Please use this identifier to cite or link to this item: http://hdl.handle.net/10261/42223
Share/Impact:
Título : Pharmacologic 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
Autor : Ramos, Adrián M., Fernández, Carlos, Amrán, Donna, Sancho, Patricia, Blas, Elena de, Aller, Patricio
Palabras clave : leukemia cells
inhibitors
Fecha de publicación : 15-May-2005
Editor: American Society of Hematology
Resumen: Treatment for 14 to 24 hours 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 cotreatment with the phosphatidylinositol 3-kinase (PI3K) inhibitors LY294002 and wortmannin, and the Akt inhibitor Akti5. However, the inhibitors did not increase the toxicity 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 27-kDa heat shock protein (HSP27) expression; the potentiation was prevented by Bcl-2 overexpression. The PI3K/Akt inhibitors decreased the intracellular glutathione content, and caused intracellular oxidation, as measured by peroxide accumulation. Cotreatment with subcytotoxic concentrations of hydrogen peroxide increased apoptosis induction by As2O3. On the other hand, the treatments did not significantly affect glutathione S-transferase π 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.
Descripción : 7 Figures. 1 Table. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734.
Versión del editor: http://bloodjournal.hematologylibrary.org/content/105/10/4013.abstract
URI : http://hdl.handle.net/10261/42223
ISSN: 0006-4971
DOI: 10.1182/blood-2004-07-2802
Citación : Blood 105(10): 4013-4020 (2005)
Appears in Collections:(CIB) Artículos

Files in This Item:
File Description SizeFormat 
restringido.pdf21,67 kBAdobe PDFView/Open
Show full item record
 
CSIC SFX LinksSFX Query


Items in Digital.CSIC are protected by copyright, with all rights reserved, unless otherwise indicated.