Terminalia Chebula provides protection against dual modes of necroptotic and apoptotic cell death upon death receptor ligation.

Yoonjung Lee,Wonhyoung Seo,Kyung-Cheol Sohn,Han-Ming Shen,Hyeong-Geug Kim,Jeong Ho Seok,Kidong Kang,So-Ra Lee,Hee Sun Byun,Gang Min Hur,Ill Young Lee,Chang Gue Son,Kyeong Ah Park,Minho Won

doi:10.1038/srep25094

Abstract

Death receptor (DR) ligation elicits two different modes of cell death (necroptosis and apoptosis) depending on the cellular context. By screening a plant extract library from cells undergoing necroptosis or apoptosis, we identified a water extract of Terminalia chebula (WETC) as a novel and potent dual inhibitor of DR-mediated cell death. Investigation of the underlying mechanisms of its anti-necroptotic and anti-apoptotic action revealed that WETC or its constituents (e.g., gallic acid) protected against tumor necrosis factor-induced necroptosis via the suppression of TNF-induced ROS without affecting the upstream signaling events. Surprisingly, WETC also provided protection against DR-mediated apoptosis by inhibition of the caspase cascade. Furthermore, it activated the autophagy pathway via suppression of mTOR. Of the WETC constituents, punicalagin and geraniin appeared to possess the most potent anti-apoptotic and autophagy activation effect. Importantly, blockage of autophagy with pharmacological inhibitors or genetic silencing of Atg5 selectively abolished the anti-apoptotic function of WETC. These results suggest that WETC protects against dual modes of cell death upon DR ligation. Therefore, WETC might serve as a potential treatment for diseases characterized by aberrantly sensitized apoptotic or non-apoptotic signaling cascades.

Highlights

The discovery of compounds that regulate apoptotic and necroptotic pathways will be useful for developing therapeutic approaches for relevant diseases
Based on earlier pharmacological and biochemical studies, this plant exhibits antioxidant and free radical-scavenging activities in vitro and in vivo[18,19]. In view of these findings, the large body of research regarding the cytoprotective effects of T. chebula has focused predominantly on necrotic cell death[30,32]
As reactive oxygen species (ROS) have a crucial role in tumor necrosis factor (TNF)-induced necroptotic cell death, it is assumed that T. chebula may inhibit necrotic cell death

Summary

Introduction

The discovery of compounds that regulate apoptotic and necroptotic pathways will be useful for developing therapeutic approaches for relevant diseases. T. chebula, a member of the Combretaceae family, is a popular traditional medicine in India and East Asia[13] It exhibits a variety of in vivo pharmacological activities, such as anti-aging, anti-ulcer, cardioprotection, and wound healing[14,15,16,17]. Elucidating the effects of the principle constituents of T. chebula on apoptosis or necroptosis will be informative for developing potential therapeutic approaches for regulating the specific modes of cell death. We investigated the protective effects of T. chebula and its constituents on the dual modes of cell death (apoptosis and necroptosis) induced by DR ligation, and the underlying mechanisms

Methods

Results

Conclusion