Pt(IV) Prodrug as a Potential Antitumor Agent with APE1 Inhibitory Activity
Pt(IV) Prodrug as a Potential Antitumor Agent with APE1 Inhibitory Activity
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Pt(IV) 前药作为具有 APE1 抑制活性的潜在抗肿瘤剂
DOI：
10.1021/acs.jmedchem.2c01318
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发表时间：
2022
影响因子：
7.3
通讯作者：
Zhuo Tang
中科院分区：
文献类型：
--
作者：
Yi Yuan;Dingqiang Fu;Yan Xu;Xuyang Wang;Xiongfei Deng;Shan Zhou;Feng Du;Xin Cui;Yun Deng;Zhuo Tang
碱基切除修复（BER）途径对于癌细胞抵抗化疗至关重要，但其重要性被低估了。本研究描述了一种新型的Pt(IV)前药AP1，其靶向关键的BER蛋白，脱嘌呤/脱嘧啶核酸内切酶1（APE1）。AP1诱导铂在细胞内积累，并激活DNA损伤反应和凋亡信号。AP1可以强烈抑制恶性细胞的生长，包括顺铂耐药的癌细胞，与顺铂相比，抑制作用高达18.11倍。而且，它对正常细胞的毒性与顺铂一样。在异种移植模型中，AP1 的效力是顺铂的 3.86 倍，且没有副作用。有趣的是，AP1可以直接抑制APE1的AP核酸内切酶活性，导致miRNA加工中断和抑癌基因PTEN上调。我们的研究结果揭示了 Pt(IV) 与靶蛋白相互作用的模式，并强调了 BER 在铂基癌症治疗中的关键作用。
The base excision repair (BER) pathway is essential for cancer cells to resist chemotherapeutic treatment, but its significance is underrated. The present study describes a novel Pt(IV) prodrug,AP1, targeting a critical BER protein, apurinic/apyrimidinic endonuclease 1 (APE1).AP1induces intracellular accumulation of platinum and activates DNA damage response and apoptosis signals.AP1can strongly inhibit the growth of malignant cells, including cisplatin-resistant cancer cells, with up to 18.11 times inhibition compared with cisplatin. Moreover, it is as toxic to normal cells as cisplatin. In a xenograft model,AP1is 3.86-fold more potent than cisplatin without adverse effects. Intriguingly,AP1can directly inhibit the AP endonuclease activity of APE1, leading to an interruption of miRNA processing and upregulation of the tumor suppressor PTEN. Our findings shed light on a mode of Pt(IV) interaction with a target protein and highlight the critical role of BER in platinum-based cancer treatment.