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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Andrew R. Lavik1, Fei Zhong1,*, Ming-Jin Chang1,*, Edward Greenberg1,2, Yuvraj Choudhary1, Mitchell R. Smith3,4, Karen S. McColl1, John Pink4, Frederic J. Reu3,4, Shigemi Matsuyama1,4, Clark W. Distelhorst1,4
1Division of Hematology/Oncology, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, Ohio, USA
2Department of Medicine, MetroHealth Medical Center and Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
3Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, The Cleveland Clinic Foundation, Cleveland, Ohio, USA
4Case Comprehensive Cancer Center, Cleveland, Ohio, USA
*These authors have contributed equally to this work
Clark W. Distelhorst, e-mail: firstname.lastname@example.org
Keywords: Bcl-2, inositol 1,4,5-trisphosphate receptor, ABT-199, Bruton's tyrosine kinase, lymphoid malignancy
Received: April 03, 2015 Accepted: July 01, 2015 Published: July 11, 2015
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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