title: Tacrine induces apoptosis through lysosome- and mitochondria-dependent pathway in HepG2 cells.
abstract: Tacrine (THA) is a competitive inhibitor of cholinesterase. Administration of THA for the treatment of Alzheimer's disease results in a reversible hepatotoxicity in 30-50% of patients, as indicated by elevated alanine aminotransferase levels. However, the intracellular mechanisms have not yet been elucidated. In our previous study, we found that THA induced cytotoxicity and mitochondria dysfunction by ROS generation and 8-OHdG formation in mitochondrial DNA in HepG2 cells. In this study, the mechanism underlying was further investigated. Our results demonstrated that THA induced dose-dependent apoptosis with cytochrome c release and activation of caspase-3. THA-induced apoptosis was inhibited by treating cells with a ROS inhibitor, YCG063. In addition, we observed that THA led to an early lysosomal membrane permeabilization and release of cathepsin B. Pretreatment with CA-074Me, a specific cathepsin B inhibitor resulted in a significant but not complete decrease in tacrine-induced apoptosis. These data suggest that tacrine-induced cell apoptosis involves both mitochondrial damage and lysosomal membrane destabilization, and ROS is the critical factor that integrates tacrine-induced mitochondrial and lysosomal death pathways.
authors.affiliation: Occupational and Environmental Health Department, Dalian Medical University, Dalian 116044, China; Dalian Municipal Central Hospital, Dalian 116033, China(2).
authors.forename: Chunpeng
authors.initials: C
authors.lastname: Gao
authors.affiliation: Occupational and Environmental Health Department, Dalian Medical University, Dalian 116044, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Ding
authors.affiliation: China-Japanese Joint Institute for Medical and Pharmaceutical Science, Dalian Medical University, Dalian 116044, China.
authors.forename: Laifu
authors.initials: L
authors.lastname: Zhong
authors.affiliation: China-Japanese Joint Institute for Medical and Pharmaceutical Science, Dalian Medical University, Dalian 116044, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Jiang
authors.affiliation: China-Japanese Joint Institute for Medical and Pharmaceutical Science, Dalian Medical University, Dalian 116044, China.
authors.forename: Chengyan
authors.initials: C
authors.lastname: Geng
authors.affiliation: Occupational and Environmental Health Department, Dalian Medical University, Dalian 116044, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Yao
authors.affiliation: Occupational and Environmental Health Department, Dalian Medical University, Dalian 116044, China. Electronic address: caojunly@163.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Cao
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000378:metabolism; D002470:Cell Survival; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D045304:Cytochromes c / Q000378:metabolism; D004151:Dipeptides / Q000008:administration & dosage / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D006835:Hydrazones / Q000008:administration & dosage / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009593:Nitroimidazoles / Q000008:administration & dosage / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors; D013619:Tacrine / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: C400541:CA 074 methyl ester; D002800:Cholinesterase Inhibitors; D004151:Dipeptides; D006835:Hydrazones; D009593:Nitroimidazoles; D017382:Reactive Oxygen Species; C555826:YCG 063; D013619:Tacrine; D045304:Cytochromes c; D002401:Cathepsin B
keywords: Apoptosis; Lysosomes; Mitochondria; Oxidative stress; Tacrine