Reawakening Apoptosis in Cancer Cells: The Advent of BH3-Mimetic Drugs
CANCER
Figure 1. Human THP-1 monocytic cells generating beaded-apoptopodia to regulate the formation of apoptotic bodies. Nowak-Sliwinska P., & Griffioen A. W. (2018). “Apoptosis on the move.” Apoptosis, 23(5-6):251-254.
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"Apoptosis refers to programmed cell death, a form of ‘cellular suicide’ that is regulated by altering the activity of specific proteins."
he uniquely fatal nature of cancer lies in unhindered proliferation, which bypasses the apoptotic machinery within the cells. Apoptosis refers to programmed cell death, a form of ‘cellular suicide’ that is regulated by altering the activity of specific proteins. Apoptosis is an orderly process that is initiated by the permeabilization of the cell’s plasma membrane, which leads to fragmentation of its DNA by activated caspase cascades and ultimately, cell death (Renehan et al., 2001). Without apoptosis, cells can continue to proliferate and grow at uninhibited and potentially threatening rates. There are two widely studied pathways for apoptosis. One is the extrinsic pathway, where an extracellular ligand binds to transmembrane cell-death receptors to stimulate apoptosis. The other is the intrinsic pathway, which involves directly modifying mitochondrial membranes by activating certain conserved
signaling pathways within the cell, ultimately inducing caspase activity. An oncogene refers to any gene which can encode a protein that is able to induce cancer within animals. A subsection of oncogenes, termed proto-oncogenes, are derived from mutations in normal cellular genes. The products of proto-oncogenes are directly involved in pathways that control cellular growth; for example, a mutant form of the normal ras proto-oncogene, the rasD oncogene, encodes an oncoprotein which directly promotes uninhibited cellular growth. Since the first discovery of an anti-apoptotic oncogene, BCL-2 (B-cell lymphoma 2), researchers have developed an entirely new class of pharmacological small molecule therapeutics. Cancer cell proliferation is maintained by forced expression of anti-apoptotic BCL-2 proteins, among various other anti-apoptotic proteins, which defend malignant cells from pro-apoptot-
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ic pressure. The significance of the equilibrating interactions between antiapoptotic and pro-survival BCL-2 proteins in cancerous cells have given rise to an increasing number of therapeutic agents, such as the dual BCL-2/ BCL-XL inhibitor Navitoclax. The inhibition of anti-apoptotic, pro-survival BCL-2 proteins and the activation of their pro-apoptotic counterparts in early stage tumorigenesis is an area of increasing interest and study. The cell life cycle is governed by the interactions of two broad classes of BCL-2 proteins: pro-apoptotic and pro-survival [Figure 2]. A third class of BCL-2 proteins, the BH3-only proteins, dictate the function of these two BCL-2 proteins types through selective binding, thus regulating the apoptotic commitment of the cell via mitochondrial membrane permeabilization. BH3-only proteins are highly specific, and differential protein–protein binding between pro-survival
