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

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 in...

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Bibliographic Details
Published in:Oncotarget 2015-09, Vol.6 (29), p.27388-27402
Main Authors: Lavik, Andrew R, Zhong, Fei, Chang, Ming-Jin, Greenberg, Edward, Choudhary, Yuvraj, Smith, Mitchell R, McColl, Karen S, Pink, John, Reu, Frederic J, Matsuyama, Shigemi, Distelhorst, Clark W
Format: Article
Language:English
Subjects:
Aniline Compounds - therapeutic use
Animals
Apoptosis
bcl-2-Associated X Protein - metabolism
Bridged Bicyclo Compounds, Heterocyclic - therapeutic use
Calcium Signaling
Cell Line, Tumor
Cell Survival
Drug Resistance, Neoplasm
HEK293 Cells
Humans
Hydrophobic and Hydrophilic Interactions
Immunohistochemistry
Inositol 1,4,5-Trisphosphate Receptors - chemistry
Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy
Lymphoma, Follicular - drug therapy
Lymphoma, Follicular - pathology
Mice
Mice, Nude
Multiple Myeloma - drug therapy
Multiple Myeloma - pathology
Neoplasm Transplantation
NIH 3T3 Cells
Peptides - chemistry
Protein Structure, Tertiary
Proto-Oncogene Proteins c-bcl-2 - metabolism
Research Paper
Sulfonamides - therapeutic use
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Summary: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.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.4489