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.
Highlights
The Bcl-2 protein is elevated in a variety of types of cancer, including those derived by malignant transformation of B-lymphocytes: chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and multiple myeloma (MM) [1]
The findings indicate that KMS-12-BM cells are not completely resistant to BIRD-2, but require a much higher concentration of BIRD-2 than NCI-H929 cells to achieve a similar degree of apoptosis
All human myeloma cell lines (HMCLs) exhibited considerable resistance to the Bruton’s tyrosine kinase (Btk) inhibitor Ibrutinib (Figure 5D). These findings indicate that BIRD-2 is capable of inducing death in HMCLs that are resistant to both the BH3 mimetic agents ABT-263 and ABT-199 and to the Btk inhibitor Ibrutinib
Summary
The Bcl-2 protein is elevated in a variety of types of cancer, including those derived by malignant transformation of B-lymphocytes: chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and multiple myeloma (MM) [1]. Bcl-2 elevation contributes to apoptosis resistance in malignant cells, a hallmark of cancer that represents a major hurdle in cancer treatment [2]. Bcl-2 has four BH domains (BH1-4), typical of most anti-apoptotic family members, while pro-apoptotic family members lack the BH4 domain and have only BH1-3 domains (e.g., Bax, Bak). Another subset of pro-apoptotic family members has only a BH3 domain (e.g., Bim). These BH3-only proteins act as sentinels of cell stress that activate Bax or Bak, which in turn trigger apoptosis by permeabilizing the outer mitochondrial membrane and releasing cytochrome c
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