Abstract
The dynamic interplay between pro-death and pro-survival Bcl-2 family proteins is responsible for a cell’s fate. Due to the recognized relevance of this family in cancer progression and response to therapy, different efforts have made in recent years in order to develop small molecules able to target anti-apoptotic proteins such as Bcl-2, Bcl-xL and Mcl-1. The limitations of the first Bcl-2 family targeted drugs, regarding on-target and off-target toxicities, have been overcome with the development of venetoclax (ABT-199), the first BH3 mimetic inhibitor approved by the FDA. The purpose of this review is to discuss the state-of-the-art in the development of drugs targeting Bcl-2 anti-apoptotic proteins and to highlight the potential of their application as single agents or in combination for improving anti-cancer therapy, focusing in particular on solid tumors.
Highlights
Apoptosis is a deeply studied form of programmed cell death that triggers cells to suicide through proteolysis of some key cellular components, which renders cells prone to be recognized by phagocytes [1] The two mechanisms of apoptotic induction are the “death receptor” or “extrinsic”pathway activated by exogenous death-inducing ligands, and the “mitochondrial” or “intrinsic”pathway induced by stress conditions [1]
B cell lymphoma-2 (Bcl-2) and Bcl-xL is able to bind other proteins that do not belong to Bcl-2 protein family, allowing them to play a role beyond their classical role in inhibiting apoptosis, in other important cellular functions such as proliferation, autophagy, differentiation, DNA repair, tumor progression, and angiogenesis [6]
The turning point in the research for Bcl-2 inhibitors was reached with the development of venetoclax, a potent and selective BH3 mimetic for Bcl-2 protein, which was able to circumvent the thrombocytopenia observed with navitoclax [122]
Summary
Apoptosis is a deeply studied form of programmed cell death that triggers cells to suicide through proteolysis of some key cellular components, which renders cells prone to be recognized by phagocytes [1] The two mechanisms of apoptotic induction are the “death receptor” or “extrinsic”. The anti-apoptotic Bcl-2 family proteins exert their pro-survival function by binding and inhibiting the pro-apoptotic proteins, the sensors of cellular stress (the BH3-only proteins) and the effectors of apoptosis (Bax and Bak) [7]. Since the discovery of Bcl-2, the founding member of the family, many papers have been published regarding the role that Bcl-2 anti-apoptotic members play in cancer and in drug resistance, as well as on their use for cancer therapy Due to their multiple functions in cancer, Bcl-2 family proteins have become interesting targets for anti-cancer drugs. Given the high volume of information about the relevance of Bcl-2 inhibitors in hematologic malignancies, including acute myeloid leukemia (AML), mature B-Cell malignancies and lymphoid malignancies [11,12,13], this article will focus mainly on Bcl-2 inhibitor application in solid tumors
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