title: A Platinum(IV) Anticancer Prodrug Targeting Nucleotide Excision Repair To Overcome Cisplatin Resistance.
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 PtIVanticancer 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.
authors.affiliation: Department of Biology and Chemistry, City University of Hong Kong, 83 Tat Chee Ave, Kowloon Tong, Hong Kong SAR, P.R. China.|City University of Hong Kong, Shenzhen Research Institute, Shenzhen, P.R. China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Biology and Chemistry, City University of Hong Kong, 83 Tat Chee Ave, Kowloon Tong, Hong Kong SAR, P.R. China.|City University of Hong Kong, Shenzhen Research Institute, Shenzhen, P.R. China.
authors.forename: Zoufeng
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Biology and Chemistry, City University of Hong Kong, 83 Tat Chee Ave, Kowloon Tong, Hong Kong SAR, P.R. China.|City University of Hong Kong, Shenzhen Research Institute, Shenzhen, P.R. China.
authors.forename: Guangyu
authors.initials: G
authors.lastname: Zhu
mesh_terms: D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004260:DNA Repair / Q000187:drug effects*; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010984:Platinum / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D010984:Platinum; D002945:Cisplatin
keywords: DNA; cancer; cisplatin; nucleotide excision repair; platinum prodrugs