Selective anti-tumor activity of Glutathione-responsive abasic site trapping agent in Anaplastic thyroid carcinoma

Abstract

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 could 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 was to exploit the elevated glutathione (GSH) levels in the tumor micro-environment (TME), and explore the GSH-responsive AP sites capture reagent (AP probe-net), which can be selectively activated by GSH, releasing reactive alkoxyamines to trap AP sites and block the APE1-mediated BER for targeted anti-tumor against ATC. In vitro experiments, including MTT andγ-H2AX assays, demonstrated their selective cytotoxicity. Flow cytometry analysis suggested that AP probe-net arrested the cell cycle in the G2/M phase and induced apoptosis of cells. Western blotting (WB) results showed that the expression of apoptotic protein increased with increasing the concentration of AP probe-net. Further in vivo experiments revealed that the AP probe-net had 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 bio-safety.