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Blood, 15 February 2005, Vol. 105, No. 4, pp. 1706-1716. Prepublished online as a Blood First Edition Paper on October 19, 2004; DOI 10.1182/blood-2004-07-2767. This Article Full Text (PDF) All Versions of this Article: 2004-07-2767v1 105/4/1706    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 Dai, Y. Articles by Grant, S. Search for Related Content PubMed PubMed Citation Articles by Dai, Y. Articles by Grant, S. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 19, 2004 Accepted October 3, 2004 Farnesyltransferase inhibitors interact synergistically with the CHK1 inhibitor UCN-01 to induce apoptosis in human leukemia cells through interruption of both AKT and MEK/ERK pathways and activation of SEK1/JNK Yun Dai, Mohamed Rahmani, Xin-Yan Pei, Payal Khanna, Song I Han, Clint Mitchell, Paul Dent, and Steven Grant* Department of Medicine, Virginia Commonwealth University/Medical College of Virginia, Richmond, VA, USA Department of Radiation Oncology, Virginia Commonwealth University/Medical College of Virginia, Richmond, VA, USA Department of Pharmacology, Virginia Commonwealth University/Medical College of Virginia, Richmond, VA, USA; Department of Radiation Oncology, Virginia Commonwealth University/Medical College of Virginia, Richmond, VA, USA Department of Medicine, Virginia Commonwealth University/Medical College of Virginia, Richmond, VA, USA; Department of Biochemistry, Virginia Commonwealth University/Medical College of Virginia, Richmond, VA, USA; Department of Pharmacology, Virginia Commonwealth University/Medical College of Virginia, Richmond, VA, USA * Corresponding author; email: stgrant{at}hsc.vcu.edu. Interactions between the Chk1 inhibitor UCN-01 and the farnesyltransferase inhibitor L744832 were examined in human leukemia cells. Combined exposure of U937 cells to sub-toxic concentrations of UCN-01 and L744352 resulted in a dramatic increase in mitochondrial dysfunction, apoptosis, and loss of clonogenicity. Similar interactions were noted in other leukemia cells (HL-60, Raji, Jurkat), and primary AML blasts. Co-administration of L744832 blocked UCN-01-mediated phosphorylation of MEK/ERK, leading to down-regulation of phospho-CREB and -p90RSK, and activation of p34cdc2 and SEK/JNK. Combined treatment also resulted in pronounced reductions in levels of phospho-Akt, -GSK-3, -p70S6K, -mTOR, -FKHR, -caspase-9, and -Bad. Ectopic expression of Bcl-2 or Bcl-xL but not dominant-negative caspase-8 blocked UCN-01/L744832-mediated mitochondrial dysfunction and apoptosis, but did not prevent activation of p34cdc2 and JNK, or inactivation of MEK/ERK and Akt. Enforced expression of myristoylated Akt but not constitutively-active MEK significantly attenuated UCN-01/L744832-induced apoptosis. However, dual transfection with Akt and MEK resulted in further protection from UCN-01/L744832-mediated lethality. Finally, down-regulation of JNK1 by siRNA significantly reduced the lethality of the UCN-01/L744832 regimen. Together, these findings suggest that farnesyltransferase inhibitors interrupt the cytoprotective Akt and MAPK pathways while reciprocally activating SAPK/JNK in leukemia cells exposed to UCN-01, and in so doing, dramatically increase mitochondria-dependent apoptosis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Y. Dai, S. Chen, X.-Y. Pei, J. A. Almenara, L. B. Kramer, C. A. Venditti, P. Dent, and S. 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[Abstract] [Full Text] [PDF] X.-Y. Pei, W. Li, Y. Dai, P. Dent, and S. Grant Dissecting the Roles of Checkpoint Kinase 1/CDC2 and Mitogen-Activated Protein Kinase Kinase 1/2/Extracellular Signal-Regulated Kinase 1/2 in Relation to 7-Hydroxystaurosporine-Induced Apoptosis in Human Multiple Myeloma Cells Mol. Pharmacol., December 1, 2006; 70(6): 1965 - 1973. [Abstract] [Full Text] [PDF] M. Ammirante, R. Di Giacomo, L. De Martino, A. Rosati, M. Festa, A. Gentilella, M. C. Pascale, M. A. Belisario, A. Leone, M. Caterina Turco, et al. 1-Methoxy-Canthin-6-One Induces c-Jun NH2-Terminal Kinase-Dependent Apoptosis and Synergizes with Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Activity in Human Neoplastic Cells of Hematopoietic or Endodermal Origin. Cancer Res., April 15, 2006; 66(8): 4385 - 4393. [Abstract] [Full Text] [PDF] M. T. A. Nguyen, H. Satoh, S. Favelyukis, J. L. Babendure, T. Imamura, J. I. Sbodio, J. Zalevsky, B. I. Dahiyat, N.-W. Chi, and J. M. 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