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  • Title: A Platinum(IV) Anticancer Prodrug Targeting Nucleotide Excision Repair To Overcome Cisplatin Resistance.
    Author: Wang Z, Xu Z, Zhu G.
    Journal: Angew Chem Int Ed Engl; 2016 Dec 12; 55(50):15564-15568. PubMed ID: 27736029.
    Abstract:
    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.
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