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Blood, 1 July 2005, Vol. 106, No. 1, pp. 318-327. Prepublished online as a Blood First Edition Paper on March 22, 2005; DOI 10.1182/blood-2004-09-3523. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-09-3523v1 106/1/318    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Mesa, R. A. Articles by Karnitz, L. M. Search for Related Content PubMed PubMed Citation Articles by Mesa, R. A. Articles by Karnitz, L. M. Related Collections Neoplasia Apoptosis Cell Cycle Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Heat shock protein 90 inhibition sensitizes acute myelogenous leukemia cells to cytarabine Ruben A. Mesa, David Loegering, Heather L. Powell, Karen Flatten, Sonnet J. H. Arlander, Nga T. Dai, Michael P. Heldebrant, Benjamin T. Vroman, B. Douglas Smith, Judith E. Karp, Cynthia J. Ten Eyck, Charles Erlichman, Scott H. Kaufmann, and Larry M. Karnitz From the Division of Hematology, Department of Medicine; Division of Oncology Research and Division of Medical Oncology, Department of Oncology; and Department of Molecular Pharmacology, Mayo Clinic College of Medicine, Rochester, MN; and Adult Leukemia Program, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, MD. Previous studies demonstrated that ataxia telangiectasia mutated– and Rad3-related (ATR) kinase and its downstream target checkpoint kinase 1 (Chk1) facilitate survival of cells treated with nucleoside analogs and other replication inhibitors. Recent results also demonstrated that Chk1 is depleted when cells are treated with heat shock protein 90 (Hsp90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). The present study examined the effects of 17-AAG and its major metabolite, 17-aminogeldanamycin (17-AG), on Chk1 levels and cellular responses to cytarabine in human acute myelogenous leukemia (AML) cell lines and clinical isolates. Cytarabine, at concentrations as low as 30 nM, caused activating phosphorylation of Chk1, loss of the phosphatase Cdc25A, and S-phase slowing. Conversely, treatment with 100 to 300 nM 17-AAG for 24 hours caused Chk1 depletion that was accompanied by diminished cytarabine-induced S-phase accumulation, decreased Cdc25A degradation, and enhanced cytotoxicity as measured by inhibition of colony formation and induction of apoptosis. Additional studies demonstrated that small inhibitory RNA (siRNA) depletion of Chk1 also sensitized cells to cytarabine, whereas disruption of the phosphatidylinositol 3-kinase (PI3k) signaling pathway, which is also blocked by Hsp90 inhibition, did not. Collectively, these results suggest that treatment with 17-AAG might represent a means of reversing checkpoint-mediated cytarabine resistance in AML. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: W. P. Vaughan and J. E. Karp The Long Road to a Cure for Acute Myelocytic Leukemia: From Intensity to Specificity J. Clin. Oncol., July 20, 2008; 26(21): 3475 - 3477. 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