI3K-independent mechanism of LY-mediated sensitization of LNCaP prostate carcinoma cells to drug-induced apoptosis. Preincubation of tumor cells to LY294002 or its inactive analogue LY303511 resulted in a significant increase in intracellular hydrogen peroxide (H₂O₂) production and enhanced sensitivity to nonapoptotic concentrations of the chemotherapeutic agent vincristine. The critical role of intracellular H₂O₂ in LY-induced death sensitization is corroborated by transient transfection of cells with a vector containing human catalase gene. Indeed, overexpression of catalase significantly blocked the amplifying effect of LY pretreatment on caspase-2 and caspase-3 activation and cell death triggered by vincristine. Furthermore, the inability of wortmannin, another inhibitor of PI3K, to induce an increase in H₂O₂ production at doses that effectively blocked Akt phosphorylation provides strong evidence to unlink inhibition of PI3K from intracellular H₂O₂ production. These data strongly support death-sensitizing effect of LY compounds independent of the PI3K pathway and underscore the critical role of H₂O₂ in creating a permissive intracellular milieu for efficient drug-induced execution of tumor cells.

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