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Translocation of Platinum Anticancer Drugs by Human Copper ATPases ATP7A and ATP7B
Author(s) -
TadiniBuoninsegni Francesco,
Bartolommei Gianluca,
Moncelli Maria Rosa,
Inesi Giuseppe,
Galliani Angela,
Sinisi Marilù,
Losacco Maurizio,
Natile Giovanni,
Arnesano Fabio
Publication year - 2014
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201307718
Subject(s) - atp7a , chemistry , oxaliplatin , p type atpase , atpase , chromosomal translocation , cisplatin , platinum , prodrug , biochemistry , pharmacology , biophysics , enzyme , biology , cancer , catalysis , gene , colorectal cancer , chemotherapy , genetics
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).