title: Potent proapoptotic actions of dihydroartemisinin in gemcitabine-resistant A549 cells.
abstract: Our recent studies have demonstrated the key roles of reactive oxygen species (ROS)-mediated caspase-8- and Bax-dependent apoptotic pathways in dihydroartemisinin (DHA)-induced apoptosis of A549 cells. This report is designed to investigate the proapoptotic mechanisms of DHA in gemcitabine (Gem)-resistant A549 (A549GR) cells. A549GR cells exhibited lower basal antioxidant capacity, higher level of basal ROS and intracellular Fe(2+) than Gem-sensitive A549 (A549) cells. In contrast to the sluggish ROS generation induced by Gem, DHA induced a rapid ROS generation within 30min. Moreover, Gem induced similar ROS generation in both cell lines, while DHA induced more ROS generation in A549GR cells than in A549 cells. More importantly, after treatment with DHA, A549GR cells showed more potent induction in Bax activation, loss of mitochondrial membrane potential (ΔΨm), caspase activation and apoptosis than A549 cells. Furthermore, NAC pretreatment potently prevented DHA-induced ROS generation and loss of ΔΨm as well as apoptosis, and silencing Bax by shRNA or inhibition of one of caspase-3, -8 and -9 also significantly prevented DHA-induced apoptosis in both cell lines, indicating the key roles of ROS and Bax as well as the caspases. Collectively, DHA presents more potent proapoptotic actions in A549GR cells preferentially over normal A549 cells via ROS-dependent apoptotic pathway, in which Bax and caspases are involved.
authors.affiliation: MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Life Science, South China Normal University, Guangzhou 510631, China.
authors.forename: Chubiao
authors.initials: C
authors.lastname: Zhao
authors.affiliation: MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Life Science, South China Normal University, Guangzhou 510631, China.
authors.forename: Guiqi
authors.initials: G
authors.lastname: Qin
authors.affiliation: MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Life Science, South China Normal University, Guangzhou 510631, China.
authors.forename: Weijie
authors.initials: W
authors.lastname: Gao
authors.affiliation: MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Life Science, South China Normal University, Guangzhou 510631, China.
authors.forename: Jingqin
authors.initials: J
authors.lastname: Chen
authors.affiliation: MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Life Science, South China Normal University, Guangzhou 510631, China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Liu
authors.affiliation: MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Life Science, South China Normal University, Guangzhou 510631, China.
authors.forename: Gaina
authors.initials: G
authors.lastname: Xi
authors.affiliation: MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Life Science, South China Normal University, Guangzhou 510631, China.
authors.forename: Tan
authors.initials: T
authors.lastname: Li
authors.affiliation: MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Life Science, South China Normal University, Guangzhou 510631, China.
authors.forename: Shengnan
authors.initials: S
authors.lastname: Wu
authors.affiliation: MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Life Science, South China Normal University, Guangzhou 510631, China. Electronic address: chentsh@scnu.edu.cn.
authors.forename: Tongsheng
authors.initials: T
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D037621:Artemisinins / Q000633:toxicity*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000633:toxicity; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D037621:Artemisinins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D003841:Deoxycytidine; C039060:artenimol; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D000093542:Gemcitabine
keywords: A549 cells; Apoptosis; Bax; Dihydroartemisinin; Gemcitabine; ROS