Embelin sensitizes acute myeloid leukemia cells to TRAIL through XIAP inhibition and NF-κB inactivation.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promising result in cancer therapy and induces apoptosis in a wide variety of tumor cells, without causing toxicity to normal cells. However, many tumor cells including acute myeloid leukemia (AML) showed certain degrees of resistance to TRAIL and the mechanism remains largely unknown. Embelin is a potent XIAP inhibitor which has been shown to inhibit the proliferation of tumor cells and cause cell apoptosis. In this study, we investigated the effects of Embelin on the TRAIL-induced apoptosis and the underlying mechanism. Here, we chose an adenovirus vector as the expression vector for TRAIL, which was named Ad-TRAIL. The results in vitro showed that the co-treatment of Embelin and Ad-TRAIL has synergistically suppressed the proliferation of AML cells. Embelin has the ability to enhance TRAIL-induced apoptosis and activate caspase pathway. More interestingly, we found that the underlying mechanism for these talent skills of Embelin is through reducing the TRAIL-mediated activation of NF-κB and decreasing its transcriptional activity. Furthermore, our results in vivo suggest that combined therapy of Embelin and Ad-TRAIL caused significant growth inhibition of HL-60 xenograft tumors. Our results suggested that Embelin could sensitize AML cell to TRAIL through the repression of NF-κB signal pathway in vitro and in vivo, and combined therapy of Ad-TRAIL and Embelin may be the attractive candidate for clinical application in treatment of AML.