title: Artesunate induces apoptosis via a ROS-independent and Bax-mediated intrinsic pathway in HepG2 cells.
abstract: This study aims to explore the detail molecular mechanism by which artesunate (ARS), an artemisinin derivative, induces apoptosis in HepG2 cells. ARS induced a loss of mitochondrial transmemberane potential (ΔΨm), phosphatidylserine (PS) externalization, as well as activations of Bax/Bak and caspases indicative of apoptosis induction. Silencing Bax but not Bak significantly inhibited ARS-induced apoptosis, demonstrating the key role of the Bax-mediated intrinsic pathway. Although ARS increased intracellular reactive oxygen species (ROS), ARS-induced apoptosis was neither prevented by pretreatment with ROS scavengers nor potentiated by pretreatment with l-buthionine-sulfoximine (BSO) that enhanced the ARS-induced intracellular ROS generation, demonstrating that ROS was not involved in ARS-induced apoptosis. In addition, ARS did not induce Bid translocation to mitochondria, and the cytotoxicity of ARS was not prevented by silencing Bim, Puma or Mcl-1, but was significantly enhanced by HA14-1 pretreatment, demonstrating that Bcl-2/-xl instead of Bid and Bim as well as Puma may be the upstream factor to regulate the Bax-mediated intrinsic pathway. Collectively, our data demonstrate that ARS induces ROS-independent apoptosis via the Bax-mediated intrinsic pathway in HepG2 cells.
authors.affiliation: MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, PR 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 Biophotonics, South China Normal University, Guangzhou 510631, PR China.
authors.forename: Liping
authors.initials: L
authors.lastname: Wu
authors.affiliation: MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, PR 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 Biophotonics, South China Normal University, Guangzhou 510631, PR China.
authors.forename: Yilin
authors.initials: Y
authors.lastname: Pang
authors.affiliation: MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, PR 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 Biophotonics, South China Normal University, Guangzhou 510631, PR China.
authors.forename: Shengnan
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Pain Management, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, PR China. Electronic address: txp2938@jnu.edu.cn.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wang
authors.affiliation: MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, PR China. Electronic address: chentsh@scnu.edu.cn.
authors.forename: Tongsheng
authors.initials: T
authors.lastname: Chen
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D037621:Artemisinins / Q000494:pharmacology*; D000077332:Artesunate; D000072224:Bcl-2-Like Protein 11; D001578:Benzopyrans / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival; D004789:Enzyme Activation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics; D008928:Mitochondria / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics; D009570:Nitriles / Q000494:pharmacology; D010718:Phosphatidylserines / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D037621:Artemisinins; C494772:BAK1 protein, human; C438378:BBC3 protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D001578:Benzopyrans; C579095:MCL1 protein, human; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009570:Nitriles; D010718:Phosphatidylserines; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C456800:ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate; D019328:Buthionine Sulfoximine; D000077332:Artesunate
keywords: Apoptosis; Artesunate; Bax; HepG2 cells; ROS