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Blood, 15 March 2005, Vol. 105, No. 6, pp. 2504-2509. Prepublished online as a Blood First Edition Paper on September 28, 2004; DOI 10.1182/blood-2004-05-1957. This Article Full Text (PDF) All Versions of this Article: 2004-05-1957v1 105/6/2504    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 Johnson, A. J Articles by Byrd, J. C Search for Related Content PubMed PubMed Citation Articles by Johnson, A. J Articles by Byrd, J. C Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 25, 2004 Accepted September 16, 2004 A novel celecoxib derivative, OSU03012, induces cytotoxicity in primary CLL cells and transformed B-cell lymphoma via a caspase and Bcl-2 independent mechanism Amy J Johnson, Lisa L Smith, Jiuxiang Zhu, Nyla A Heerema, Sara Jefferson, Andrew Mone, Michael Grever, Ching-Shih Chen, and John C Byrd* Division of Hematology and Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA Department of Pathology, The Ohio State University, Columbus, Ohio, USA Division of Hematology and Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA * Corresponding author; email: byrd-3{at}medctr.osu.edu. Chronic lymphocytic leukemia (CLL) is an incurable adult leukemia characterized by disrupted apoptosis. OSU03012 is a bioavailable third generation celecoxib derivative devoid of cyclooxygenase-2 inhibitory activity that potently induces apoptosis in prostate cancer cell lines and is being developed as an anti-cancer therapy in the NCI Rapid Access to Interventional Therapy (RAID). We assessed the ability of OSU03012 to induce cytotoxicity in primary CLL cells and the mechanism by which this occurs. The LC50 (lethal concentration 50%) of OSU03012 at 24 hours was 7.1 µM and this decreased to 5.5 µM at 72 hours. Additionally, we have demonstrated that OSU03012 mediates apoptosis by activation of the intrinsic, mitochondrial pathway of apoptosis but also activates alternative cell death pathways that are caspase independent. The early activation of both caspase dependent and independent pathways of apoptosis is novel to OSU03012 and suggests it has great potential promise for the treatment of CLL. Moreover, unlike the great majority of therapeutic agents utilized to treat leukemia or other forms of cancer, OSU03012 induces apoptosis entirely independent of bcl-2 expression. Overall, these data provide justification for further pre-clinical development of OSU03012 as a potential therapeutic agent for CLL. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Y.-C. Wang, S. K. Kulp, D. Wang, C.-C. Yang, A. M. Sargeant, J.-H. Hung, Y. Kashida, M. Yamaguchi, G.-D. Chang, and C.-S. Chen Targeting Endoplasmic Reticulum Stress and Akt with OSU-03012 and Gefitinib or Erlotinib to Overcome Resistance to Epidermal Growth Factor Receptor Inhibitors Cancer Res., April 15, 2008; 68(8): 2820 - 2830. [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] Q. Liu, X. Zhao, F. Frissora, Y. Ma, R. Santhanam, D. Jarjoura, A. Lehman, D. Perrotti, C.-S. Chen, J. T. Dalton, et al. FTY720 demonstrates promising preclinical activity for chronic lymphocytic leukemia and lymphoblastic leukemia/lymphoma Blood, January 1, 2008; 111(1): 275 - 284. [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] A. J. Johnson, D. M. Lucas, N. Muthusamy, L. L. Smith, R. B. Edwards, M. D. De Lay, C. M. Croce, M. R. Grever, and J. C. Byrd Characterization of the TCL-1 transgenic mouse as a preclinical drug development tool for human chronic lymphocytic leukemia Blood, August 15, 2006; 108(4): 1334 - 1338. [Abstract] [Full Text] [PDF] P. Secchiero, E. Barbarotto, A. Gonelli, M. Tiribelli, C. Zerbinati, C. Celeghini, C. Agostinelli, S. A. Pileri, and G. Zauli Potential Pathogenetic Implications of Cyclooxygenase-2 Overexpression in B Chronic Lymphoid Leukemia Cells Am. J. Pathol., December 1, 2005; 167(6): 1599 - 1607. [Abstract] [Full Text] [PDF] H.-K. Kang, E. Lee, H. Pyo, and S.-J. Lim Cyclooxygenase-independent down-regulation of multidrug resistance-associated protein-1 expression by celecoxib in human lung cancer cells Mol. Cancer Ther., September 1, 2005; 4(9): 1358 - 1363. [Abstract] [Full Text] [PDF] H M. Prince, L. Mileshkin, A. Roberts, V. Ganju, C. Underhill, J. Catalano, R. Bell, J. F. Seymour, D. Westerman, P. J. Simmons, et al. A Multicenter Phase II Trial of Thalidomide and Celecoxib for Patients with Relapsed and Refractory Multiple Myeloma Clin. Cancer Res., August 1, 2005; 11(15): 5504 - 5514. [Abstract] [Full Text] [PDF]

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