Activation of cell surface
death receptors by their cognate
ligands triggers apoptosis. Several human
death receptors (Fas, TNF-R1, TRAMP, DR4, DR5, DR6, EDA-R and
NGF-R) have been identified. The most promising
cytokine for anticancer
therapy is TRAIL/APO-2L, which induces apoptosis in
cancer cells by binding to
death receptors TRAIL-R1/DR4 and TRAIL-R2/DR5. The cytotoxic activity of TRAIL is relatively selective to
cancer cells compared to normal cells. Signaling by TRAIL and its receptors is tightly regulated process essential for key physiological functions in a variety of organs, as well as the maintenance of immune homeostasis. Despite early promising results, recent studies have identified several TRAIL-resistant
cancer cells of various origins. Based on molecular analysis of
death-receptor signaling pathways several new approaches have been developed to increase the efficacy of TRAIL. Resistance of
cancer cells to TRAIL appears to occur through the modulation of various molecular targets. They may include differential expression of
death receptors, constitutively active Akt and NFkappaB, overexpression of cFLIP and IAPs, mutations in Bax and Bak genes, and defects in the release of
mitochondrial proteins in resistant cells. Conventional chemotherapeutic and chemopreventive drugs, and irradiation can sensitize TRAIL-resistant cells to undergo apoptosis. Thus, these agents enhance the therapeutic potential of TRAIL in TRAIL-sensitive cells and sensitize TRAIL-resistant cells. TRAIL and TRAIL-receptor
antibodies may prove to be useful for
cancer therapy, either alone or in association with conventional approaches such as
chemotherapy or
radiation therapy. This review discusses intracellular mechanisms of TRAIL resistance and various approaches that can be taken to sensitize TRAIL-resistant
cancer cells.