A synthetic peptide targeting the BH4 domain of Bcl-2 induces apoptosis in multiple myeloma and follicular lymphoma cells alone or in combination with agents targeting the BH3-binding pocket of Bcl-2 |
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Authors: | Andrew R. Lavik Fei Zhong Ming-Jin Chang Edward Greenberg Yuvraj Choudhary Mitchell R. Smith Karen S. McColl John Pink Frederic J. Reu Shigemi Matsuyama Clark W. Distelhorst |
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Affiliation: | 1. Division of Hematology/Oncology, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, Ohio, USA;2. Department of Medicine, MetroHealth Medical Center and Case Western Reserve University School of Medicine, Cleveland, Ohio, USA;3. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, The Cleveland Clinic Foundation, Cleveland, Ohio, USA;4. Case Comprehensive Cancer Center, Cleveland, Ohio, USA |
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Abstract: | Bcl-2 inhibits apoptosis by two distinct mechanisms but only one is targeted to treat Bcl-2-positive malignancies. In this mechanism, the BH1-3 domains of Bcl-2 form a hydrophobic pocket, binding and inhibiting pro-apoptotic proteins, including Bim. In the other mechanism, the BH4 domain mediates interaction of Bcl-2 with inositol 1,4, 5-trisphosphate receptors (IP3Rs), inhibiting pro-apoptotic Ca2+ signals. The current anti-Bcl-2 agents, ABT-263 (Navitoclax) and ABT-199 (Venetoclax), induce apoptosis by displacing pro-apoptotic proteins from the hydrophobic pocket, but do not inhibit Bcl-2-IP3R interaction. Therefore, to target this interaction we developed BIRD-2 (Bcl-2 IP3 Receptor Disruptor-2), a decoy peptide that binds to the BH4 domain, blocking Bcl-2-IP3R interaction and thus inducing Ca2+-mediated apoptosis in chronic lymphocytic leukemia, multiple myeloma, and follicular lymphoma cells, including cells resistant to ABT-263, ABT-199, or the Bruton’s tyrosine kinase inhibitor Ibrutinib. Moreover, combining BIRD-2 with ABT-263 or ABT-199 enhances apoptosis induction compared to single agent treatment. Overall, these findings provide strong rationale for developing novel therapeutic agents that mimic the action of BIRD-2 in targeting the BH4 domain of Bcl-2 and disrupting Bcl-2-IP3R interaction. |
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Keywords: | Bcl-2, inositol 1,4,5-trisphosphate receptor, ABT-199, Bruton’ s tyrosine kinase, lymphoid malignancy |
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