Abstract
BackgroundGastric 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.MethodsThe 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.ResultsWe 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.ConclusionsIn 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.
Highlights
Gastric cancer is the leading cause of cancer related death worldwide
APG-115 inhibited proliferation of gastric cancer cell lines We evaluated p53, Murine double minute 2 (MDM2) protein levels in six untreated gastric cancer cell lines by western blot (Fig. 1b)
We found that four gastric cancer cell with p53 deletion and p53 mutation were not sensitive to APG-115 and the IC50 were more than 10 uM
Summary
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. We investigated that the radiosensitivity of APG-115 in gastric adenocarcinoma in vitro and in vivo. P53 which is a tumor suppressor protein, known as ‘guardian of the genom’, plays a critical role in regulating stress responses such as DNA damage by ionizing radiation and mediating a series of proteins participating in cell cycle, check-points, DNA repair and cell apoptosis. Because the important effect of both p53 and MDM2 in the regulation of ionizing radiation damage, the combination of APG-115 and radiation may provide a hopeful therapeutic remedy in gastric adenocarcinoma. We analyzed the capability of APG-115 to enhance radiation response in gastric cancer both in vitro and in vivo. We preliminary explored the potential molecular mechanisms involving in the radiosensitivity of APG-115
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
