A Platinum(IV) Anticancer Prodrug Targeting Nucleotide Excision Repair To Overcome Cisplatin Resistance

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

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Original languageEnglish
Pages (from-to)15564-15568
Journal / PublicationAngewandte Chemie - International Edition
Issue number50
Publication statusPublished - 12 Dec 2016


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.

Research Area(s)

  • cancer, cisplatin, DNA, nucleotide excision repair, platinum prodrugs