Modulation of death receptors by cancer therapeutic agents.

Death receptors are important modulators of the extrinsic apoptotic pathway. Activating certain death receptors such as death receptors for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (i.e., DR4 and DR5) selectively kills cancer cells via induction of apoptosis while sparing normal cells. Thus, soluble recombinant TRAIL and agonistic antibodies to DR4 or DR5 have progressed to phase I and phase II clinical trials. Many cancer therapeutic drugs including chemotherapeutic agents have been shown to induce the expression or redistribution at the cell surface of death receptors including TRAIL death receptors. In addition, chemotherapeutic agents have also been shown to enhance induction of apoptosis by TRAIL or agonistic antibodies or overcome cell resistance to TRAIL or agonistic antibodies. Targeted induction of apoptosis by activation of the death receptor-mediated extrinsic apoptotic pathway should be an ideal therapeutic strategy to eliminate cancer cells. Therefore, death receptors, particularly TRAIL death receptors, have emerged as an important cancer therapeutic target. This article will focus on reviewing and discussing the modulation of death receptors by cancer therapeutic agents and its implications in cancer therapy.