Embelin Sensitizes Acute Myeloid Leukemia Cells to TRAIL through XIAP Inhibition and NF-κB Inactivation

Abstract

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.

<p>Embelin Promotes Oncolytic Vaccinia Virus-Mediated Antitumor Immunity Through Disruption of IL-6/STAT3 Signaling in Lymphoma</p>

“…21 Embelin can further serve to inhibit the X chromosome-linked inhibitor-ofapoptosis protein, 22 promoting the apoptotic death of tumor cells via interfering with nuclear factor-kappa B (NF-κB) signaling, 23 in addition to driving TRAILmediated apoptosis, 24 inhibiting STAT3 activation, 25 and blocking Akt/mTOR/S6K1 signaling. 26 In the previous work, we have determined that embelin is capable of rendering acute myeloid leukemia (AML) cells more sensitive to trail via repressing NF-κB both in vitro and in vivo, 27 which raises the possibility that embelin might be combined with oncolytic viruses in order to enhance their therapeutic utility as a means of treating this cancer. However, at present how embelin directly affects OVV replication and functionality remains uncertain.…”

Targeting of X-linked inhibitor of apoptosis protein and PI3-kinase/AKT signaling by embelin suppresses growth of leukemic cells

“…Embelin is a potent small molecule inhibitor of XIAP which prevents the binding of XIAP to procaspase-9 [19] and exhibits cytotoxic effects via suppressing the activity various signaling cascades including PI3-kinase/AKT in a variety of cancer cell lines [4, 5, 21–23]. Embelin has been found to sensitise acute myeloid leukemic cells to TRAIL through the inhibition of XIAP and inactivation of NF-kB activity [24–26]. Therefore, we investigated the antitumor activity of embelin using leukemic cell lines, with an interest in supporting previous findings that XIAP can be considered as potential target for anticancer therapy [27, 28].…”

XIAP inhibitor Embelin inhibits bladder cancer survival and invasion in vitro

“…XIAP, which can regulate cell apoptosis via inhibiting activity of caspase pathways, is most extensively studied and well characterized among the mammalian IAPs. Embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone), one of small-molecule inhibitors of XIAP, is reported to possess anti-oxidant, anti-bacterial, and antiinflammatory activities [7][8][9]. Embelin was identified as a small molecular weight inhibitor of XIAP which has been identified as one of the most potent inhibitors of caspase activity and apoptosis.…”