ABT-737, an inhibitor of Bcl-2 family proteins, is a potent inducer of apoptosis in multiple myeloma cells

• Published in: Leukemia Vol. 21; no. 7; pp. 1549 - 1560
• Main Authors: KLINE, M. P, RAJKUMAR, S. V, TIMM, M. M, KIMLINGER, T. K, HAUG, J. L, LUST, J. A, GREIPP, P. R, KUMAR, S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 01.07.2007; Nature Publishing Group
• Subjects: Antimitotic agents; Antineoplastic agents; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - drug effects; BAX protein; Bcl-2 protein; bcl-2-Associated X Protein - analysis; Bcl-x protein; Biological and medical sciences; Biphenyl Compounds - pharmacology; Bone marrow; Caspase; Caspases - metabolism; Cell death; Cell Line; Cell survival; Cells, Cultured; Cytokines; Cytotoxicity; Depolarization; Diagnosis; Dosage and administration; Drug therapy; Flow Cytometry; General aspects; Growth factors; Hematology; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Inhibitors; Insulin; Intercellular Signaling Peptides and Proteins - pharmacology; Interleukin 6; Intracellular levels; Leukemia; Medical sciences; Membrane potential; Microenvironments; Mitochondria; Multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - pathology; Nitrophenols - pharmacology; NMR; Nuclear magnetic resonance; Patients; Penicillin; Pharmacology. Drug treatments; Physiological aspects; Piperazines - pharmacology; Plasma; Proteins; Proto-Oncogene Proteins c-bcl-2 - analysis; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Sulfonamides - pharmacology; Survival; Tumor cells; Vascular endothelial growth factor; United States; United States > US; Antineoplastic agent; Human; Bcl-2; Immunopathology; Protein inhibitor; multiple myeloma; Hematology; Malignant hemopathy; Myeloma; Bcl-xL; Cancerology; Treatment; Immunoglobulinopathy; Cell death; Lymphoproliferative syndrome; C-Onc gene; Genetics; Protooncogene; Apoptosis
• DOI: 10.1038/sj.leu.2404719
• ISSN: 0887-6924

Disruption of pathways leading to programmed cell death plays a major role in most malignancies, including multiple myeloma (MM). ABT-737 is a BH3 mimetic small-molecule inhibitor that binds with high affinity to Bcl-2 and Bcl-xL, preventing the sequestration of proapoptotic molecules and shifting the cell survival/apoptosis balance toward apoptosis induction. In this study, we show that ABT-737 is cytotoxic to MM cell lines, including those resistant to conventional therapies, and primary tumor cells. Flow cytometric analysis of intracellular levels of Bcl-2 family proteins demonstrates a clear inversion of the Bax/Bcl-2 ratio leading to induction of apoptosis. Activation of the mitochondrial apoptosis pathway was indicated by mitochondrial membrane depolarization and caspase cleavage. Additionally, several signaling pathways known to be important for MM cell survival are disrupted following treatment with ABT-737. The impact of ABT-737 on survival could not be overcome by the addition of interleukin-6, vascular endothelial growth factor or insulin-like growth factor, suggesting that ABT-737 may be effective in preventing the growth and survival signals provided by the microenvironment. These data indicate that therapies targeting apoptotic pathways may be effective in MM treatment and warrant clinical evaluation of ABT-737 and similar drugs alone or in combination with other agents in the setting of MM.