| Title | A novel small molecule inhibitor of MDM2-p53 (APG-115) enhances radiosensitivity of gastric adenocarcinoma |
| Authors | 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 |
| Affiliation | Sun Yat Sen Univ, Dept Expt Res, State Key Lab Oncol South China, Collaborat Innovat Ctr Canc Med,Canc Ctr, 651 Dongfeng Rd East, Guangzhou 510060, Guangdong, Peoples R China. Ningbo Univ, Med Sch, YinZhou Hosp, Ningbo 315000, Zhejiang, Peoples R China. Peking Univ, Shenzhen Hosp, Guangzhou 510060, Guangdong, Peoples R China. Guangzhou Red Cross Hosp, Guangzhou 510060, Guangdong, Peoples R China. Ascentage Pharma, Taizhou 225300, Jiangsu, Peoples R China. Suzhou Ascentage Pharma Inc, Taizhou 215123, Jiangsu, Peoples R China. Sun Yat Sen Univ, Canc Ctr, Dept Med Oncol, 651 Dongfeng Rd East, Guangzhou 510060, Guangdong, Peoples R China. Collaborat Innovat Ctr Canc Med, State Key Lab Oncol South China, 651 Dongfeng Rd East, Guangzhou 510060, Guangdong, Peoples R China. Sun Yat Sen Univ, Dept Expt Res, State Key Lab Oncol South China, Collaborat Innovat Ctr Canc Med,Canc Ctr, 651 Dongfeng Rd East, Guangzhou 510060, Guangdong, Peoples R China. Qiu, MZ (reprint author), Sun Yat Sen Univ, Canc Ctr, Dept Med Oncol, 651 Dongfeng Rd East, Guangzhou 510060, Guangdong, Peoples R China. Qiu, MZ (reprint author), Collaborat Innovat Ctr Canc Med, State Key Lab Oncol South China, 651 Dongfeng Rd East, Guangzhou 510060, Guangdong, Peoples R China. |
| Keywords | Small molecule inhibitors MDM2 p53 Gastric cancer Radiation Apoptosis P53 TUMOR SUPPRESSION DNA-DAMAGE RESPONSE CANCER CELLS PERIOPERATIVE CHEMOTHERAPY P53-INDEPENDENT ROLE MDM-2 ONCOGENE RADIATION MICE PHOSPHORYLATION ACTIVATION |
| Issue Date | 2018 |
| Publisher | JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH |
| Citation | JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH. 2018, 37. |
| Abstract | 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. |
| URI | http://hdl.handle.net/20.500.11897/513237 |
| ISSN | 1756-9966 |
| DOI | 10.1186/s13046-018-0765-8 |
| Indexed | SCI(E) PubMed |
| Appears in Collections: | 深圳医院 |
