title: Translocation of platinum anticancer drugs by human copper ATPases ATP7A and ATP7B.
abstract: Cisplatin, carboplatin, and oxaliplatin are widely used anticancer drugs. Their efficacy is strongly reduced by development of cell resistance. Down-regulation of CTR1 and up-regulation of the Cu-ATPases, ATP7A and ATP7B, have been associated to augmented drug resistance. To gain information on translocation of Pt drugs by human Cu-ATPases, we performed electrical measurements on the COS-1 cell microsomal fraction, enriched with recombinant ATP7A, ATP7B, and selected mutants, and adsorbed on a solid supported membrane. The experimental results indicate that Pt drugs activate Cu-ATPases and undergo ATP-dependent translocation in a fashion similar to that of Cu. We then used NMR spectroscopy and ESI-MS to determine the binding mode of these drugs to the first N-terminal metal-binding domain of ATP7A (Mnk1).
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence (Italy).
authors.forename: Francesco
authors.initials: F
authors.lastname: Tadini-Buoninsegni
authors.forename: Gianluca
authors.initials: G
authors.lastname: Bartolommei
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Moncelli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Inesi
authors.forename: Angela
authors.initials: A
authors.lastname: Galliani
authors.forename: Marilù
authors.initials: M
authors.lastname: Sinisi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Losacco
authors.forename: Giovanni
authors.initials: G
authors.lastname: Natile
authors.forename: Fabio
authors.initials: F
authors.lastname: Arnesano
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D020816:Amino Acid Motifs; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D019556:COS Cells; D027682:Cation Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D002945:Cisplatin / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D003300:Copper / Q000737:chemistry / Q000378:metabolism; D000079923:Copper Transporter 1; D000073840:Copper-Transporting ATPases; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008861:Microsomes / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D000077150:Oxaliplatin; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D021241:Spectrometry, Mass, Electrospray Ionization; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; D047908:Intracellular Signaling Peptides and Proteins; D009944:Organoplatinum Compounds; D011994:Recombinant Proteins; C490079:SLC31A1 protein, human; D000077150:Oxaliplatin; D003300:Copper; D000255:Adenosine Triphosphate; C491395:MKNK1 protein, human; D017346:Protein Serine-Threonine Kinases; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases; D002945:Cisplatin
keywords: ATPases; NMR spectroscopy; charge measurements; copper; platinum drugs