Therapeutics Targeting the Core Apoptotic Machinery

Abstract

Therapeutic targeting of the apoptotic pathways for the treatment of cancer is emerging as a valid and exciting approach in anti-cancer therapeutics. Accumulating evidence demonstrates that cancer cells are typically "addicted" to a small number of anti-apoptotic proteins for their survival, and direct targeting of these proteins could provide valuable approaches for directly killing cancer cells. Several approaches and agents are in clinical development targeting either the intrinsic mitochondrial apoptotic pathway or the extrinsic death receptor mediated pathways. In this review, we discuss the main apoptosis pathways and the key molecular targets which are the subject of several drug development approaches, the clinical development of these agents and the emerging resistance factors and combinatorial treatment approaches for this class of agents with existing and emerging novel targeted anti-cancer therapeutics.

Keywords: FLIP; apoptosis; cancer therapeutics; resistance.

Figure 1

Intrinsic apoptotic pathway. In the intrinsic pathway, internal stresses such as DNA damage can lead to the B-cell lymphoma family-2 homology domain -3 (BH3) sensor proteins being activated and inhibiting anti-apoptotic B-cell lymphoma family-2 (BCL-2) proteins, leading to oligomerisation and activation of BCL-2 associated X protein (BAX)and BCL-2 antagonist killer 1 (BAK) and the formation of pores in the outer mitochondrial membrane. Mitochondrial outer membrane permeabilization (MOMP) releases cytochrome c and second mitochondrial activator of caspase (SMAC). Cytochrome c forms a complex with apoptotic protease-activating factor 1 (APAF1) and pro-caspase-9, termed the apoptosome, in which procaspase-9 dimerises and becomes activated triggering the activation of a caspase cascade. The active caspase-9 heterodimer cleaves and activates the apoptotic effector caspases -3 and -7. SMAC inhibits X-linked inhibitor of apoptosis (XIAP) to facilitate activation of procaspase-3 and -7. Created with BioRender.com (accessed on 25 May 2021).

Figure 2

The extrinsic apoptosis pathway. The death receptor-mediated extrinsic apoptosis pathway is initiated following ligand binding to a trimeric death receptor. In the case of Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) binding the TRAIL receptor (TRAIL-R) the adaptor protein, Fas-associated death domain (FADD), is recruited to the death receptor via homotypic death domain interactions. FADD subsequently recruits procaspase-8 through interactions of their respective death effector domains, forming the death inducing signaling complex (DISC). Procaspase-8 dimerizes and is activated to release the active caspase-8 homodimer. FADD-like IL1β-converting enzyme inhibitory protein (FLIP) can also be recruited to the DISC where it can modulate the activation of caspase-8. In Type I cells, caspase-8 directly activates effector procaspase-3 and -7. In type II cells, apoptosis depends on caspase-8-mediated cleavage of BH3-interacting domain death agonist (BID). Activated tBID translocates to the mitochondria to induce BCL-2 associated X protein (BAX)/ BCL-2 antagonist killer 1 (BAK) mediated mitochondrial outer membrane permeabilization (MOMP). Subsequent second mitochondrial activator of caspase (SMAC) release neutralizes X-linked inhibitor of apoptosis (XIAP) and permits the final auto-catalytic step in the activation of caspases-3/7. Created with BioRender.com (accessed on 25 May 2021).

Figure 3

B-cell lymphoma family-2 (BCL-2) Family Members. Family members of the BCL-2 protein family comprising: (i) B-cell lymphoma family-2 homology domain -3 (BH3)-only pro-apoptotic initiating proteins; (ii) the anti-apoptotic family members that protect against apoptosis by inhibiting the BH3-only proteins or neutralising the effector proteins directly; and (iii) the pro-apoptotic effector proteins which once activated trigger mitochondrial outer membrane permeabilization (MOMP), releasing apoptogenic factors from the mitochondria, leading to caspase activation and apoptosis. Listed are the agents developed to target specifically the indicated target(s).

Figure 4

Timeline of progress in therapeutics targeting the apoptotic core machinery. This figure summarizes some of the major advances in the development of different therapeutic agents targeting key anti-apoptotic proteins from the early 1980’s to the current time. Abbreviations:B-cell lymphoma family (BCL-2), BCL-2 associated X protein (BCL-XL), B-cell lymphoma-w (BCL-W), BCL-2 homology domain-3 (BH3), Chronic Lymphocytic leukaemia (CLL), Circularly permuted TRAIL (CPT), Death receptor (DR), US Food and Drug Administration (FDA), Fas-associated death domain (FADD)-like IL1β-converting enzyme-inhibitory protein (FLIP), messenger RNA (mRNA), Second mitochondria-derived activator of caspases (SMAC), Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL).