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Blood, 15 June 2007, Vol. 109, No. 12, pp. 5430-5438. Prepublished online as a Blood First Edition Paper on March 13, 2007; DOI 10.1182/blood-2006-10-047951. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-10-047951v1 blood-2006-10-047951v2 109/12/5430    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 Trudel, S. Articles by Stewart, A. K. Search for Related Content PubMed PubMed Citation Articles by Trudel, S. Articles by Stewart, A. K. Related Collections Neoplasia Apoptosis Oncogenes and Tumor Suppressors Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Preclinical studies of the pan-Bcl inhibitor obatoclax (GX015-070) in multiple myeloma Suzanne Trudel1, Zhi Hua Li1, Jennifer Rauw1, Rodger E. Tiedemann2, Xiao Yan Wen1, and A. Keith Stewart1,2 1 Hematology-Oncology, Princess Margaret Hospital, Toronto, ON; 2 Hematology-Oncology, Mayo Clinic College of Medicine, Scottsdale, AZ Bcl family members Bcl-2, Bcl-xL, and Mcl-1, are frequently expressed and implicated in the survival of myeloma cells. Obatoclax (GX015-070) is a novel, small-molecule antagonist of the BH3-binding groove of the Bcl family of proteins. We show that GX015-070 inhibits the binding of Bak to Mcl-1, up-regulates Bim, induces cytochrome c release, and activates capase-3 in human myeloma cell lines (HMCLs), confirming the predicted mechanism of action. Consequently, GX015-070 potently inhibited the viability of 15 of 16 HMCLs (mean IC50 of 246 nM), including those resistant to melphalan and dexamethasone. In combination studies, GX015-070 enhanced the antimyeloma activity induced by melphalan, dexamethasone, or bortezomib. Sensitivity to GX015-070 correlated with the absence or near absence of Bcl-xL. Coculture with interleukin-6 or adherence to bone marrow stroma conferred modest resistance; however, it did not overcome GX015-070–induced cytotoxicity. Of importance, GX015-070 as a single agent induced potent cytotoxic responses against patient-derived tumor cells. GX015-070 inhibited normal bone marrow–derived colony formation; however, cytotoxicity to human blood lymphocytes was not observed. Taken together, these studies describe a novel BH3 mimic with selectivity for Mcl-1, and support the therapeutic application of GX015-070 for diverse neoplasias including multiple myeloma. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: F. A. Sinicrope, R. L. Rego, N. R. Foster, S. N. Thibodeau, S. R. Alberts, H. E. Windschitl, and D. J. Sargent Proapoptotic Bad and Bid Protein Expression Predict Survival in Stages II and III Colon Cancers Clin. Cancer Res., July 1, 2008; 14(13): 4128 - 4133. [Abstract] [Full Text] [PDF] M. Nguyen, R. C. Marcellus, A. Roulston, M. Watson, L. Serfass, S. R. Murthy Madiraju, D. Goulet, J. Viallet, L. Belec, X. Billot, et al. Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis PNAS, December 4, 2007; 104(49): 19512 - 19517. [Abstract] [Full Text] [PDF]

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