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Prepublished online as a Blood First Edition Paper on May 8, 2003; DOI 10.1182/blood-2002-12-3785. This Article Full Text (PDF) All Versions of this Article: 2002-12-3785v1 102/5/1824    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 Jai, W. Articles by Grant, S. Search for Related Content PubMed PubMed Citation Articles by Jai, W. Articles by Grant, S. Social Bookmarking                   What's this? Submitted December 13, 2002 Accepted April 9, 2003 Synergistic antileukemic interactions between 17-AAG and UCN-01 involve interruption of Raf/MEK- and Akt-related pathways Wentao Jai, Chunrong Yu, Mohamed Rahmani, Geoffery Krystal, Edward A Sausville, Paul Dent, and Steven Grant* Medicine, Virginia Commonwealth University, Richmond, VA, USA Developmental Therapeutics Program, National Cancer Institute, Bethesda, MD, USA Radiation Oncology, Virginia Commonwealth University, Richmond, VA, USA * Corresponding author; email: stgrant{at}hsc.vcu.edu. Interactions between the protein kinase C (PKC) and Chk1 inhibitor UCN-01 and the heat shock protein 90 (Hsp90) antagonist 17-AAG have been examined in human leukemia cells in relation to effects on signal transduction pathways and apoptosis. Simultaneous exposure (30 hr) of U937 monocytic leukemia cells to minimally toxic concentrations of 17-AAG (e.g., 400 nM) and UCN-01 (e.g., 150 nM) triggered a pronounced increase in mitochondrial injury (i.e., loss of m; cytosolic release of cytochrome c), caspase activation, and apoptosis. Synergistic induction of apoptosis was also observed in other human leukemia cell types (e.g., Jurkat, NB4). Co-exposure of human leukemia cells to 17-AAG and the PKC inhibitor bisindolylmaleimide (GFX) did not result in enhanced lethality, arguing against the possibility that the PKC inhibitory actions of UCN-01 are responsible for synergistic interactions. The enhanced cytotoxicity of this combination was associated with diminished Akt activation, and marked down-regulation of Raf-1, MEK1/2 and MAP kinase. Co-administration of 17-AAG and UCN-01 did not modify expression of Hsp90, Hsp27, phospho-JNK, or phospho-p38 MAPK, but was associated with further p34cdc2 dephosphorylation and diminshed expression of Bcl-2, Mcl-1, and XIAP. In addition, inducible expression of both a constitutively active MEK1/2 or myristolated Akt construct, which overcame inhibition of ERK and Akt activation respectively, significantly attenuated 17-AAG/UCN-01-mediated lethality. Together, these findings indicate that the Hsp90 antagonist 17-AAG potentiates UCN-01 cytotoxicity in a variety of human leukemia cell types, and suggest that interference with both the Akt and Raf-1/MEK/MAP kinase cytoprotective signaling pathways contribute to this phenomenon. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: X. Cao, M. Bloomston, T. Zhang, W. L. Frankel, G. Jia, B. Wang, N. C. Hall, R. M. Koch, H. Cheng, M. V. Knopp, et al. 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