B Cell Lymphoma 2: A Potential Therapeutic Target for Cancer Therapy

Abstract

Defects in the apoptosis mechanism stimulate cancer cell growth and survival. B cell lymphoma 2 (Bcl-2) is an anti-apoptotic molecule that plays a central role in apoptosis. Bcl-2 is the founding constituent of the Bcl-2 protein family of apoptosis controllers, the primary apoptosis regulators linked with cancer. Bcl-2 has been identified as being over-expressed in several cancers. Bcl-2 is induced by protein kinases and several signaling molecules which stimulate cancer development. Identifying the important function played by Bcl-2 in cancer progression and development, and treatment made it a target related to therapy for multiple cancers. Among the various strategies that have been proposed to block Bcl-2, BH3-mimetics have appeared as a novel group of compounds thanks to their favorable effects on many cancers within several clinical settings. Because of the fundamental function of Bcl-2 in the regulation of apoptosis, the Bcl-2 protein is a potent target for the development of novel anti-tumor treatments. Bcl-2 inhibitors have been used against several cancers and provide a pre-clinical platform for testing novel therapeutic drugs. Clinical trials of multiple investigational agents targeting Bcl-2 are ongoing. This review discusses the role of Bcl-2 in cancer development; it could be exploited as a potential target for developing novel therapeutic strategies to combat various types of cancers. We further highlight the therapeutic activity of Bcl-2 inhibitors and their implications for the therapeutic management of cancer.

Keywords: B cell lymphoma 2; apoptosis; cancers; clinical trials; inhibitors; targeted therapy.

Figure 1

The intrinsic and extrinsic pathways of apoptosis. The two pathways that initiate apoptosis are the extrinsic (or death receptor initiated by ligand binding and subsequent activation of caspase-8) pathway and intrinsic pathway (driven by Bcl-2 family proteins, release cyt-c and activation of caspase-9) of apoptosis. Both pathways lead to a common apoptosis pathway by activating caspases-3, -6, and -7, triggering apoptosis. Bcl-2 family proteins are primarily localized to mitochondria and present on the ER and the perinuclear membrane in hematopoietic cells.

Figure 2

Structural composition of Bcl-2.(A) Figure indicating the position of the Bcl-2 gene and promoters in the human chromosome. (B) The figure shows the Bcl-2 gene composed of three exons, exon 1 and exon 2 encoding the four BH (BH1-4) domains and exon 3 encoding the transmembrane (TM) domain.

Figure 3

Bcl-2 amino-acid sequences and three-dimensional structure. (A) Bcl-2 is a 26 kDa, 239 amino-acid protein that is composed of four domains, the BH4 domain (residues 10–30), BH3 domain (residues 93–107), BH1 domain (residues 136–155), and BH2 domain (residues 187–202). (B) The amino acid sequences of the BH1-4 domains of Bcl-2. The colored letters denote various α-helices α1–α8 (Hα1–Hα8) and BH1-4 domains of Bcl-2. (C) The tertiary structure of Bcl-2; highlighted regions denote α-helices (α1–α8) and BH1-4 domains. The left panel indicates the Bcl-2 tertiary structure with α1–α8 with various colors, showing the same color coding as (B) (PDB ID: 1G5M). The right panel indicates the structure of Bcl-2 with the BH1-4 domains.

Figure 4

Bcl-2-mediated apoptosis cascade and the mechanism of action of inhibitors. Over-expression of Bcl-2 might be blocked and inhibited through Bcl-2 inhibitors. Inhibitors block cancer progression by targeting signaling molecules or protein kinases that abrogate Bcl-2 expression and decrease the expression of Bcl-2 by inhibiting cell growth and proliferation and initiating apoptosis.