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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).

SUBMITTER: Tadini-Buoninsegni F

PROVIDER: S-EPMC3937162 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Translocation of platinum anticancer drugs by human copper ATPases ATP7A and ATP7B.

Tadini-Buoninsegni Francesco F Bartolommei Gianluca G Moncelli Maria Rosa MR Inesi Giuseppe G Galliani Angela A Sinisi Marilù M Losacco Maurizio M Natile Giovanni G Arnesano Fabio F

Angewandte Chemie (International ed. in English) 20131227 5

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 s ...[more]

PMID: 24375922

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