Related Experiment Video
Updated: Jun 21, 2025
Spontaneous Murine Model of Anaplastic Thyroid Cancer
Published on: February 3, 2023
Selective anti-tumor activity of glutathione-responsive abasic site trapping agent in anaplastic thyroid carcinoma
Jinyan Chai1, Mengxue Su1, Ruiguo Zhang1
1Department of Nuclear Medicine, Tianjin Medical University General Hospital, Anshan Road No. 154, He ping District, Tianjin, 300052, P.R. China.
Abstract:
Anaplastic thyroid carcinoma (ATC) is a rare but highly aggressive thyroid cancer with poor prognosis. Killing cancer cells by inducing DNA damage or blockage of DNA repair is a promising strategy for chemotherapy. It is reported that aldehyde-reactive alkoxyamines can capture the AP sites, one of the most common DNA lesions, and inhibit apurinic/apyrimidinic endonuclease 1(APE1)-mediated base excision repair (BER), leading to cell death. Whether this strategy can be employed for ATC treatment is rarely investigated. The aim of this study is to exploit GSH-responsive AP site capture reagent (AP probe-net), which responses to the elevated glutathione (GSH) levels in the tumor micro-environment (TME), releasing reactive alkoxyamine to trap AP sites and block the APE1-mediated BER for targeted anti-tumor activity against ATC. In vitro experiments, including MTT andγ-H2AX assays, demonstrate their selective cytotoxicity towards ATC cells over normal thyroid cells. Flow cytometry analysis suggests that AP probe-net arrests the cell cycle in the G2/M phase and induces apoptosis. Western blotting (WB) results show that the expression of apoptotic protein increased with the increased concentration of AP probe-net. Further in vivo experiments reveal that the AP probe-net has a good therapeutic effect on subcutaneous tumors of the ATC cells. In conclusion, taking advantage of the elevated GSH in TME, our study affords a new strategy for targeted chemotherapy of ATC with high selectivity and reduced adverse effects.
Insights
This study introduces a novel AP probe-net that targets anaplastic thyroid carcinoma (ATC) by blocking DNA repair. This targeted chemotherapy selectively kills ATC cells, offering a promising new treatment strategy with reduced side effects.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Anaplastic thyroid carcinoma (ATC) is an aggressive cancer with limited treatment options.
- Targeting DNA damage and repair pathways is a key strategy in cancer chemotherapy.
- Apurinic/apyrimidinic endonuclease 1 (APE1)-mediated base excision repair (BER) is crucial for DNA repair.
Purpose of the Study:
- To develop and evaluate a glutathione (GSH)-responsive AP site capture reagent (AP probe-net) for targeted ATC chemotherapy.
- To investigate the mechanism of AP probe-net in inducing DNA damage and cell death in ATC.
- To assess the in vitro and in vivo efficacy and selectivity of AP probe-net against ATC.
Main Methods:
- Synthesis and characterization of the GSH-responsive AP probe-net.
- In vitro cytotoxicity assays (MTT, γ-H2AX) on ATC and normal thyroid cells.
- Cell cycle analysis and apoptosis assays (flow cytometry, Western blotting) to determine mechanism of action.
- In vivo studies on subcutaneous ATC tumor models to evaluate therapeutic effects.
Main Results:
- AP probe-net demonstrated selective cytotoxicity against ATC cells compared to normal thyroid cells.
- The reagent induced G2/M cell cycle arrest and apoptosis in ATC cells.
- In vivo experiments showed significant therapeutic effects of AP probe-net on ATC tumors.
Conclusions:
- AP probe-net effectively targets ATC by trapping AP sites and inhibiting APE1-mediated BER, leveraging elevated tumor microenvironment GSH levels.
- This strategy offers a highly selective approach for ATC chemotherapy with potentially reduced adverse effects.
- The study presents a novel therapeutic avenue for treating aggressive anaplastic thyroid carcinoma.
