Creating a New Cancer Therapeutic Agent by Targeting the Interaction between Bcl-2 and IP₃Receptors

Abstract

Bcl-2 is a member of a family of proteins that regulate cell survival. Expression of Bcl-2 is aberrantly elevated in many types of cancer. Within cells of the immune system, Bcl-2 has a physiological role in regulating immune responses. However, in cancers arising from cells of the immune system Bcl-2 promotes cell survival and proliferation. This review summarizes discoveries over the past 30 years that have elucidated Bcl-2's role in the normal immune system, including its actions in regulating calcium (Ca 2+ ) signals necessary for the immune response, and for Ca 2+ -mediated apoptosis at the end of an immune response. How Bcl-2 modulates the release of Ca 2+ from intracellular stores via inositol 1,4,5-trisphosphate receptors (IP 3 R) is discussed, and in particular, the role of Bcl-2/IP 3 R interactions in promoting the survival of cancer cells by preventing Ca 2+ -mediated cell death. The development and usage of a peptide, referred to as TAT-Pep8, or more recently, BIRD-2, that induces death of cancer cells by inhibiting Bcl-2's control over IP 3 R-mediated Ca 2+ elevation is discussed. Studies aimed at discovering a small molecule that mimics BIRD-2's anticancer mechanism of action are summarized, along with the prospect of such a compound becoming a novel therapeutic option for cancer.

Fundamentals of Cellular Calcium Signaling: A Primer

“…However, in some deleterious situations (e.g., hypertension) hypertrophy can progress to a maladapted state in which Ca 2+ signals are reduced, and the heart becomes weaker (Roderick et al 2007). Moreover, the altered expression or mutation of the Ca 2+ signaling toolkit components can lead to oncogenesis and malignant cellular behavior, as is observed in several cancer types (Distelhorst and Bootman 2019;Roberts-Thomson et al 2019).…”

“…(From Bootman et al 2009; adapted, with permission, from Company of Biologists © 2009. ) death, a pathway that is often dysregulated in cancers but might be therapeutically targeted (Distelhorst and Bootman 2019;Ivanova et al 2019).…”

Lessons from the Endoplasmic Reticulum Ca2+ Transporters—A Cancer Connection

“…Nonetheless, these complexes of anti-apoptotic Bcl-2 proteins and IP 3 R channels may open the door for innovative therapeutic interventions. As a matter of fact, recent years have witnessed the tremendous breakthrough in the use of synthetic peptides to disrupt the Bcl-2-IP 3 R complex in chronic lymphocytic leukemia, multiple myeloma, follicular lymphoma and small cell lung cancer either alone or with other mimetics to potentiate anti-neoplastic effects and / or tackle chemo-resistance [ 109 , 110 , 111 , 112 , 113 ]. On the other end of the spectrum, a growing body of evidence suggests that IP 3 R activity is subject to regulation by tumor suppressors.…”

BDA-366, a putative Bcl-2 BH4 domain antagonist, induces apoptosis independently of Bcl-2 in a variety of cancer cell models

“…However, also the targeting of Bcl-2's BH4 domain recently emerged as a promising strategy to drive cancer cell death 12,13 . One strategy has been to use IP 3 R-derived peptides (such as BIRD-2; Bcl-2/IP 3 receptor disrupter-2) that represent the binding site for Bcl-2's BH4 domain 5,14,15 . Such peptides can be used as a decoy for Bcl-2, stripping it from IP 3 R channels and favoring proapoptotic Ca 2+ fluxes 16,17 .…”