甲状腺未分化癌（ATC）是一种罕见但高度侵袭性的甲状腺癌，预后较差。通过诱导 DNA 损伤或阻止 DNA 修复来杀死癌细胞是一种有前景的化疗策略。据报道，醛反应性烷氧基胺可以捕获AP位点（最常见的DNA损伤之一），并抑制脱嘌呤/脱嘧啶核酸内切酶1（APE1）介导的碱基切除修复（BER），导致细胞死亡。这种策略是否可以用于 ATC 治疗很少有研究。本研究的目的是开发 GSH 响应性 AP 位点捕获试剂（AP 探针网），该试剂可响应肿瘤微环境 (TME) 中升高的谷胱甘肽 (GSH) 水平，释放反应性烷氧基胺以捕获 AP 位点并阻断 APE1 介导的 BER，从而实现针对 ATC 的靶向抗肿瘤活性。体外实验（包括 MTT 和 γ-H2AX 测定）证明了它们对 ATC 细胞的选择性细胞毒性高于正常甲状腺细胞。流式细胞术分析表明 AP 探针网将细胞周期阻滞在 G2/M 期并诱导细胞凋亡。 Western blotting（WB）结果显示，随着AP探针网浓度的增加，凋亡蛋白的表达量增加。进一步的体内实验表明AP探针网对ATC细胞的皮下肿瘤具有良好的治疗效果。总之，利用 TME 中 GSH 升高的优势，我们的研究为 ATC 靶向化疗提供了一种高选择性并减少不良反应的新策略。© 2024。作者。

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.© 2024. The Author(s).