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Blood, 15 May 2005, Vol. 105, No. 10, pp. 4021-4027. Prepublished online as a Blood First Edition Paper on January 21, 2005; DOI 10.1182/blood-2004-07-2967. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-07-2967v1 105/10/4021    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 Tseng, P.-H. Articles by Chen, C.-S. Search for Related Content PubMed PubMed Citation Articles by Tseng, P.-H. Articles by Chen, C.-S. Related Collections Neoplasia Oncogenes and Tumor Suppressors Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Synergistic interactions between imatinib mesylate and the novel phosphoinositide-dependent kinase-1 inhibitor OSU-03012 in overcoming imatinib mesylate resistance Ping-Hui Tseng, Ho-Pi Lin, Jiuxiang Zhu, Kuen-Feng Chen, Erinn M. Hade, Donn C. Young, John C. Byrd, Michael Grever, Kara Johnson, Brian J. Druker, and Ching-Shih Chen From the Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH; Comprehensive Cancer Center Biostatistics Core, Center for Biostatistics, The Ohio State University, Columbus, OH; Division of Hematology and Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH; and Division of Hematology and Medical Oncology, Oregon Health and Science University Cancer Institute, Portland, OR. Resistance to the Ableson protein tyrosine (Abl) kinase inhibitor imatinib mesylate has become a critical issue for patients in advanced phases of chronic myelogenous leukemia. Imatinib-resistant tumor cells develop, in part, as a result of point mutations within the Abl kinase domain. As protein kinase B (Akt) plays a pivotal role in Abl oncogene-mediated cell survival, we hypothesize that concurrent inhibition of Akt will sensitize resistant cells to the residual apoptotic activity of imatinib mesylate, thereby overcoming the resistance. Here, we examined the effect of OSU-03012, a celecoxib-derived phosphoinositide-dependent kinase-1 (PDK-1) inhibitor, on imatinib mesylate-induced apoptosis in 2 clinically relevant breakpoint cluster region (Bcr)-Abl mutant cell lines, Ba/F3p210E255K and Ba/F3p210T315I. The 50% inhibitory concentration (IC50) values of imatinib mesylate to inhibit the proliferation of Ba/F3p210E255K and Ba/F3p210T315I were 14 ± 4 and 30 ± 2 µM, respectively. There was no cross-resistance to OSU-03012 in these mutant cells with an IC50 of 5 µM irrespective of mutations. Nevertheless, in the presence of OSU-03012 the susceptibility of these mutant cells to imatinib-induced apoptosis was significantly enhanced. This synergistic action was, at least in part, mediated through the concerted effect on phospho-Akt. Together these data provide a novel therapeutic strategy to overcome imatinib mesylate resistance, especially with the Abl mutant T315I. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. Marston, V. Weston, J. Jesson, E. Maina, C. McConville, A. Agathanggelou, A. Skowronska, K. Mapp, K. Sameith, J. E. Powell, et al. Stratification of pediatric ALL by in vitro cellular responses to DNA double-strand breaks provides insight into the molecular mechanisms underlying clinical response Blood, January 1, 2009; 113(1): 117 - 126. [Abstract] [Full Text] [PDF] S.-C. Weng, Y. Kashida, S. K. Kulp, D. Wang, R. W. Brueggemeier, C. L. Shapiro, and C.-S. Chen Sensitizing estrogen receptor-negative breast cancer cells to tamoxifen with OSU-03012, a novel celecoxib-derived phosphoinositide-dependent protein kinase-1/Akt signaling inhibitor Mol. Cancer Ther., April 1, 2008; 7(4): 800 - 808. [Abstract] [Full Text] [PDF] M. A. Park, A. Yacoub, M. Rahmani, G. Zhang, L. Hart, M. P. Hagan, S. K. Calderwood, M. Y. Sherman, C. Koumenis, S. Spiegel, et al. OSU-03012 Stimulates PKR-Like Endoplasmic Reticulum-Dependent Increases in 70-kDa Heat Shock Protein Expression, Attenuating Its Lethal Actions in Transformed Cells Mol. Pharmacol., April 1, 2008; 73(4): 1168 - 1184. [Abstract] [Full Text] [PDF] M. Mayerhofer, K. V. Gleixner, J. Mayerhofer, G. Hoermann, E. Jaeger, K. J. Aichberger, R. G. Ott, K. Greish, H. Nakamura, S. Derdak, et al. Targeting of heat shock protein 32 (Hsp32)/heme oxygenase-1 (HO-1) in leukemic cells in chronic myeloid leukemia: a novel approach to overcome resistance against imatinib Blood, February 15, 2008; 111(4): 2200 - 2210. [Abstract] [Full Text] [PDF] K. To, Y. Zhao, H. Jiang, K. Hu, M. Wang, J. Wu, C. Lee, D. W. Yokom, A. L. Stratford, U. Klinge, et al. The Phosphoinositide-Dependent Kinase-1 Inhibitor 2-Amino-N-[4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-acetamide (OSU-03012) Prevents Y-Box Binding Protein-1 from Inducing Epidermal Growth Factor Receptor Mol. Pharmacol., September 1, 2007; 72(3): 641 - 652. [Abstract] [Full Text] [PDF] A. M. Sargeant, R. D. Klein, R. C. Rengel, S. K. Clinton, S. K. Kulp, Y. Kashida, M. Yamaguchi, X. Wang, and C.-S. Chen Chemopreventive and Bioenergetic Signaling Effects of PDK1/Akt Pathway Inhibition in a Transgenic Mouse Model of Prostate Cancer Toxicol Pathol, June 1, 2007; 35(4): 549 - 561. [Abstract] [Full Text] [PDF] T. K. Nguyen, M. Rahmani, H. Harada, P. Dent, and S. Grant MEK1/2 inhibitors sensitize Bcr/Abl+ human leukemia cells to the dual Abl/Src inhibitor BMS-354/825 Blood, May 1, 2007; 109(9): 4006 - 4015. [Abstract] [Full Text] [PDF] P.-H. Tseng, Y.-C. Wang, S.-C. Weng, J.-R. Weng, C.-S. Chen, R. W. Brueggemeier, C. L. Shapiro, C.-Y. Chen, S. E. Dunn, M. Pollak, et al. Overcoming Trastuzumab Resistance in HER2-Overexpressing Breast Cancer Cells by Using a Novel Celecoxib-Derived Phosphoinositide-Dependent Kinase-1 Inhibitor Mol. Pharmacol., November 1, 2006; 70(5): 1534 - 1541. [Abstract] [Full Text] [PDF] M. Baccarani, G. Saglio, J. Goldman, A. Hochhaus, B. Simonsson, F. Appelbaum, J. Apperley, F. Cervantes, J. Cortes, M. Deininger, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet Blood, September 15, 2006; 108(6): 1809 - 1820. [Abstract] [Full Text] [PDF] T.-C. 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