Targeting cell death signaling in colorectal cancer: current strategies and future perspectives

Abstract

The evasion from controlled cell death induction has been considered as one of the hallmarks of cancer cells. Defects in cell death signaling are a fundamental phenomenon in colorectal cancer. Nearly any non-invasive cancer treatment finally aims to induce cell death. However, apoptosis resistance is the major cause for insufficient therapeutic success and disease relapse in gastrointestinal oncology. Various compounds have been developed and evaluated with the aim to meet with this obstacle by triggering cell death in cancer cells. The aim of this review is to illustrate current approaches and future directions in targeting cell death signaling in colorectal cancer. The complex signaling network of apoptosis will be demonstrated and the "druggability" of targets will be identified. In detail, proteins regulating mitochondrial cell death in colorectal cancer, such as Bcl-2 and survivin, will be discussed with respect to potential therapeutic exploitation. Death receptor signaling and targeting in colorectal cancer will be outlined. Encouraging clinical trials including cell death based targeted therapies for colorectal cancer are under way and will be demonstrated. Our conceptual understanding of cell death in cancer is rapidly emerging and new types of controlled cellular death have been identified. To meet this progress in cell death research, the implication of autophagy and necroptosis for colorectal carcinogenesis and therapeutic approaches will also be depicted. The main focus of this topic highlight will be on the revelation of the complex cell death concepts in colorectal cancer and the bridging from basic research to clinical use.

Keywords: Apoptosis; Autophagy; BH-3 mimetics; Bcl-2 proteins; Clinical trial; Colorectal cancer; Inflammatory bowel disease; Necroptosis.

Figure 1

Apoptosis signaling and cell death relevant drugs. Cell death based cancer therapy can be approached by targeting proteins in the extrinsic or intrinsic pathway. Relevant agents, currently under clinical investigation, are listed and placed to their targets. APAF1: Apoptotic protease activating factor-1; CytC: Cytochrome C; IAP: Inhibitors of apoptosis; tBID: Truncated BID; FADD: Fas-associated protein with death domain; TNF: Tumor necrosis factor; TRAIL: Tumor necrosis factor related apoptosis-inducing ligand.