A Platinum(IV) Anticancer Prodrug Targeting Nucleotide Excision Repair To Overcome Cisplatin Resistance.
A Platinum(IV) Anticancer Prodrug Targeting Nucleotide Excision Repair To Overcome Cisplatin Resistance.
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DOI：
10.1002/anie.201608936
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发表时间：
2016-12
影响因子：
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通讯作者：
Zhigang Wang;Zoufeng Xu;G. Zhu
中科院分区：
文献类型：
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作者：
Zhigang Wang;Zoufeng Xu;G. Zhu
DNA损伤反应不仅在维持基因组完整性方面起关键作用，而且在介导DNA损伤性抗肿瘤药物的抗肿瘤功效方面起关键作用。在此，我们报告了PtIV抗癌前药抑制核苷酸切除修复（NER）的合理设计和评价，核苷酸切除修复是顺铂诱导的DNA损伤形成后最关键的过程之一，该过程使药物失活并导致临床耐药性。这种双重作用的前药有效地进入细胞并引起DNA损伤，同时抑制NER以促进凋亡反应。该前药对顺铂耐药性人癌细胞的增殖具有强烈的活性，与顺铂相比，生长抑制增加高达88倍，并且该前药比顺铂和NER抑制剂的混合物活性高得多。我们的研究强调了在铂诱导的DNA损伤形成后靶向下游途径作为克服顺铂耐药的新策略的重要性。
DNA damage response plays a key role not only in maintaining genome integrity but also in mediating the antitumor efficacy of DNA-damaging antineoplastic drugs. Herein, we report the rational design and evaluation of a PtIV anticancer prodrug inhibiting nucleotide excision repair (NER), one of the most pivotal processes after the formation of cisplatin-induced DNA damage that deactivates the drug and leads to drug resistance in the clinic. This dual-action prodrug enters cells efficiently and causes DNA damage while simultaneously inhibiting NER to promote apoptotic response. The prodrug is strongly active against the proliferation of cisplatin-resistant human cancer cells with an up to 88-fold increase in growth inhibition compared with cisplatin, and the prodrug is much more active than a mixture of cisplatin and an NER inhibitor. Our study highlights the importance of targeting downstream pathways after the formation of Pt-induced DNA damage as a novel strategy to conquer cisplatin resistance.