Targeting death receptors for TRAIL by agents designed by Mother Nature

• Nutraceuticals can upregulate DRs by various mechanisms including ROS, CHOP, p53, Sp1, ERK1/2, JNK1/2, NF-κB, and YY1.
• Nutraceuticals can increase the anticancer potential of TRAIL or agonistic antibodies against DR4 or DR5.

Selective killing of cancer cells is one of the major goals of cancer therapy. Although chemotherapeutic agents are being used for cancer treatment, they lack selectivity toward tumor cells. Among the six different death receptors (DRs) identified to date, DR4 and DR5 are selectively expressed on cancer cells. Therefore, unlike chemotherapeutic agents, these receptors can potentially mediate selective killing of tumor cells. In this review we outline various nutraceuticals derived from ‘Mother Nature’ that can upregulate DRs and thus potentiate apoptosis. These nutraceuticals increase tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis of cancer cells through different mechanisms. First, nutraceuticals have been found to induce DRs through the upregulation of various signaling molecules. Second, nutraceuticals can downregulate tumor cell-survival pathways. Third, nutraceuticals alone have been found to activate cell-death pathways. Although both TRAIL and agonistic antibodies against DR4 and DR5 are in clinical trials, combination with nutraceuticals is likely to boost their anticancer potential.