AT-406, an IAP Inhibitor, Activates Apoptosis and Induces Radiosensitization of Normoxic and Hypoxic Cervical Cancer Cells

Journal of Pharmacological Sciences

Chi Zhang⁴  Jing Lu⁴  Hong-Cheng Zhu⁴  Xin-Chen Sun⁴  He-Qing Cui²  Hong-Yan Cheng³  Li-Ping Xu⁴  Xi Yang⁴  Ciu-Ciu Meng²  Qin Qin⁴  Liang-Liang Zhan⁴  Zhe-Ming Liu⁴  Jing Cai¹  Jia Liu⁴  Di Wang² 

[1] Department of Radiation Oncology, the Affiliated Tumor Hospital of Nantong University, China;Department of Radiation Oncology, the Second People’s Hospital of Lian Yungang, Lian Yungang Hospital Affiliated to Bengbu Medical College, China;Department of Synthetic Internal Medicine, the First Affiliated Hospital of Nanjing Medical University, China;Department of Radiation Oncology, the First Affiliated Hospital of Nanjing Medical University, China

关键词: AT-406;    inhibitor of apoptosis protein (IAP);    radiosensitization;    cervical cancer;    hypoxia;   

DOI  :  10.1254/jphs.14079FP

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(36)Cited-By(2)Supplementary materials(1)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.

【 授权许可】

Unknown