Novel antagonist APG-115 targets MDM2-p53 to induce p53-mediated apoptosis and radiosensitization in colorectal cancer.

Colorectal cancer remains a major global health burden, and treatment outcomes for advanced disease are still unsatisfactory. APG-115 is a next-generation small-molecule MDM2 inhibitor developed in China that restores wild-type p53 activity. However, its therapeutic potential in colorectal cancer has not been fully explored. APG-115's impact on colorectal cancer cells was evaluated through CCK-8 assays and AnnexinV-FITC/PI staining. The dependence of APG-115 activity on p53 status was assessed in p53-knockdown cell lines. In vivo, the antitumor efficacy and radiosensitizing effects of APG-115 were evaluated in nude-mouse xenograft models. APG-115 exerted a potent inhibitory effect on the proliferation of p53 wild-type colorectal cancer cell lines LOVO, RKO, and HCT116, while showed no significant impact on p53-mutant lines. In wild-type cells, APG-115 induced apoptosis in a dose-dependent manner and caused G0/G1 cell-cycle arrest. APG-115 significantly upregulated p53 and its downstream targets (MDM2, p21, PUMA), whereas these effects were absent in p53-mutant or p53-knockdown cells. In vivo, APG-115 suppressed RKO tumor growth in a dose-dependent manner, accompanied by increased p53, MDM2 and p21 expression and reduced Ki-67. Immunofluorescence further confirmed enhanced apoptosis following treatment. Importantly, the combination of APG-115 with radiotherapy significantly promoted apoptosis, decreased the S-phase proportion, and increased G2-phase arrest in p53 wild-type cells. Radiosensitization was abolished in p53-knockout RKO xenografts, confirming the requirement of an intact MDM2-p53 pathway. APG-115 effectively inhibits proliferation, induces apoptosis, and enhances radiosensitivity in p53 wild-type colorectal cancer. These findings support APG-115 as a promising therapeutic candidate for colorectal cancers retaining functional p53.