title: A CK2-targeted Pt(IV) prodrug to disrupt DNA damage response.
abstract: A Pt(IV) prodrug, Cx-platin, containing CX-4945 (a CK2 inhibitor) as an axial ligand was designed and prepared by targeting CK2 to disrupt DNA damage response. In vitro study indicated that Cx-platin had superior cytotoxicity to cisplatin against a number of cancer cell lines with distinct CK2-expressed levels, caused CK2-overexpressed cancer cells death via suppressing CK2-mediated DNA damage repair and reversed cisplatin resistance. Mechanistic investigation suggested that the potent antitumor activity of Cx-platin resulted from its major suppression of CK2-phosphorylated MDC1 to combine FHA domain of aprataxin to DNA double strand breaks (DSBs) caused by improved cellular uptakes of Pt and ATM deactivation. Further in vivo tests exhibited that Cx-platin displayed high tumor inhibition rates, increased weight gain, and hardly toxicity effects in contrast to cisplatin.
authors: Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
authors: Feihong
authors: F
authors: Chen
authors: Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
authors: Xiaochao
authors: X
authors: Huang
authors: Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
authors: Mian
authors: M
authors: Wu
authors: Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China. Electronic address: sgou@seu.edu.cn.
authors: Shaohua
authors: S
authors: Gou
authors: Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
authors: Weiwei
authors: W
authors: Hu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018797:Cell Cycle Proteins; D002945:Cisplatin / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D015195:Drug Design; D005260:Female; D045325:HCT116 Cells; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009287:Naphthyridines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D010619:Phenazines; D010766:Phosphorylation; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D054730:Protein Interaction Domains and Motifs; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C438188:APTX protein, human; D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C000621688:Cx-platin; D004268:DNA-Binding Proteins; D004338:Drug Combinations; C413163:MDC1 protein, human; D009287:Naphthyridines; D009687:Nuclear Proteins; D009944:Organoplatinum Compounds; D010619:Phenazines; D011355:Prodrugs; D047428:Protein Kinase Inhibitors; D015534:Trans-Activators; C555142:silmitasertib; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D047390:Casein Kinase II; D002945:Cisplatin
keywords: CK2; Cisplatin resistance; DSBs repair; Pt(IV) complex