A Platinum(IV) Anticancer Prodrug Targeting Nucleotide Excision Repair To Overcome Cisplatin Resistance |
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| Authors: | Zhigang Wang Zoufeng Xu Prof Dr Guangyu Zhu |
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| Affiliation: | 1. Department of Biology and Chemistry, City University of Hong Kong, Kowloon Tong, Hong Kong SAR, P.R. China;2. City University of Hong Kong, Shenzhen Research Institute, Shenzhen, P.R. China |
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| 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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| Keywords: | cancer cisplatin DNA platinum prodrugs nucleotide excision repair |
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