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

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 Pt^IV 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.