Targeting Bcl-2-IP3 receptor interaction to treat cancer: A novel approach inspired by nearly a century treating cancer with adrenal corticosteroid hormones.

Bcl-2 inhibits cell death by at least two different mechanisms. On the one hand, its BH3 domain binds to pro-apoptotic proteins such as Bim and prevents apoptosis induction. On the other hand, the BH4 domain of Bcl-2 binds to the inositol 1,4,5-trisphosphate receptor (IP3R), preventing Ca2+ signals that mediate cell death. In normal T-cells, Bcl-2 levels increase during the immune response, protecting against cell death, and then decline as apoptosis ensues and the immune response dissipates. But in many cancers Bcl-2 is aberrantly expressed and exploited to prevent cell death by inhibiting IP3R-mediated Ca2+ elevation. This review summarizes what is known about the mechanism of Bcl-2's control over IP3R-mediated Ca2+ release and cell death induction. Early insights into the role of Ca2+ elevation in corticosteroid-mediated cell death serves as a model for how targeting IP3R-mediated Ca2+ elevation can be a highly effective therapeutic approach for different types of cancer. Moreover, the successful development of ABT-199 (Venetoclax), a small molecule targeting the BH3 domain of Bcl-2 but without effects on Ca2+, serves as proof of principle that targeting Bcl-2 can be an effective therapeutic approach. BIRD-2, a synthetic peptide that inhibits Bcl-2-IP3R interaction, induces cell death induction in ABT-199 (Venetoclax)-resistant cancer models, attesting to the value of developing therapeutic agents that selectively target Bcl-2-IP3R interaction, inducing Ca2+-mediated cell death.