A novel manganese complex LMnAc selectively kills cancer cells by induction of ROS-triggered and mitochondrial-mediated cell death  

作　　者：LI Xiang ZHAO KaiDi GUO WenJie LIU Xu LIU Jia GAO Jing CHEN QiuYun BAI YiDong 

机构地区：[1]School of Pharmacy, Jiangsu University [2]School of Chemistry & Chemical Engineering, Jiangsu University [3]Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio

出　　处：《Science China(Life Sciences)》2014年第10期998-1010,共13页中国科学（生命科学英文版）

基　　金：supported by the National Natural Science Foundation of China(21271090);the Natural Science Foundation of Jiangsu Province(BK2012710);the Society Developing Program of Zhenjiang(SH2008072);the Senior Talent Start-up Fund of Jiangsu University(13JDG064)

摘　　要：We previously identified a novel synthesized metal compound, LMnAc （[L2Mn2（Ac）（H20）e]（Ac） （L=bis（2-pyridylmethyl） amino-2-propionic acid））. This compound exhibited significant inhibition on cancer cell proliferation and was more selective against cancer cells than was the popular chemotherapeutic reagent cisplatin. In this study, we further investigated the underlying molecular mechanisms of LMnAc-induced cancer cell death. We found that LMnAc achieved its selectivity against cancer cells through the transferrin-transferrin receptor system, which is highly expressed in tumor cells. LMnAc triggered cancer cells to commit autophagy and apoptosis, which was mediated by the mitochondrial pathway. Moreover, LMnAc disrupted mitochondrial function, resulting in mitochondrial membrane potential collapse and ATP reduction. In addition, LMnAc induced intracellular Ca^2＋ overload and reactive oxygen species generation. Interestingly, its anticancer effect was significantly reduced following pretreatment with the antioxidant N-acetyl cysteine, indicating that reactive oxygen species triggered cell death. Altogether, our data suggest that LMnAc appears to be a selectively promising anticancer drug candidate.We previously identified a novel synthesized metal compound,LMnAc([L2Mn2(Ac)(H2O)2](Ac)(L=bis(2-pyridylmethyl)amino-2-propionic acid)).This compound exhibited significant inhibition on cancer cell proliferation and was more selective against cancer cells than was the popular chemotherapeutic reagent cisplatin.In this study,we further investigated the underlying molecular mechanisms of LMnAc-induced cancer cell death.We found that LMnAc achieved its selectivity against cancer cells through the transferrin-transferrin receptor system,which is highly expressed in tumor cells.LMnAc triggered cancer cells to commit autophagy and apoptosis,which was mediated by the mitochondrial pathway.Moreover,LMnAc disrupted mitochondrial function,resulting in mitochondrial membrane potential collapse and ATP reduction.In addition,LMnAc induced intracellular Ca2+overload and reactive oxygen species generation.Interestingly,its anticancer effect was significantly reduced following pretreatment with the antioxidant N-acetyl cysteine,indicating that reactive oxygen species triggered cell death.Altogether,our data suggest that LMnAc appears to be a selectively promising anticancer drug candidate.

关 键 词：Mn（II） complex selective ANTITUMOR autophagy apoptosis MITOCHONDRIA ROS 

分 类 号：R730.5[医药卫生—肿瘤]