Apoptosis: A Target for Anticancer Therapy

Abstract

Apoptosis, the cell's natural mechanism for death, is a promising target for anticancer therapy. Both the intrinsic and extrinsic pathways use caspases to carry out apoptosis through the cleavage of hundreds of proteins. In cancer, the apoptotic pathway is typically inhibited through a wide variety of means including overexpression of antiapoptotic proteins and under-expression of proapoptotic proteins. Many of these changes cause intrinsic resistance to the most common anticancer therapy, chemotherapy. Promising new anticancer therapies are plant-derived compounds that exhibit anticancer activity through activating the apoptotic pathway.

Keywords: anticancer therapy; apoptosis; apoptotic evasion; curcumin.

Figure 1

The pathway of intrinsic apoptosis. BH3-only proteins are upregulated in response to apoptotic stress. They activate BAX (BCL-2-associated X protein) and BAK (BCL-2 homologous antagonist killer) which oligomerize and results in mitochondrial membrane permeabilization. Cytochrome c, SMAC (second mitochondria-derived activator of caspase), and Omi are released and the apoptosome is formed from procaspase-9, dATP, cytochrome c, and APAF-1. Caspases are then activated and begin to cleave cellular proteins resulting in apoptosis. Arrows represent activation and T bars represent inhibition.

Figure 2

The extrinsic pathway begins with a death ligand docking on a death receptor. An adaptor protein binds to the receptor. DISC (death-inducing signaling complex) is formed from the adaptor protein and procaspases-8 and -10. Caspase-8 becomes activated which activates caspases-3, -6 and -7 and BID (BH3 interacting-domain death agonist). BID goes on to activate BAX and BAK which activates the intrinsic pathway. Caspases-3, -6 and -7 are the executioner caspases that result in cell death. Arrows represent activation and T bars represent inhibition.