SMAC agonists blaze the TRAIL to tumor cells

Abstract

Of prime concern in cancer therapy is the resistance of many tumors to current treatment regimes, often because of defects in the ability of tumor cells to undergo apoptosis. The aim of cancer biologists is therefore to develop new strategies that exclusively target tumor cells that are resistant to apoptosis. Apoptosis resulting in activation of caspases can be initiated by at least two stimulatory pathways: one requires activation of death receptors by death-inducing ligand members of the tumor necrosis factor (TNF) family and the other, initiated by chemotherapeutic agents, involves the release of pro-apoptotic factors such as cytochrome c and SMAC (second mitochondria-derived activator of caspases) from mitochondria. The cytotoxic ligand TRAIL (TNF-related apoptosis-inducing ligand) is a promising candidate for cancer therapy because it is selectively toxic to tumor cells with little or no toxicity evident in normal cells. The apoptotic signal initiated by TRAIL often results in mitochondrial perturbation and in many cells TRAIL engages a mitochondrial amplification loop for maximal cytotoxicity.