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Blood, 15 February 2005, Vol. 105, No. 4, pp. 1768-1776. Prepublished online as a Blood First Edition Paper on October 28, 2004; DOI 10.1182/blood-2004-09-3413. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-09-3413v1 105/4/1768    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 George, P. Articles by Bhalla, K. Search for Related Content PubMed PubMed Citation Articles by George, P. Articles by Bhalla, K. Related Collections Oncogenes and Tumor Suppressors Signal Transduction Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3 Prince George, Purva Bali, Srinivas Annavarapu, Anna Scuto, Warren Fiskus, Fei Guo, Celia Sigua, Gautam Sondarva, Lynn Moscinski, Peter Atadja, and Kapil Bhalla From the Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, and Novartis Pharmaceutical Inc, Cambridge, MA. Present studies show that LBH589, a novel cinnamic hydroxamic acid analog histone deacetylase inhibitor, induces acetylation of histone H3 and H4 and of heat shock protein 90 (hsp90), increases p21 levels, as well as induces cell-cycle G1 phase accumulation and apoptosis of the human chronic myeloid leukemia blast crisis (CML-BC) K562 cells and acute leukemia MV4-11 cells with the activating length mutation of FLT-3. In MV4-11 cells, this was associated with marked attenuation of the protein levels of p-FLT-3, FLT-3, p-AKT, and p-ERK1/2. In K562 cells, exposure to LBH589 attenuated Bcr-Abl, p-AKT, and p-ERK1/2. Treatment with LBH589 inhibited the DNA binding activity of signal transducers and activators of transcription 5 (STAT5) in both K562 and MV4-11 cells. The hsp90 inhibitor 17-allyl-amino-demethoxy geldanamycin (17-AAG) also induced polyubiquitylation and proteasomal degradation of FLT-3 and Bcr-Abl by reducing their chaperone association with hsp90. Cotreatment with LBH589 and 17-AAG exerted synergistic apoptosis of MV4-11 and K562 cells. In the imatinib mesylate (IM)-refractory leukemia cells expressing Bcr-Abl with the T315I mutation, treatment with the combination attenuated the levels of the mutant Bcr-Abl and induced apoptosis. Finally, cotreatment with LBH589 and 17-AAG also induced more apoptosis of IM-resistant primary CML-BC and acute myeloid leukemia (AML) cells (with activating mutation of FLT-3) than treatment with either agent alone. (Blood. 2005;105:1768-1776) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Quintas-Cardama and J. Cortes Therapeutic Options Against BCR-ABL1 T315I-Positive Chronic Myelogenous Leukemia Clin. Cancer Res., July 15, 2008; 14(14): 4392 - 4399. [Abstract] [Full Text] [PDF] L. Ellis, Y. Pan, G. K. Smyth, D. J. George, C. McCormack, R. Williams-Truax, M. Mita, J. Beck, H. Burris, G. Ryan, et al. 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