title: Glutathione selectively modulates the binding of platinum drugs to human copper chaperone Cox17.
abstract: The copper chaperone Cox17 (cytochrome c oxidase copper chaperone) has been shown to facilitate the delivery of cisplatin to mitochondria, which contributes to the overall cytotoxicity of the drug [Zhao et al. (2014) Chem. Commun. 50: , 2667-2669]. Kinetic data indicate that Cox17 has reactivity similar to glutathione (GSH), the most abundant thiol-rich molecule in the cytoplasm. In the present study, we found that GSH significantly modulates the reaction of platinum complexes with Cox17. GSH enhances the reactivity of three anti-cancer drugs (cisplatin, carboplatin and oxaliplatin) to Cox17, but suppresses the reaction of transplatin. Surprisingly, the pre-formed cisplatin-GSH adducts are highly reactive to Cox17; over 90% platinum transfers from GSH to Cox17. On the other hand, transplatin-GSH adducts are inert to Cox17. These different effects are consistent with the drug activity of these platinum complexes. In addition, GSH attenuates the protein aggregation of Cox17 induced by platination. These results indicate that the platinum-protein interactions could be substantially influenced by the cellular environment.
authors.affiliation: CAS Key Laboratory of Soft Matter Chemistry, CAS High Magnetic Field Laboratory, Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China The Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, Jiangsu 210096, China.
authors.forename: Linhong
authors.initials: L
authors.lastname: Zhao
authors.affiliation: CAS Key Laboratory of Soft Matter Chemistry, CAS High Magnetic Field Laboratory, Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: CAS Key Laboratory of Soft Matter Chemistry, CAS High Magnetic Field Laboratory, Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China.
authors.forename: Han
authors.initials: H
authors.lastname: Wu
authors.affiliation: CAS Key Laboratory of Soft Matter Chemistry, CAS High Magnetic Field Laboratory, Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China.
authors.forename: Zhaoyong
authors.initials: Z
authors.lastname: Xi
authors.affiliation: CAS Key Laboratory of Soft Matter Chemistry, CAS High Magnetic Field Laboratory, Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China liuyz@ustc.edu.cn.
authors.forename: Yangzhong
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001059:Apoproteins / Q000235:genetics / Q000378:metabolism; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003300:Copper / Q000378:metabolism*; D000079922:Copper Transport Proteins; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008024:Ligands; D009944:Organoplatinum Compounds / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D010084:Oxidation-Reduction; D017671:Platinum Compounds / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D066329:Protein Aggregates / Q000187:drug effects; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012995:Solubility
chemical_list: D000970:Antineoplastic Agents; D001059:Apoproteins; C491006:COX17 protein, human; D002352:Carrier Proteins; D000079922:Copper Transport Proteins; D008024:Ligands; D009944:Organoplatinum Compounds; D017671:Platinum Compounds; D066329:Protein Aggregates; D011994:Recombinant Proteins; D003300:Copper; D005978:Glutathione
keywords: anti-tumour drugs; copper chaperone; cytochrome c oxidase copper chaperone (Cox17); glutathione; platinum