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Blood, 15 December 2005, Vol. 106, No. 13, pp. 4330-4338. Prepublished online as a Blood First Edition Paper on August 25, 2005; DOI 10.1182/blood-2005-07-2819. This Article Full Text (PDF) All Versions of this Article: 2005-07-2819v1 106/13/4330    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 Kardosh, A. Articles by Schonthal, A. H Search for Related Content PubMed PubMed Citation Articles by Kardosh, A. Articles by Schonthal, A. H Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 15, 2005 Accepted August 18, 2005 Multi-target inhibition of drug-resistant multiple myeloma cell lines by dimethyl-celecoxib (DMC), a non-COX-2-inhibitory analog of celecoxib Adel Kardosh, Nathaniel Soriano, Yen-Ting Liu, Jasim Uddin, Nicos A Petasis, Florence M Hofman, Thomas C Chen, and Axel H Schonthal* Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, USA Department of Pathology, University of Southern California, Los Angeles, CA, USA Department of Chemistry, University of Southern California, Los Angeles, CA, USA Department of Pathology, University of Southern California, Los Angeles, CA, USA; Department of Neurosurgery, University of Southern California, Los Angeles, CA, USA * Corresponding author; email: schontha{at}usc.edu. 2,5-dimethyl-celecoxib (DMC) is a close structural analog of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib (Celebrex®) that lacks COX-2-inhibitory function. We and others have demonstrated that DMC, despite its inability to block COX-2, is able to potently mimic the anti-tumor effects of celecoxib in vitro and in vivo. In this current study, we investigated whether DMC would also be able to inhibit the growth of highly drug-resistant tumor cell variants. We focused on human multiple myeloma (MM) cells, as patients with MM frequently develop drug-resistant disease and ultimately succumb to death. Here we show that DMC (and celecoxib) inhibits the proliferation of various multiple myeloma cell lines, including several (multi)drug-resistant variants. Growth inhibition in drug-sensitive and drug-resistant cells is mediated via multiple effects, which include diminished STAT-3 and MAP kinase kinase (MEK) activity, reduced expression of survivin and various cyclins, and is followed by apoptotic cell death. Thus, our study demonstrates that inhibition of proliferation and induction of apoptosis by DMC (and celecoxib) can be accomplished even in highly drug-resistant multiple myeloma cells, and that this effect is achieved via the blockage of multiple targets that are critical for multiple myeloma cell growth and survival. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Not all that glitters is gold Yair Gazitt Blood 2005 106: 4025-4026. [Full Text] [PDF] This article has been cited by other articles: A. Kardosh, E. B. Golden, P. Pyrko, J. Uddin, F. M. Hofman, T. C. Chen, S. G. Louie, N. A. Petasis, and A. H. Schonthal Aggravated Endoplasmic Reticulum Stress as a Basis for Enhanced Glioblastoma Cell Killing by Bortezomib in Combination with Celecoxib or Its Non-Coxib Analogue, 2,5-Dimethyl-Celecoxib Cancer Res., February 1, 2008; 68(3): 843 - 851. [Abstract] [Full Text] [PDF] L. H. Wang, X. Y. Yang, X. Zhang, and W. L. Farrar Inhibition of adhesive interaction between multiple myeloma and bone marrow stromal cells by PPAR{gamma} cross talk with NF-{kappa}B and C/EBP Blood, December 15, 2007; 110(13): 4373 - 4384. [Abstract] [Full Text] [PDF] P. Pyrko, A. Kardosh, W. Wang, W. Xiong, A. H. Schonthal, and T. C. Chen HIV-1 Protease Inhibitors Nelfinavir and Atazanavir Induce Malignant Glioma Death by Triggering Endoplasmic Reticulum Stress Cancer Res., November 15, 2007; 67(22): 10920 - 10928. [Abstract] [Full Text] [PDF] S. Zhang, A. Suvannasankha, C. D. Crean, V. L. White, A. Johnson, C.-S. Chen, and S. S. Farag OSU-03012, a Novel Celecoxib Derivative, Is Cytotoxic to Myeloma Cells and Acts through Multiple Mechanisms Clin. Cancer Res., August 15, 2007; 13(16): 4750 - 4758. [Abstract] [Full Text] [PDF] P. Pyrko, A. Kardosh, Y.-T. Liu, N. Soriano, W. Xiong, R. H. Chow, J. Uddin, N. A. Petasis, A. K. Mircheff, R. A. Farley, et al. Calcium-activated endoplasmic reticulum stress as a major component of tumor cell death induced by 2,5-dimethyl-celecoxib, a non-coxib analogue of celecoxib Mol. Cancer Ther., April 1, 2007; 6(4): 1262 - 1275. [Abstract] [Full Text] [PDF] J. Lou, N. Fatima, Z. Xiao, S. Stauffer, G. Smythers, P. Greenwald, and I. U. Ali Proteomic profiling identifies cyclooxygenase-2-independent global proteomic changes by celecoxib in colorectal cancer cells. Cancer Epidemiol. Biomarkers Prev., September 1, 2006; 15(9): 1598 - 1606. [Abstract] [Full Text] [PDF] B. Hoang, L. Zhu, Y. Shi, P. Frost, H. Yan, S. Sharma, S. Sharma, L. Goodglick, S. Dubinett, and A. Lichtenstein Oncogenic RAS mutations in myeloma cells selectively induce cox-2 expression, which participates in enhanced adhesion to fibronectin and chemoresistance Blood, June 1, 2006; 107(11): 4484 - 4490. [Abstract] [Full Text] [PDF]

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