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A novel small molecule inhibitor of MDM2-p53 (APG-115) enhances radiosensitivity of gastric adenocarcinoma

BACKGROUND: Gastric cancer is the leading cause of cancer related death worldwide. Radiation alone or combined with chemotherapy plays important role in locally advanced and metastatic gastric adenocarcinoma. MDM2–p53 interaction and downstream signaling affect cellular response to DNA damage which...

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Autores principales: Yi, Hanjie, Yan, Xianglei, Luo, Qiuyun, Yuan, Luping, Li, Baoxia, Pan, Wentao, Zhang, Lin, Chen, Haibo, Wang, Jing, Zhang, Yubin, Zhai, Yifan, Qiu, Miao-Zhen, Yang, Da-Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5930807/
https://www.ncbi.nlm.nih.gov/pubmed/29716622
http://dx.doi.org/10.1186/s13046-018-0765-8
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author Yi, Hanjie
Yan, Xianglei
Luo, Qiuyun
Yuan, Luping
Li, Baoxia
Pan, Wentao
Zhang, Lin
Chen, Haibo
Wang, Jing
Zhang, Yubin
Zhai, Yifan
Qiu, Miao-Zhen
Yang, Da-Jun
author_facet Yi, Hanjie
Yan, Xianglei
Luo, Qiuyun
Yuan, Luping
Li, Baoxia
Pan, Wentao
Zhang, Lin
Chen, Haibo
Wang, Jing
Zhang, Yubin
Zhai, Yifan
Qiu, Miao-Zhen
Yang, Da-Jun
author_sort Yi, Hanjie
collection PubMed
description BACKGROUND: Gastric cancer is the leading cause of cancer related death worldwide. Radiation alone or combined with chemotherapy plays important role in locally advanced and metastatic gastric adenocarcinoma. MDM2–p53 interaction and downstream signaling affect cellular response to DNA damage which leads to cell cycle arrest and apoptosis. Therefore, restoring p53 function by inhibiting its interaction with MDM2 is a promising therapeutic strategy for cancer. APG-115 is a novel small molecule inhibitor which blocks the interaction of MDM2 and p53. In this study, we investigated that the radiosensitivity of APG-115 in gastric adenocarcinoma in vitro and in vivo. METHODS: The role of APG-115 in six gastric cancer cells viability in vitro was determined by CCK-8 assay. The expression level of MDM2, p21, PUMA and BAX in AGS and MKN45 cell lines was measured via real-time PCR (RT-PCR). The function of treatment groups on cell cycle and cell apoptosis were detected through Flow Cytometry assay. Clonogenic assays were used to measure the radiosensitivity of APG-115 in p53 wild type gastric cancer cell lines. Western blot was conducted to detect the protein expressions of mdm2-p53 signal pathway. Xenograft models in nude mice were established to explore the radiosensitivity role of APG-115 in gastric cancer cells in vivo. RESULTS: We found that radiosensitization by APG-115 occurred in p53 wild-type gastric cancer cells. Increasing apoptosis and cell cycle arrest was observed after administration of APG-115 and radiation. Radiosensitivity of APG-115 was mainly dependent on MDM2-p53 signal pathway. In vivo, APG-115 combined with radiation decreased xenograft tumor growth much more significantly than either single treatment. Moreover, the number of proliferating cells (Ki-67) significantly decreased in combination group compared with single treatment group. CONCLUSIONS: In summary, we found that combination of MDM2-p53 inhibitor (APG-115) and radiotherapy can enhance antitumor effect both in vitro and in vivo. This is the first report on radiosensitivity of APG-115 which shed light on clinical trial of the combination therapy of radiation with APG-115 in gastric adenocarcinoma. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13046-018-0765-8) contains supplementary material, which is available to authorized users.
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spelling pubmed-59308072018-05-09 A novel small molecule inhibitor of MDM2-p53 (APG-115) enhances radiosensitivity of gastric adenocarcinoma Yi, Hanjie Yan, Xianglei Luo, Qiuyun Yuan, Luping Li, Baoxia Pan, Wentao Zhang, Lin Chen, Haibo Wang, Jing Zhang, Yubin Zhai, Yifan Qiu, Miao-Zhen Yang, Da-Jun J Exp Clin Cancer Res Research BACKGROUND: Gastric cancer is the leading cause of cancer related death worldwide. Radiation alone or combined with chemotherapy plays important role in locally advanced and metastatic gastric adenocarcinoma. MDM2–p53 interaction and downstream signaling affect cellular response to DNA damage which leads to cell cycle arrest and apoptosis. Therefore, restoring p53 function by inhibiting its interaction with MDM2 is a promising therapeutic strategy for cancer. APG-115 is a novel small molecule inhibitor which blocks the interaction of MDM2 and p53. In this study, we investigated that the radiosensitivity of APG-115 in gastric adenocarcinoma in vitro and in vivo. METHODS: The role of APG-115 in six gastric cancer cells viability in vitro was determined by CCK-8 assay. The expression level of MDM2, p21, PUMA and BAX in AGS and MKN45 cell lines was measured via real-time PCR (RT-PCR). The function of treatment groups on cell cycle and cell apoptosis were detected through Flow Cytometry assay. Clonogenic assays were used to measure the radiosensitivity of APG-115 in p53 wild type gastric cancer cell lines. Western blot was conducted to detect the protein expressions of mdm2-p53 signal pathway. Xenograft models in nude mice were established to explore the radiosensitivity role of APG-115 in gastric cancer cells in vivo. RESULTS: We found that radiosensitization by APG-115 occurred in p53 wild-type gastric cancer cells. Increasing apoptosis and cell cycle arrest was observed after administration of APG-115 and radiation. Radiosensitivity of APG-115 was mainly dependent on MDM2-p53 signal pathway. In vivo, APG-115 combined with radiation decreased xenograft tumor growth much more significantly than either single treatment. Moreover, the number of proliferating cells (Ki-67) significantly decreased in combination group compared with single treatment group. CONCLUSIONS: In summary, we found that combination of MDM2-p53 inhibitor (APG-115) and radiotherapy can enhance antitumor effect both in vitro and in vivo. This is the first report on radiosensitivity of APG-115 which shed light on clinical trial of the combination therapy of radiation with APG-115 in gastric adenocarcinoma. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13046-018-0765-8) contains supplementary material, which is available to authorized users. BioMed Central 2018-05-02 /pmc/articles/PMC5930807/ /pubmed/29716622 http://dx.doi.org/10.1186/s13046-018-0765-8 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Yi, Hanjie
Yan, Xianglei
Luo, Qiuyun
Yuan, Luping
Li, Baoxia
Pan, Wentao
Zhang, Lin
Chen, Haibo
Wang, Jing
Zhang, Yubin
Zhai, Yifan
Qiu, Miao-Zhen
Yang, Da-Jun
A novel small molecule inhibitor of MDM2-p53 (APG-115) enhances radiosensitivity of gastric adenocarcinoma
title A novel small molecule inhibitor of MDM2-p53 (APG-115) enhances radiosensitivity of gastric adenocarcinoma
title_full A novel small molecule inhibitor of MDM2-p53 (APG-115) enhances radiosensitivity of gastric adenocarcinoma
title_fullStr A novel small molecule inhibitor of MDM2-p53 (APG-115) enhances radiosensitivity of gastric adenocarcinoma
title_full_unstemmed A novel small molecule inhibitor of MDM2-p53 (APG-115) enhances radiosensitivity of gastric adenocarcinoma
title_short A novel small molecule inhibitor of MDM2-p53 (APG-115) enhances radiosensitivity of gastric adenocarcinoma
title_sort novel small molecule inhibitor of mdm2-p53 (apg-115) enhances radiosensitivity of gastric adenocarcinoma
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5930807/
https://www.ncbi.nlm.nih.gov/pubmed/29716622
http://dx.doi.org/10.1186/s13046-018-0765-8
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