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

Oncotarget
Haibo ChenNingyi Jiang

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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Citations

May 7, 2020·Metallomics : Integrated Biometal Science·Xinyang LiZunzhen Zhang
Feb 13, 2020·Mini Reviews in Medicinal Chemistry·Ankur VaidyaSanjay Kumar Jain
May 3, 2018·Journal of Experimental & Clinical Cancer Research : CR·Hanjie YiDa-Jun Yang
Feb 19, 2021·European Journal of Medicinal Chemistry·Darshana BoraNagula Shankaraiah

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Methods Mentioned

BETA
flow cytometry
PCR
xenograft
xenografts
Assay

Clinical Trials Mentioned

NCT02935907

Software Mentioned

Living Image
GraphPad Prism
MutiCycle
Panoramic Viewer
xCELLigence RTCA Control Unit
xCELLigence real - time cell analysis ( RTCA )
Accuri

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