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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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 (IP ₃Rs), inhibiting pro-apoptotic Ca ²⁺ 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-IP ₃R interaction. Therefore, to target this interaction we developed BIRD-2 (Bcl-2 IP ₃ Receptor Disruptor-2), a decoy peptide that binds to the BH4 domain, blocking Bcl-2-IP ₃R interaction and thus inducing Ca ²⁺-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-IP ₃R interaction.

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Author and article information

Journal

Journal ID (nlm-ta): Oncotarget

Journal ID (iso-abbrev): Oncotarget

Journal ID (publisher-id): ImpactJ

Title: Oncotarget

Publisher: Impact Journals LLC

ISSN (Electronic): 1949-2553

Publication date Collection: 29 September 2015

Publication date (Electronic): 11 July 2015

Volume: 6

Issue: 29

Pages: 27388-27402

Affiliations

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

Author notes

Correspondence to: Clark W. Distelhorst, cwd@ 123456case.edu

Article

DOI: 10.18632/oncotarget.4489

PMC ID: 4694997

PubMed ID: 26317541

SO-VID: a00cf525-aa84-4651-8365-4ba2b03ab05b

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 3 April 2015

Date accepted : 1 July 2015

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