Targeting TNF-related apoptosis-inducing ligand (TRAIL) receptor by natural products as a potential therapeutic approach for cancer therapy

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to selectively induce apoptotic cell death in various tumor cells by engaging its death-inducing receptors (TRAIL-R1 and TRAIL-R2). This property has led to the development of a number of TRAIL-receptor agonists such as the soluble recombinant TRAIL and agonistic antibodies, which have shown promising anticancer activity in preclinical studies. However, besides activating caspase-dependent apoptosis in several cancer cells, TRAIL may also activate nonapoptotic signal transduction pathways such as nuclear factor-kappa B, mitogen-activated protein kinases, AKT, and signal transducers and activators of transcription 3, which may contribute to TRAIL resistance that is being now frequently encountered in various cancers. TRAIL resistance can be overcome by the application of efficient TRAIL-sensitizing pharmacological agents. Natural compounds have shown a great potential in sensitizing cells to TRAIL treatment through suppression of distinct survival pathways. In this review, we have summarized both apoptotic and nonapoptotic pathways activated by TRAIL, as well as recent advances in developing TRAIL-receptor agonists for cancer therapy. We also briefly discuss combination therapies that have shown great potential in overcoming TRAIL resistance in various tumors.

Keywords: NF-κB; TRAIL; apoptosis; cancer; natural products.

Figure 1

A schematic diagram of TRAIL-induced apoptotic signaling cascades. Binding of TRAIL to TRAIL death receptors results in recruitment of the FADD and caspase-8 to form DISC. DISC leads to the cleavage and activation of caspase-8, which can activate caspase effectors and the BH3-only protein Bid. In the extrinsic pathway, activation of caspase-8 is sufficient to activate downstream caspases-3, -6, and -7, leading to cell death. However, in the intrinsic pathway, cleavage of Bid into its truncated form (tBid) is essential to induce cell death. tBid can rapidly translocate to the mitochondria and drive (through Bax and Bak) permeabilization of the outer mitochondrial membrane, releasing mitochondrial cytochrome c and Smac. This process can be blocked by overexpression of Bcl-2 and Bcl-xL. Once in the cytosol, cytochrome c binds to the adaptor Apaf-1 to recruit the initiator caspase-9 into the apoptosome, which can activate caspase-9 and the effector caspases. Release of Smac augments apoptosis by antagonizing the inhibitory effect of XIAP on the various effector caspases. (A color version of this figure is available in the online journal.)

Figure 2

A schematic overview of prosurvival signals elicited by the activation of TRAIL receptors. With agonists binding to TRAIL-R1/R2, a secondary complex can be formed after receptor activation, leading to the activation of various signaling pathways that are involved in induction of nonapoptotic responses as indicated. (A color version of this figure is available in the online journal.)