title: AT-406, an IAP inhibitor, activates apoptosis and induces radiosensitization of normoxic and hypoxic cervical cancer cells.
abstract: IAP antagonists increased the antitumor efficacy of X-irradiation in some types of cancers, but their effects on hypoxic cancer cells remain unclarified. We aims to investigate the radiosensitizing effect of an IAP inhibitor AT-406 on cervical cancer cell lines under both normoxia and hypoxia conditions. Hela and Siha cells were treated to investigate the effects of drug administration on cell proliferation, apoptosis, and radiosensitivity. Western blot analysis was used to determine the role of AT-406 in inhibition of IAPs. The pathway of apoptosis was characterized by caspases activity assay. AT-406 potently sensitized Hela cells but not Siha cells to radiation under normoxia. Notably, the radiosensitizing effect of AT-406 on hypoxic cells was more evident than on normoxic cells in both cell lines. Further mechanism studies by western blot showed that under normoxia AT-406 decreased the level of cIAP1 in Hela cells in a dose-dependent manner; while additional downregulation of XIAP expression was induced by AT-406 treatment under hypoxia in both cell lines. Finally, AT-406 works on both extrinsic death receptor and intrinsic mitochondrial apoptosis pathways to activate apoptosis. Totally, AT-406 acts as a strong radiosensitizer in human cervical cancer cells, especially in hypoxic condition.
authors.affiliation: Department of Radiation Oncology, the First Affiliated Hospital of Nanjing Medical University, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.forename: Qin
authors.initials: Q
authors.lastname: Qin
authors.forename: Liang-Liang
authors.initials: LL
authors.lastname: Zhan
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.forename: Hong-Cheng
authors.initials: HC
authors.lastname: Zhu
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Xu
authors.forename: Zhe-Ming
authors.initials: ZM
authors.lastname: Liu
authors.forename: Di
authors.initials: D
authors.lastname: Wang
authors.forename: He-Qing
authors.initials: HQ
authors.lastname: Cui
authors.forename: Ciu-Ciu
authors.initials: CC
authors.lastname: Meng
authors.forename: Jing
authors.initials: J
authors.lastname: Cai
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Cheng
authors.forename: Xin-Chen
authors.initials: XC
authors.lastname: Sun
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D001392:Azocines / Q000494:pharmacology*; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006367:HeLa Cells; D006801:Humans; D000860:Hypoxia / Q000473:pathology*; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism / Q000494:pharmacology*; D008928:Mitochondria / Q000473:pathology; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000473:pathology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D001392:Azocines; D001559:Benzhydryl Compounds; D051034:Inhibitor of Apoptosis Proteins; C559144:N-benzhydryl-5-(2-(methylamino)propanamido)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo(1,2-a)(1,5)diazocine-8-carboxamide; D011838:Radiation-Sensitizing Agents; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human