title: SurvivinT34A increases the therapeutic efficacy of arsenic trioxide in mouse hepatocellular carcinoma models.
abstract: Arsenic trioxide (ATO) has demonstrated clinical efficacy in acute promyelocytic leukemia (APL) and in vitro activity in various solid tumors. As2O3 as single agent exhibits poor efficacy for treatment of hepatocellular carcinoma (HCC) in phase II trial, suggesting that new modalities of treatment with enhanced therapeutic effect and alleviated toxicity are needed for application of As2O3 on patients with HCC. Survivin is the strongest inhibitor of apoptosis protein over-expressed in tumors, which has been proposed as an attractive target for new anticancer interventions. Disruption of survivin by the plasmid encoding the phosphorylation-defective mouse survivin threonine 34→alanine mutant (Msurvivin T34A plasmid) has proved a promising strategy for suppressing a variety of murine cancer. In the present study, we attempted to test Msurvivin T34A and arsenic trioxide (ATO) on a cell line and mice bearing subcutaneous tumors, with regard to their effects and mechanisms. We observed that the co-treatment with surivinT34A and ATO significantly enhanced the antitumor activity by induction of apoptosis in Hepa1-6 tumor cells in vitro, compared with control groups. The synergistic apoptosis-inducing effect of combination of these two drugs resulted in elevation of reactive oxygen species (ROS) level which could be antagonized by the antioxidant N-acetyl-l-cysteine. The combination treatment induced ROS-dependent collapse of the mitochondrial membrane potential. Moreover, the tumor growth in vivo was also remarkably inhibited by combination of surivinT34A and ATO when compared with control groups. Our findings demonstrate that the combination of surivinT34A and ATO exerted synergistic antitumor effects, providing a new perspective for clinical treatment of HCC.
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy/Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Anliang
authors.initials: A
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy/Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Dan
authors.initials: D
authors.lastname: Yue
authors.affiliation: Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Danying
authors.initials: D
authors.lastname: Liao
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy/Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Liuliu
authors.initials: L
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy/Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Jinhu
authors.initials: J
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy/Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy/Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Aiping
authors.initials: A
authors.lastname: Tong
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy/Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Ping
authors.initials: P
authors.lastname: Cheng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005260:Female; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000378:metabolism; D008081:Liposomes; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense; D009368:Neoplasm Transplantation; D010087:Oxides / Q000008:administration & dosage*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D000077022:Survivin
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D008081:Liposomes; D010087:Oxides; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D000077022:Survivin; D000077237:Arsenic Trioxide