PEITC triggers multiple forms of cell death by GSH-iron-ROS regulation in K7M2 murine osteosarcoma cells  

作　　者：Huan-huan Lv Chen-xiao Zhen Jun-yu Liu Peng Shang 

机构地区：[1]School of Life Sciences,Northwestern Polytechnical University,Xi'an 710072,China [2]Research&Development Institute of Northwestern Polytechnical University in Shenzhen,Shenzhen 518057,China [3]Key Laboratory for Space Bioscience and Biotechnology,Northwestern Polytechnical University,Xi'an 710072,China [4]Research Center of Microfluidic Chip for Health Care and Environmental Monitoring,Yangtze River Delta Research Institute of Northwestern Polytechnical University in Taicang,Suzhou 215400,China

出　　处：《Acta Pharmacologica Sinica》2020年第8期1119-1132,共14页中国药理学报（英文版）

基　　金：the National Natural Science Foundation of China[No.81803032];the Natural Science Foundation of Shaanxi Province[No.2019JQ632];the Zhejiang Postdoctoral Science Fund,and the Fundamental Research Funds for the Central Universities[No.31020170QD111].

摘　　要：Phenethyl isothiocyanate(PEITC)is an isothiocyanate that largely exists in cruciferous vegetables and exhibits chemopreventive and chemotherapeutic potential against various cancers.However,it is little known about the molecular mechanisms of its antitumor action against osteosarcoma,which is the second highest cause of cancer-related death in children and adolescents.In this study,we investigated the effects of PEITC on K7M2murine osteosarcoma both in vitro and in vivo.We found that treatment with PEITC dose-dependently inhibited the viability of K7M2 murine osteosarcoma cells with an lCso value of 33.49μM at 24h.PEITC(1,15,30μM)dose-dependently inhibited the cell proliferation,caused G/M cell cycle arrest,depleted glutathione(GSH)generated reactive oxygen species(ROS),altered iron metabolism,and triggered multiple forms of cell death,namely ferroptosis apoptosis,and autophagy in K7M2 cells.We further revealed that PEITC treatment activated MAPK signaling pathway,and ROS generation was a major cause ofPEITC-induced cell death.In a syngeneic orthotopic osteosarcoma mouse model,administration of PEITC(30,60 mg/kg every day,ig,for 24 days)significantly inhibited the tumor growth,but higher dose of PEITC(90 mg/kg every day)compromised its ant-osteosarcoma effect.Histological examination showed that multiple cell death processes were initiated,iron metabolism was altered and MAPK signaling pathway was activated in the tumor tissues.In conclusion,we demonstrate that PEITC induces ferroptosis,autophagy,and apoptosis in K7M2 osteosarcoma cell by activating the ROS-elated MAPK signaling pathway.PEITC has promising anti-osteosarcoma activity.This study sheds light on,the redox signaling-based chemotherapeutics for cancers.

关 键 词：OSTEOSARCOMA PEITC redox system iron metabolism MAPK signaling pathway cell death 

分 类 号：R96[医药卫生—药理学]