|
|
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.
 Previous Article | Next Article 
Submitted August 2, 2004
Accepted January 11, 2005
Synergistic interactions between imatinib and the novel phosphoinositide-dependent kinase-1 inhibitor OSU-03012 in overcoming imatinib 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*
Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA
Comprehensive Cancer Center Biostatistics Core, Center for Biostatistics, The Ohio State University, Columbus, OH, USA
Division of Hematology and Oncology, Department of Internal Medicine, The Ohio State Univeristy, Columbu, OH, USA
Division of Hematology and Medical Oncology, Oregon Health and Science University Cancer Institute, Portland, OR, USA
Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA; Division of Hematology and Oncology, Department of Internal Medicine, The Ohio State Univeristy, Columbu, OH, USA
* Corresponding author; email: chen.844{at}osu.edu.
Resistance to the Abl kinase inhibitor imatinib 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 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, thereby overcoming the resistance. Here, we examined the effect of OSU-03012, a celecoxib-derived phosphoinositide-dependent kinase-1 (PDK-1) inhibitor, on imatinib-induced apoptosis in two clinically relevant Bcr-Abl mutant cell lines, Ba/F3p210E255K and Ba/F3p210T315I. The IC50 values of imatinib 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 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 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:
|
|
|
|
 
H.-C. Chiu, S. K. Kulp, S. Soni, D. Wang, J. S. Gunn, L. S. Schlesinger, and C.-S. Chen
Eradication of Intracellular Salmonella enterica Serovar Typhimurium with a Small-Molecule, Host Cell-Directed Agent
Antimicrob. Agents Chemother.,
December 1, 2009;
53(12):
5236 - 5244.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. Jagani, K. Song, J. L. Kutok, M. R. Dewar, A. Melet, T. Santos, A. Grassian, S. Ghaffari, C. Wu, R. Ren, et al.
Proteasome Inhibition Causes Regression of Leukemia and Abrogates BCR-ABL-Induced Evasion of Apoptosis in Part through Regulation of Forkhead Tumor Suppressors
Cancer Res.,
August 15, 2009;
69(16):
6546 - 6555.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
M. Gao, P. Y. Yeh, Y.-S. Lu, C.-H. Hsu, K.-F. Chen, W.-C. Lee, W.-C. Feng, C.-S. Chen, M.-L. Kuo, and A.-L. Cheng
OSU-03012, a Novel Celecoxib Derivative, Induces Reactive Oxygen Species-Related Autophagy in Hepatocellular Carcinoma
Cancer Res.,
November 15, 2008;
68(22):
9348 - 9357.
[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. Chou
Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies
Pharmacol. Rev.,
September 1, 2006;
58(3):
621 - 681.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Yacoub, M. A. Park, D. Hanna, Y. Hong, C. Mitchell, A. P. Pandya, H. Harada, G. Powis, C.-S. Chen, C. Koumenis, et al.
OSU-03012 Promotes Caspase-Independent but PERK-, Cathepsin B-, BID-, and AIF-Dependent Killing of Transformed Cells
Mol. Pharmacol.,
August 1, 2006;
70(2):
589 - 603.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A. McCubrey, M. M. LaHair, and R. A. Franklin
OSU-03012 in the Treatment of Glioblastoma
Mol. Pharmacol.,
August 1, 2006;
70(2):
437 - 439.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
