Preclinical studies of the pan-Bcl inhibitor obatoclax (GX015-070) in multiple myeloma.
Bcl family members Bcl-2, Bcl-x(L), 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 IC(50) 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-x(L). 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.
Trudel
Suzanne
S
Hematology-Oncology, Princess Margaret Hospital, Toronto, ON, Canada.
Li
Zhi Hua
ZH
Rauw
Jennifer
J
Tiedemann
Rodger E
RE
Wen
Xiao Yan
XY
Stewart
A Keith
AK
D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000235:genetics; D000072224:Bcl-2-Like Protein 11; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000187:drug effects / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles; D008565:Membrane Proteins / Q000187:drug effects / Q000235:genetics; D009101:Multiple Myeloma / Q000188:drug therapy*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D015854:Up-Regulation / Q000187:drug effects; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C494772:BAK1 protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D007211:Indoles; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D050998:bcl-2 Homologous Antagonist-Killer Protein; D045304:Cytochromes c; D053148:Caspase 3; C520962:obatoclax