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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.


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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.


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