Targeting BCL-2 family proteins using BH3 mimetic drugs for cancer therapy: A systematic review of randomized clinical trials

Apoptosis plays a significant role in both carcinogenesis and cancer treatment. Apoptotic dysfunction may allow cancer cells to survive. Overexpression of anti-apoptotic B cell lymphoma-2 (BCL-2) family protein members is predicted to majorly contribute to apoptotic dysfunction. Therefore, targeting proteins in cancer has been of interest to scientists and drug developers. The most successful method to regulate apoptosis in cancer cells so far has been found in the development of BH3-mimetic drugs that may work towards downregulating anti-apoptotic BCL-2 protein functions. Clinical trials have dealt with a few molecules that mimic the function of BH3-only proteins and therefore inhibit their anti-apoptotic functions. Currently, this approach is one of the most promising and effective strategies for cancer treatment. Since the family has more than fifteen protein members, this review will focus on three members that have garnered interest as therapeutic targets: Bcl-2, Bcl-X_L, and myeloid cell leukaemia 1 (Mcl-1), all are anti-apoptosis proteins. In addition, it covers the major functions of Bcl-2, Bcl-X_L, and MCL-1, their implication in malignancy, as well as their pharmacologic inhibitors. The Food and Drug Administration has approved the first BH-3 mimetic, venetoclax, an oral Bcl-2 inhibitor shown to treat chronic lymphocytic leukemia. This systematic review of clinical trials investigates the efficacy and clinical relevance of BCL-2 family protein inhibitors in managing malignancies.