Chemical Regulation of the Apoptosome: New Alternative Treatments for Cancer

Abstract Many chemotherapeutic drugs and treatments initiate apoptotic cell death by inducing the release of cytochrome c from the mitochondria, which activates Apaf-1. This large (approximately 130–140 kDa) protein is a mammalian homolog of CED-4, an essential protein involved in programmed cell death in the nematode Caenorhabditis elegans. Cytochrome c activates Apaf-1, which oligomerizes to form the Apaf-1 apoptosome complex, which recruits caspase-9, an initiator caspase, to form a holoenzyme complex. Subsequently, the Apaf-1/caspase-9 holoenzyme complex recruits and processes effector caspases-3 and -7, thereby initiating the caspase cascade that is responsible for the execution phase of apoptosis. Intracellular levels of XIAP, an inhibitor of apoptosis protein, and at least two mitochondrial-released proteins, Smac/DIABLO and Omi/Htra2, a serine protease, tightly regulate formation and function of the apoptosome. The formation, structure and functioning of the apoptosome complex have been extensively studied, and are reviewed in this chapter. Emerging evidence which is reviewed in this chapter suggests that defects in this pathway can also lead or contribute to drug-resistant cancers, particularly melanomas. However, new evidence also suggests that in the absence of Apaf-1, mitochondrial stress and cytochrome c release can still kill cells by inducing caspase-independent cell death. Although this form of cell death seems to be a slower process, it still ultimately destroys the cell and implies that Apaf-1 is not essential for cell death in terminally differentiated cells. However, it is clear that the presence of Apaf-1 and a functioning apoptosome pathway greatly enhances or accelerates cell death by rapid activation of the caspases. Significantly, a number of studies have shown that a variety of small molecules can directly activate or inhibit caspase activation by acting on the formation and function of the apoptosome complex. These results suggest that compounds which can activate or synergize the apoptosome pathway in cancer cells could provide new alternative treatments for cancer.