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Blood, 15 May 2005, Vol. 105, No. 10, pp. 4013-4020. Prepublished online as a Blood First Edition Paper on January 21, 2005; DOI 10.1182/blood-2004-07-2802. This Article Full Text (PDF) All Versions of this Article: 2004-07-2802v1 105/10/4013    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ramos, A. M Articles by Aller, P. Search for Related Content PubMed PubMed Citation Articles by Ramos, A. M Articles by Aller, P. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 21, 2004 Accepted January 11, 2005 Pharmacological inhibitors of PI3K/Akt potentiate the apoptotic action of the antileukemic drug arsenic trioxide via glutathione depletion and increased peroxide accumulation in myeloid leukemia cells Adrian M Ramos, Carlos Fernandez, Donna Amran, Patricia Sancho, Elena de Blas, and Patricio Aller* Centro de Investigaciones Biologicas, Consejo Superior de Investigaciones Cientificas, Madrid, Spain * Corresponding author; email: aller{at}cib.csic.es. Treatment for 14-24 h with low concentrations of arsenic trioxide (As2O3, 1-4 µM) caused apoptosis in U-937 promonocytes and other human myeloid leukemia cell lines (HL-60, NB4). This effect was potentiated by co-treatment with the phosphatidylinositol 3-kinase (PI3K) inhibitors LY294002 and wortmannin, and the Akt inhibitor Akti5. However, the inhibitors did not increase the toxiciy of the mitochondria-targeting drug lonidamine, and the DNA-specific drugs camptothecin and cisplatin, when used under similar experimental conditions as As2O3. The potentiation of As2O3-provoked apoptosis involved the increased disruption of mitochondrial transmembrane potential, increased caspase-3 activation and cytochrome c release from mitochondria, increased Bax and Bid activation, and attenuation of HSP27 expression; and was prevented by Bcl-2 over-expression. The PI3K/Akt inhibitors decreased the intracellular glutathione content, and caused intracellular oxidation, as measured by peroxide accumulation. Co-treatment with subcytotoxic concentrations of hydrogen peroxide increased apoptosis induction by As2O3. On the other hand, the treatments did not significantly affect glutathione S-transferase expression and activity. These results, which indicate that glutathione is a target of PI3K/Akt in myeloid leukemia cells, may partially explain the selective increase of As2O3 toxicity by PI3K/Akt inhibitors, and may provide a rationale to improve the efficacy of these inhibitors as therapeutic agents. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: K. K. Mann, M. Colombo, and W. H. Miller Jr. Arsenic trioxide decreases AKT protein in a caspase-dependent manner Mol. Cancer Ther., June 1, 2008; 7(6): 1680 - 1687. [Abstract] [Full Text] [PDF] B. Dolniak, E. Katsoulidis, N. Carayol, J. K. Altman, A. J. Redig, M. S. Tallman, T. Ueda, R. Watanabe-Fukunaga, R. Fukunaga, and L. C. Platanias Regulation of Arsenic Trioxide-induced Cellular Responses by Mnk1 and Mnk2 J. Biol. Chem., May 2, 2008; 283(18): 12034 - 12042. [Abstract] [Full Text] [PDF] D. Chen, R. Chan, S. Waxman, and Y. Jing Buthionine Sulfoximine Enhancement of Arsenic Trioxide-Induced Apoptosis in Leukemia and Lymphoma Cells Is Mediated via Activation of c-Jun NH2-Terminal Kinase and Up-regulation of Death Receptors Cancer Res., December 1, 2006; 66(23): 11416 - 11423. [Abstract] [Full Text] [PDF] P. Kannan-Thulasiraman, E. Katsoulidis, M. S. Tallman, J. S. C. Arthur, and L. C. Platanias Activation of the Mitogen- and Stress-activated Kinase 1 by Arsenic Trioxide J. Biol. Chem., August 11, 2006; 281(32): 22446 - 22452. [Abstract] [Full Text] [PDF] D. M. B. Kerbauy, V. Lesnikov, N. Abbasi, S. Seal, B. Scott, and H. J. Deeg NF-{kappa}B and FLIP in arsenic trioxide (ATO)-induced apoptosis in myelodysplastic syndromes (MDSs) Blood, December 1, 2005; 106(12): 3917 - 3925. [Abstract] [Full Text] [PDF]

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