Abstract
Simple SummaryApoptosis, a programmed form of cell death, represents the main mechanism by which cells die. Such phenomenon is highly regulated by the BCL-2 family of proteins, which includes both pro-apoptotic and pro-survival proteins. The decision whether cells live or die is tightly controlled by a balance between these two classes of proteins. Notably, the pro-survival Bcl-2 proteins are frequently overexpressed in cancer cells dysregulating this balance in favor of survival and also rendering cells more resistant to therapeutic interventions. In this review, we outlined the most important steps in the development of targeting the BCL-2 survival proteins, which laid the ground for the discovery and the development of the selective BCL-2 inhibitor venetoclax as a therapeutic drug in hematological malignancies. The limitations and future directions are also discussed.The major form of cell death in normal as well as malignant cells is apoptosis, which is a programmed process highly regulated by the BCL-2 family of proteins. This includes the antiapoptotic proteins (BCL-2, BCL-XL, MCL-1, BCLW, and BFL-1) and the proapoptotic proteins, which can be divided into two groups: the effectors (BAX, BAK, and BOK) and the BH3-only proteins (BIM, BAD, NOXA, PUMA, BID, BIK, HRK). Notably, the BCL-2 antiapoptotic proteins are often overexpressed in malignant cells. While this offers survival advantages to malignant cells and strengthens their drug resistance capacity, it also offers opportunities for novel targeted therapies that selectively kill such cells. This review provides a comprehensive overview of the extensive preclinical and clinical studies targeting BCL-2 proteins with various BCL-2 proteins inhibitors with emphasis on venetoclax as a single agent, as well as in combination with other therapeutic agents. This review also discusses recent advances, challenges focusing on drug resistance, and future perspectives for effective targeting the Bcl-2 family of proteins in cancer.
Highlights
One of the main steps of tumor initiation and progression is the evasion of apoptosis [1].While cancer cells are fully equipped with apoptosis machinery, they develop various strategies to block the apoptosis process
Induction of apoptosis occurs through two main pathways: the intrinsic pathway generally activated by cellular stress and the extrinsic pathway activated by death receptors (Tumor Necrosis Factors, Trail, Fas, etc.)
The former includes BCL-2, BCL-XL, mantle cell lymphoma (MCL)-1, BCL-W, and BFL-1 known as A1, whereas the latter includes effector proteins BAK, BAX, and BOK; and BH3 only proteins, which are grouped into sensitizers: BAD, NOXA, BMF, HRK, BIK; and activators: BIM, BID, and PUMA [5,6]
Summary
One of the main steps of tumor initiation and progression is the evasion of apoptosis [1]. In the intrinsic pathway of apoptosis, caspases activation requires mitochondrial outer membrane permeabilization (MOMP), an event that leads to the release of cytochrome c from the mitochondrial intermembrane space into the cytosol [4] These steps are tightly regulated by the BCL-2 family of proteins, which includes anti-apoptotic and pro-apoptotic proteins. Accumulating evidences indicate that virtually all malignancies can be associated with apoptosis resistance; the mechanisms of this phenomenon differ from one tumor to another [15,16] In this regard, overexpression of anti-apoptotic BCL-2 members (e.g., BCL-2, BCL-XL, MCL-1) is quite frequent in newly diagnosed cancer as well as after. The ability to activate the BH3 only proteins PUMA and NOXA is often impaired due to p53 deficiency in many cancer cells [19] Another mechanism of apoptotic evasion involves epigenetic aberration. These considerations have prompted extensive efforts aiming at targeting the pro-survival BCL-2 members
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