AT-406, an IAP Inhibitor, Activates Apoptosis and Induces Radiosensitization of Normoxic and Hypoxic Cervical Cancer Cells
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 condit...
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doaj-3947c51315a44fd4826ddaf1af9490f42020-11-25T01:21:29ZengElsevierJournal of Pharmacological Sciences1347-86132014-01-0112615665AT-406, an IAP Inhibitor, Activates Apoptosis and Induces Radiosensitization of Normoxic and Hypoxic Cervical Cancer CellsJing Lu0Qin Qin1Liang-Liang Zhan2Jia Liu3Hong-Cheng Zhu4Xi Yang5Chi Zhang6Li-Ping Xu7Zhe-Ming Liu8Di Wang9He-Qing Cui10Ciu-Ciu Meng11Jing Cai12Hong-Yan Cheng13Xin-Chen Sun14Department of Radiation Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, P.R. ChinaDepartment of Radiation Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, P.R. ChinaDepartment of Radiation Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, P.R. ChinaDepartment of Radiation Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, P.R. ChinaDepartment of Radiation Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, P.R. ChinaDepartment of Radiation Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, P.R. ChinaDepartment of Radiation Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, P.R. ChinaDepartment of Radiation Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, P.R. ChinaDepartment of Radiation Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, P.R. ChinaDepartment of Radiation Oncology, the Second People’s Hospital of Lian Yungang, Lian Yungang Hospital Affiliated to Bengbu Medical College, Lian Yungang 222000, P.R. ChinaDepartment of Radiation Oncology, the Second People’s Hospital of Lian Yungang, Lian Yungang Hospital Affiliated to Bengbu Medical College, Lian Yungang 222000, P.R. ChinaDepartment of Radiation Oncology, the Second People’s Hospital of Lian Yungang, Lian Yungang Hospital Affiliated to Bengbu Medical College, Lian Yungang 222000, P.R. ChinaDepartment of Radiation Oncology, the Affiliated Tumor Hospital of Nantong University, Nantong 226000, P.R. ChinaDepartment of Synthetic Internal Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, P.R. ChinaDepartment of Radiation Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, P.R. China; Corresponding author. sunxinchen2012@163.comIAP 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.[Supplementary Figures: available only at http://dx.doi.org/10.1254/jphs.14079FP] Keywords:: AT-406, inhibitor of apoptosis protein (IAP), radiosensitization, cervical cancer, hypoxiahttp://www.sciencedirect.com/science/article/pii/S1347861319300477 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jing Lu Qin Qin Liang-Liang Zhan Jia Liu Hong-Cheng Zhu Xi Yang Chi Zhang Li-Ping Xu Zhe-Ming Liu Di Wang He-Qing Cui Ciu-Ciu Meng Jing Cai Hong-Yan Cheng Xin-Chen Sun |
spellingShingle |
Jing Lu Qin Qin Liang-Liang Zhan Jia Liu Hong-Cheng Zhu Xi Yang Chi Zhang Li-Ping Xu Zhe-Ming Liu Di Wang He-Qing Cui Ciu-Ciu Meng Jing Cai Hong-Yan Cheng Xin-Chen Sun AT-406, an IAP Inhibitor, Activates Apoptosis and Induces Radiosensitization of Normoxic and Hypoxic Cervical Cancer Cells Journal of Pharmacological Sciences |
author_facet |
Jing Lu Qin Qin Liang-Liang Zhan Jia Liu Hong-Cheng Zhu Xi Yang Chi Zhang Li-Ping Xu Zhe-Ming Liu Di Wang He-Qing Cui Ciu-Ciu Meng Jing Cai Hong-Yan Cheng Xin-Chen Sun |
author_sort |
Jing Lu |
title |
AT-406, an IAP Inhibitor, Activates Apoptosis and Induces Radiosensitization of Normoxic and Hypoxic Cervical Cancer Cells |
title_short |
AT-406, an IAP Inhibitor, Activates Apoptosis and Induces Radiosensitization of Normoxic and Hypoxic Cervical Cancer Cells |
title_full |
AT-406, an IAP Inhibitor, Activates Apoptosis and Induces Radiosensitization of Normoxic and Hypoxic Cervical Cancer Cells |
title_fullStr |
AT-406, an IAP Inhibitor, Activates Apoptosis and Induces Radiosensitization of Normoxic and Hypoxic Cervical Cancer Cells |
title_full_unstemmed |
AT-406, an IAP Inhibitor, Activates Apoptosis and Induces Radiosensitization of Normoxic and Hypoxic Cervical Cancer Cells |
title_sort |
at-406, an iap inhibitor, activates apoptosis and induces radiosensitization of normoxic and hypoxic cervical cancer cells |
publisher |
Elsevier |
series |
Journal of Pharmacological Sciences |
issn |
1347-8613 |
publishDate |
2014-01-01 |
description |
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.[Supplementary Figures: available only at http://dx.doi.org/10.1254/jphs.14079FP] Keywords:: AT-406, inhibitor of apoptosis protein (IAP), radiosensitization, cervical cancer, hypoxia |
url |
http://www.sciencedirect.com/science/article/pii/S1347861319300477 |
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