A Novel Small Molecule Inhibitor of MDM2-p53 (APG-115) Has Antitumor Activity in Gastric Adenocarcinoma

Abstract

Gastric cancer (GC) is the third leading cause of cancer related death. APG-115, a novel MDM2-P53 inhibitor, is a potential anticancer agent. In this study, we aim to investigate the anticancer effect and mechanisms of APG-115 in GC. The anti-tumor activity of APG-115 was evaluated both in vitro and in vivo. Western blot analysis and siRNA interference for mechanism exploration of APG-115. We found that APG-115 exerted potent proliferation inhibition on p53 wild-type gastric cancer cells AGS and MKN-45 in a time-and dose-dependent manner. Besides, APG-115 could induce apoptosis and cell-cycle arrest in G1/G0 phase in the p53 wild-type gastric cancer cells. In vivo, APG-115 exhibited potent antitumor activity against human gastric cancer xenografts. Our data provide solid preclinical evidence that APG-115 can serve as an effective and precise therapeutic strategy for gastric cancer. Funding Statement: This work was supported by Natural Science Foundation of Guangdong Province, China (grant no. 2018A030310260); Medical Scientific Research Foundation of Guangdong Province, China (grant no. 2018102516469945); National Natural Science Foundation of China (Grant number. 81602066 and 81772587); the Fundamental Research Funds for the Central Universities (Grant number. 16ykpy25); the third outstanding young talents training plan and Medical Scientist program of Sun Yat-sen University cancer center; Science and Technology Planning Project of Guangzhou, China (Grant number. 201510161726583); National Science and Technology Major Project, China (Grant number. 2016ZX09101004). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: All animal experiments were performed under the guidance of Sun Yat-Sen University Committee for Use and Care of Laboratory Animals and approved by the animal experimentation ethics committee.