Medicarpin, a legume phytoalexin sensitizes myeloid leukemia cells to TRAIL-induced apoptosis through the induction of DR5 and activation of the ROS - JNK - CHOP pathway

Abstract

Tumor necrosis factor α-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent with cancer cell-selective cell death inducing effect. However, the major limitation in the usage of TRAIL as a chemotherapeutic agent is the development of TRAIL resistance in many cancer types including myeloid leukemia. In this study, we report for the first time that Medicarpin, a naturally occurring phytoalexin sensitizes myeloid leukemia cells to TRAIL-induced apoptosis. Combination of Medicarpin and TRAIL induced significantly higher apoptosis compared to that of the individual treatments of either agent alone through activation of both the extrinsic as well as intrinsic cell death pathways in the myeloid leukemia cells. Medicarpin treatment downregulated anti-apoptotic proteins (Survivin, Bcl2, Bcl-xL, XIAP and c-FLIP) and upregulated the pro-apoptotic protein (Bax, p-eIF2α, Bip and CHOP) expression. Medicarpin treatment increased the expression of the functional TRAIL receptor DR5 through activation of the reactive oxygen species (ROS)-JNK-CHOP pathway. Gain and loss of function studies clearly indicated that DR5 expression was critical for Medicarpin induced TRAIL sensitization. The concomitant treatment with Medicarpin and TRAIL showed robust apoptotic effects in primary myeloid leukemia cells but had no toxic effects in primary human PBMCs. In conclusion, our results suggest that Medicarpin sensitizes myeloid leukemia cells to TRAIL induced apoptosis through the up-regulation of DR5 through activation of the ROS- JNK-CHOP pathway. These results in myeloid leukemia cell lines and primary cells provide a rationale for testing the combination of Medicarpin and TRAIL in management of myeloid leukemia.