A novel small molecule inhibitor of MDM2-p53 (APG-115) enhances radiosensitivity of gastric adenocarcinoma
Open accessAbstract
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.
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APG-115 has significant activity, which is more than 10 times that of SAR-405838, and can overcome the chronic isomerization of SAR-405838.
“APG-115 has significant activity, which is more than 10 times that of SAR-405838, and can overcome the chronic isomerization of SAR-405838.404,405”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [405]
APG-115 is an MDM2 inhibitor that activates p53 through the MDM2-p53 interaction.
“APG-115 is an MDM2 inhibitor could activate p53 through MDM2-p53 interaction”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [405]
APG-115 combined with pembrolizumab showed good tolerability and preliminary indications of antitumor activity in a clinical trial for patients with metastatic melanoma and advanced-stage solid tumors.
“its combination with pembrolizumab has been shown good tolerability and preliminary indications of antitumor activity in a clinical trial for patients with metastatic melanoma and advanced-stage solid tumors (NCT03611868).403,405”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [405]
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References 42 · Cited by 71
- Authors
- Yi, H., Yan, X., Luo, Q., Yuan, L., Li, B., Pan, W., Zhang, L., Chen, H., Wang, J., Zhang, Y., Zhai, Y., Qiu, M.-Z., & Yang, D.-J.
- Affiliations
- Ningbo University (CN)
- Sun Yat-sen University Cancer Center (CN)
- Peking University Shenzhen Hospital (CN)
- Corresponding author
- Qiu, Miao-Zhen
- Yang, Da-Jun
- Venue
- Journal of Experimental & Clinical Cancer Research
- Published
- 2018-05-02
- Volume
- 37
- Issue
- 1
- Pages
- 97-97
- ISSN
- 0392-9078 (ISSN-L)
- 1756-9966
- PMC
- PMC5930807
- OpenAlex
- W2805484370
- Cited by
- 71
- References
- 42
- Citations by year
- 2026: 5 · 2025: 13 · 2024: 10 · 2023: 11 · 2022: 11 · 2021: 5 · 2020: 8 · 2019: 7 · 2018: 1
- FWCI
- 2.06
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Experimental & Clinical Cancer Research (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (81602066, 81772587)
- Fundamental Research Funds for the Central Universities (16ykpy25)
- Science and Technology Planning Project of Guangzhou (201510161726583)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Gastric Cancer Management and Outcomes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- p53-MDM2 interaction, radiosensitization, gastric adenocarcinoma, radiotherapy combination therapy, apoptosis, cell cycle arrest, p21, PUMA, Bax, xenograft tumor growth, Ki-67
- MeSH terms
- Adenocarcinoma, Animals, Humans, Mice, Nude, Radiation Tolerance, Stomach Neoplasms, Tumor Suppressor Protein p53, Apoptosis, Mice, Proto-Oncogene Proteins c-mdm2
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