Oncotarget

Research Papers:

Restoration of p53 using the novel MDM2-p53 antagonist APG115 suppresses dedifferentiated papillary thyroid cancer cells

Haibo Chen, Dingyuan Luo, Lin Zhang, Xiaofeng Lin, Qiuyun Luo, Hanjie Yi, Jing Wang, Xianglei Yan, Baoxia Li, Yuelei Chen, Xingguang Liu, Hong Zhang, Sheng Liu, Miaozhen Qiu, Dajun Yang _ and Ningyi Jiang

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Oncotarget. 2017; 8:43008-43022. https://doi.org/10.18632/oncotarget.17398

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Abstract

Haibo Chen1,*, Dingyuan Luo2,*, Lin Zhang3,4,*, Xiaofeng Lin1, Qiuyun Luo3, Hanjie Yi3, Jing Wang5, Xianglei Yan3, Baoxia Li3, Yuelei Chen6, Xingguang Liu1, Hong Zhang1, Sheng Liu1, Miaozhen Qiu7, Dajun Yang3,8 and Ningyi Jiang1

1Department of Nuclear Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China

2Department of Vascular and Thyroid Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China

3Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China

4Department of Clinical Laboratory, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China

5Department of Pharmacy, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China

6The State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China

7Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou 510120, China

8Suzhou Ascentage Pharma Inc., Jiangsu 215123, China

*These authors have contributed equally to this work

Correspondence to:

Dajun Yang, email: yangdj@sysucc.org.cn

Ningyi Jiang, email: ningyij0@163.com

Keywords: dedifferentiated thyroid cancer, radioiodine, anti-tumor, MDM2-p53 interaction, apoptosis

Received: February 10, 2017    Accepted: April 06, 2017    Published: April 24, 2017

ABSTRACT

Dedifferentiated papillary thyroid cancer (DePTC) is characterized by aggressive growth, recurrence, distant metastasis, and resistance to radioactive iodine (RAI) therapy. DePTC is also accompanied by poor prognosis and high early-mortality. Nevertheless, most DePTC cells show intact p53 downstream functionality. In cells with wild-type p53, the murine double minute2 (MDM2) protein interacts with p53 and abrogates its activity. Inhibition of the MDM2-p53 interaction restores p53 activity and leads to cell cycle arrest and apoptosis. Restoring p53 function by inhibiting its interaction with p53 suppressors such as MDM2 is thus a promising therapeutic strategy for the treatment of DePTC. The novel MDM2-p53 interaction antagonist APG115 is an analogue of SAR405838, and is being tested in a phase I clinical trial. In this study, we evaluated the efficacy of APG115 as a single-agent to treat DePTC. APG115 diminished the viability of p53 wild-type DePTC cells and induced cell cycle arrest and apoptosis. In a human xenograft mouse model, APG115 elicited robust tumor regression and cell apoptosis. These data demonstrate that further research is warranted to determine whether APG115 can be used to effectively treat DePTC patients.


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