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

31 Pages Posted: 29 Mar 2019

See all articles by Lin Zhang

Lin Zhang

Sun Yat-Sen University (SYSU) - Department of Laboratory Medicine

Qiuyun Luo

Sun Yat-Sen University (SYSU) - Department of Experimental Research

Xianglei Yan

Sun Yat-Sen University (SYSU) - Department of Experimental Research

Xueping Wan

Sun Yat-Sen University (SYSU)

Luping Yuan

Sun Yat-Sen University (SYSU) - Department of Experimental Research

Suna Zhou

Sun Yat-Sen University (SYSU) - Department of Experimental Research

Yuxin Zhang

Sun Yat-Sen University (SYSU) - Department of Experimental Research

Wanli Liu

Sun Yat-Sen University (SYSU) - Department of Laboratory Medicine

Miao-Zhen Qiu

Sun Yat-Sen University (SYSU) - Department of Medical Oncology; Sun Yat-Sen University (SYSU) - Department of Experimental Research

Da-Jun Yang

Sun Yat-Sen University (SYSU) - Department of Experimental Research; Suzhou Ascentage Pharma Inc.

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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.

Keywords: MDM2, p53, APG-115, Gastric cancer, Apoptosis

Suggested Citation

Zhang, Lin and Luo, Qiuyun and Yan, Xianglei and Wan, Xueping and Yuan, Luping and Zhou, Suna and Zhang, Yuxin and Liu, Wanli and Qiu, Miao-Zhen and Yang, Da-Jun, A Novel Small Molecule Inhibitor of MDM2-p53 (APG-115) Has Antitumor Activity in Gastric Adenocarcinoma (March 27, 2019). Available at SSRN: https://ssrn.com/abstract=3361158 or http://dx.doi.org/10.2139/ssrn.3361158

Lin Zhang (Contact Author)

Sun Yat-Sen University (SYSU) - Department of Laboratory Medicine ( email )

Guangzhou
China

Qiuyun Luo

Sun Yat-Sen University (SYSU) - Department of Experimental Research

651 Dongfeng Road East
Guangzhou, 510060
China

Xianglei Yan

Sun Yat-Sen University (SYSU) - Department of Experimental Research

651 Dongfeng Road East
Guangzhou, 510060
China

Xueping Wan

Sun Yat-Sen University (SYSU)

135, Xingang Xi Road
Guangzhou, Guangdong 510275
China

Luping Yuan

Sun Yat-Sen University (SYSU) - Department of Experimental Research

651 Dongfeng Road East
Guangzhou, 510060
China

Suna Zhou

Sun Yat-Sen University (SYSU) - Department of Experimental Research

651 Dongfeng Road East
Guangzhou, 510060
China

Yuxin Zhang

Sun Yat-Sen University (SYSU) - Department of Experimental Research

651 Dongfeng Road East
Guangzhou, 510060
China

Wanli Liu

Sun Yat-Sen University (SYSU) - Department of Laboratory Medicine ( email )

651 Dongfeng Road East
Guangzhou, 510060
China

Miao-Zhen Qiu

Sun Yat-Sen University (SYSU) - Department of Medical Oncology ( email )

651 Dongfeng Road East
Guangzhou, 510060
China

Sun Yat-Sen University (SYSU) - Department of Experimental Research ( email )

651 Dongfeng Road East
Guangzhou, 510060
China

Da-Jun Yang

Sun Yat-Sen University (SYSU) - Department of Experimental Research ( email )

651 Dongfeng Road East
Guangzhou, 510060
China

Suzhou Ascentage Pharma Inc. ( email )

Jiangsu
China

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