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A model for a wogonin-conjugated Pt(IV) prodrug to circumvent cisplatin resistance via attenuating CK2-mediated NF-κB pathways and inducing DNA double and single strands breaks in human gastric cancer cells.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.