Role of apoptosis in colon cancer biology, therapy, and prevention

Abstract

Deregulation of apoptosis is a hallmark of human cancer and contributes to therapeutic resistance. Recent advances in cancer genomics reveal a myriad of alterations in key pathways that directly or indirectly increase tumor cell survival. This review will outline the pathways of apoptosis in mammalian cells, and highlight the common alterations of apoptosis regulators found in colon cancer, the role of apoptosis and underlying mechanisms in colon cancer treatment and prevention, including recent advances on investigational agents, such as kinase inhibitors, proteasome inhibitors, HSP90 inhibitors, BH3 mimetics, TRAIL, and IAP antagonists. Topics will also include novel concepts, as well as opportunities and challenges for drug discovery and combination therapy by exploring cancer-specific genetic defects, and therefore selective induction of apoptosis in cancer cells. Although the emphasis is on colon cancer, the main theme and many of the aspects are applicable to other solid tumors.

Keywords: BH3 mimetics; BH3-only protein; Bcl-2 family; EGFR; Hsp90 inhibitors; IAPs; K-RAS; NSAIDs; PI3K; SMAC mimetics; TRAIL; apoptosis; autophagy; b-Raf; c-Myc; colon cancer; death receptor; mitochondria; necrosis; protesome inhibitors; regorafinib; sorafenib; synthetic lethality; targeted therapies; vemurafenib.

Figure 1. Coaxing cancer cells into apoptosis

Apoptosis in mammalian cells is mediated through the intrinsic and extrinsic pathways. The intrinsic pathway is predominantly regulated by the Bcl-2 family and mitochondria. The extrinsic pathway is engaged upon binding of proapoptotic ligands, such as TRAILor Fas to their respective death receptors on the cell surface. Apoptosis initiation is regulated by transcription as well as the cross-talk of two apoptotic pathways via Bid. Apoptosis is activated by anticancer agents, such as radiation, chemotherapy, kinase inhibitors, BH3 or Smac mimetics, and chemopreventive agents acting on both pathways and various players, to trigger a caspase activation cascade. Inhibition of apoptosis or certain caspases such as caspase-8 can lead to increased autophagy or necrosis, providing additional targets for drug development. Antiapoptotic proteins are colored in green while proapoptotic proteins are colored in red. Cyto c, cytochrome c.