title: Autophagic Cell Death and Apoptosis Jointly Mediate Cisatracurium Besylate-Induced Cell Injury.
abstract: Cisatracurium besylate is an ideal non-depolarizing muscle relaxant which is widely used in clinical application. However, some studies have suggested that cisatracurium besylate can affect cell proliferation. Moreover, its specific mechanism of action remains unclear. Here, we found that the number of GFP-LC3 (green fluoresent protein-light chain 3) positive autophagosomes and the rate of mitochondria fracture both increased significantly in drug-treated GFP-LC3 and MitoDsRed stable HeLa cells. Moreover, cisatracurium promoted the co-localization of LC3 and mitochondria and induced formation of autolysosomes. Levels of mitochondrial proteins decreased, which were reversed by the lysosome inhibitor Bafinomycin A1. Similar results with evidence of dose-dependent effects were found in both HeLa and Human Umbilical Vein Endothelial Cells (HUVECs). Cisatracurium lowered HUVEC viability to 0.16 (OD490) at 100 µM and to 0.05 (OD490) after 48 h in vitro; it increased the cell death rate to 56% at 100 µM and to 60% after 24 h in a concentration- and time-dependent manner (p < 0.01). Cell proliferation decreased significantly by four fold in Atg5 WT (wildtype) MEF (mouse embryonic fibroblast) (p < 0.01) but was unaffected in Atg5 KO (Knockout) MEF, even upon treatment with a high dose of cisatracurium. Cisatracurium induced significant increase in cell death of wild-type MEFs even in the presence of the apoptosis inhibitor zVAD. Thus, we conclude that activation of both the autophagic cell death and cell apoptosis pathways contributes to cisatracurium-mediated cell injury.
authors.affiliation: Department of Anesthesiology, Guangdong Medical University, Zhanjiang 524001, China. Haixia_Zhuang00@163.com.
authors.forename: Haixia
authors.initials: H
authors.lastname: Zhuang
authors.affiliation: Guangdong Key Laboratory of Age-Related Cardiac-Cerebral Vascular Disease, Institute of Neurology, Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China. hanxiaoweili@163.com.
authors.forename: Weili
authors.initials: W
authors.lastname: Tian
authors.affiliation: Guangdong Key Laboratory of Age-Related Cardiac-Cerebral Vascular Disease, Institute of Neurology, Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China. liwen410@163.com.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: Guangdong Key Laboratory of Age-Related Cardiac-Cerebral Vascular Disease, Institute of Neurology, Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China. Xingli_Zhang00@163.com.
authors.forename: Xingli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Guangdong Medical University, Zhanjiang 524001, China. Jingjing_Wang00@163.com.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Guangdong Medical University, Zhanjiang 524001, China. Yue_Yang00@163.com.
authors.forename: Yue
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Anesthesiology, Guangdong Medical University, Zhanjiang 524001, China. kiddodo@gmail.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Anesthesiology Research Laboratory, Department of Anesthesiology, University of Hong Kong, Hong Kong, China. zyxia@hkucc.hku.hk.
authors.forename: Zhengyuan
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Guangdong Key Laboratory of Age-Related Cardiac-Cerebral Vascular Disease, Institute of Neurology, Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China. feng_du@foxmail.com.|The Department of Developmental Biology, Harvard School of Dental Medicine, Harvard Medical School, Boston, MA 02115, USA. feng_du@foxmail.com.
authors.forename: Du
authors.initials: D
authors.lastname: Feng
authors.affiliation: Department of Anesthesiology, Guangdong Medical University, Zhanjiang 524001, China. zhanglq1970@163.com.
authors.forename: Liangqing
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001279:Atracurium / Q000009:adverse effects / Q000031:analogs & derivatives*; D001343:Autophagy / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D006367:HeLa Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D009466:Neuromuscular Blocking Agents / Q000009:adverse effects*; D059748:Proteolysis / Q000187:drug effects
chemical_list: D024101:Mitochondrial Proteins; D009466:Neuromuscular Blocking Agents; D001279:Atracurium; C101584:cisatracurium
keywords: apoptosis; autophagosome; cisatracurium; mitochondria