title: A novel manganese complex LMnAc selectively kills cancer cells by induction of ROS-triggered and mitochondrial-mediated cell death.
abstract: 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 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.
authors.affiliation: School of Pharmacy, Jiangsu University, Zhenjiang, 212013, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.forename: KaiDi
authors.initials: K
authors.lastname: Zhao
authors.forename: WenJie
authors.initials: W
authors.lastname: Guo
authors.forename: Xu
authors.initials: X
authors.lastname: Liu
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.forename: Jing
authors.initials: J
authors.lastname: Gao
authors.forename: QiuYun
authors.initials: Q
authors.lastname: Chen
authors.forename: YiDong
authors.initials: Y
authors.lastname: Bai
mesh_terms: D000111:Acetylcysteine / Q000737:chemistry; D000255:Adenosine Triphosphate / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry*; D000975:Antioxidants / Q000737:chemistry; D017209:Apoptosis; D001343:Autophagy; D002118:Calcium / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D056831:Coordination Complexes / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor; D049452:Green Fluorescent Proteins / Q000737:chemistry; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D017895:Manganese Compounds / Q000737:chemistry*; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism*; D011422:Propionates / Q000737:chemistry*; D017382:Reactive Oxygen Species; D011990:Receptors, Transferrin / Q000737:chemistry; D014168:Transferrin / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D056831:Coordination Complexes; D017895:Manganese Compounds; D011422:Propionates; D017382:Reactive Oxygen Species; D011990:Receptors, Transferrin; D014168:Transferrin; D049452:Green Fluorescent Proteins; D000255:Adenosine Triphosphate; C029658:propionic acid; D002118:Calcium; D000111:Acetylcysteine