title: Reversal of cisplatin resistance in human gastric cancer cells by a wogonin-conjugated Pt(IV) prodrug via attenuating Casein Kinase 2-mediated Nuclear Factor-κB pathways.
abstract: Pt(IV) prodrugs, with two additional coordination sites in contrast to Pt(II) drugs, have been actively studied nowadays, for they can perform well in enhancing the accumulation and retention of the corresponding Pt(II) drugs in cancer cells. Our designed Pt(II) drug, DN604, was recently found to exhibit significant anticancer activity and low toxicity, while, wogonin, a naturally O-methylated flavones, has been widely investigated for its tumor therapeutic potential. Thus, two Pt(IV)-based prodrugs were derived by addition of a wogonin unit to the axial position of DN604 and its analogue DN603 via a linker group. In vitro cytotoxicity assay indicated that the resulting compound 8 not only inherited the genotoxicity of DN604 on gastric cancer cells, but also obtained the COX inhibitory property arising from wogonin. Further studies revealed that compound 8 caused the accumulation of ROS production and decreased the mitochondrial membrane potential (ΔΨm). The CK2α kinase activity assay, ChIP and luciferase assays showed that CK2 plays an important role in the blockade of compound 8 on activated NF-κB survival pathways, which were established for sensitivity of cancer cells to platinum drugs. Similarly in vivo, in nude mice with SGC-7901/cDDP xenografts, compound 8 improved the effectiveness of DN604 via reversing tumor resistance and maintaining low toxicity. Overall, compound 8 is a promising Pt(IV) prodrug, which could be used to promote the anticancer activity of its counterpart Pt(II) species and reverse drug resistance via attenuating CK2-mediated NF-κB pathways during platinum-based chemotherapies.
authors.affiliation: Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China.
authors.forename: Feihong
authors.initials: F
authors.lastname: Chen
authors.affiliation: Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Qin
authors.affiliation: Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Xu
authors.affiliation: Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China. Electronic address: sgou@seu.edu.cn.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Gou
authors.affiliation: Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China.
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Jin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D044950:Flavanones / Q000737:chemistry / Q000494:pharmacology*; D045325:HCT116 Cells; D056945:Hep G2 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013274:Stomach Neoplasms / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects / Q000502:physiology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D044950:Flavanones; D016328:NF-kappa B; D009944:Organoplatinum Compounds; D011355:Prodrugs; D047390:Casein Kinase II; C085514:wogonin; D002945:Cisplatin
keywords: Ascorbic acid (PubChem CID: 54670067); CK2; COX; Carboplatin (PubChem CID: 38904); Cisplatin (PubChem CID: 2767); Cisplatin resistance; DMSO (PubChem CID: 679); DN604; Ethidium bromide (PubChem CID: 14710); MTT (PubChem CID: 64965); NF-κB; Oxaliplatin (PubChem CID: 5310940); Penicillin (PubChem CID: 5904); Streptomycin (PubChem CID: 19649); Wogonin; Wogonin (PubChem CID: 5281703)