Article: Activation of carboplatin and nedaplatin by the N-terminus of human copper transporter 1 (hCTR1)

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TitleActivation of carboplatin and nedaplatin by the N-terminus of human copper transporter 1 (hCTR1)
AuthorsWang, X2
Li, H2
Du, X2
Harris, J2 3
Guo, Z1
Sun, H2
KeywordsAnticancer compounds
Anticancer drug
Bidentate ligands
Blood plasma
Carboplatin
Issue Date2012
PublisherRoyal Society of Chemistry. The Journal's web site is located at http://www.rsc.org/publishing/journals/sc/About.asp
CitationChemical Science, 2012, v. 3 n. 11, p. 3206-3215 [How to Cite?]
DOI: http://dx.doi.org/10.1039/c2sc20738a
AbstractHuman copper transporter 1 (hCTR1) is a major copper uptake protein. Interestingly, it also mediates the uptake of selected platinum (Pt) anticancer drugs such as cisplatin and carboplatin. Here we studied the interactions of the N-terminus of hCTR1 (hCTR1-N) with carboplatin and its analogue nedaplatin by NMR spectroscopy and electrospray ionization mass spectrometry (ESI-MS). Our 2D [ 1H, 15N] SOFAST-HMQC NMR data demonstrated that hCTR1-N binds to these Pt drugs through methionine residues to form ring-opened monofunctional adducts. Such a binding significantly activated these platinum drugs. High resolution ESI-MS spectra showed that a maximum of two Pt atoms bound per monomer of the protein for carboplatin and nedaplatin in a similar manner to cisplatin. In contrast, transplatin interacted with hCTR1-N more rapidly, yielding a different binding species with a maximum of five transplatin bound per monomer of the protein. The nucleophiles in serum, e.g. chloride and bicarbonate, can also play a role in the pre-activation of carboplatin and nedaplatin in the blood plasma prior to reaching their cellular targets. This study provides an insight into the possible mechanism of in vivo activation of Pt anticancer compounds with bidentate ligands. © 2012 The Royal Society of Chemistry.
ISSN2041-6520
2011 Impact Factor: 7.525
DOIhttp://dx.doi.org/10.1039/c2sc20738a
DC Field
Value
dc.contributor.authorWang, X
dc.contributor.authorLi, H
dc.contributor.authorDu, X
dc.contributor.authorHarris, J
dc.contributor.authorGuo, Z
dc.contributor.authorSun, H
dc.date.accessioned2012-08-16T05:48:57Z
dc.date.available2012-08-16T05:48:57Z
dc.date.issued2012
dc.description.abstractHuman copper transporter 1 (hCTR1) is a major copper uptake protein. Interestingly, it also mediates the uptake of selected platinum (Pt) anticancer drugs such as cisplatin and carboplatin. Here we studied the interactions of the N-terminus of hCTR1 (hCTR1-N) with carboplatin and its analogue nedaplatin by NMR spectroscopy and electrospray ionization mass spectrometry (ESI-MS). Our 2D [ 1H, 15N] SOFAST-HMQC NMR data demonstrated that hCTR1-N binds to these Pt drugs through methionine residues to form ring-opened monofunctional adducts. Such a binding significantly activated these platinum drugs. High resolution ESI-MS spectra showed that a maximum of two Pt atoms bound per monomer of the protein for carboplatin and nedaplatin in a similar manner to cisplatin. In contrast, transplatin interacted with hCTR1-N more rapidly, yielding a different binding species with a maximum of five transplatin bound per monomer of the protein. The nucleophiles in serum, e.g. chloride and bicarbonate, can also play a role in the pre-activation of carboplatin and nedaplatin in the blood plasma prior to reaching their cellular targets. This study provides an insight into the possible mechanism of in vivo activation of Pt anticancer compounds with bidentate ligands. © 2012 The Royal Society of Chemistry.
dc.description.natureLink_to_subscribed_fulltext
dc.identifier.citationChemical Science, 2012, v. 3 n. 11, p. 3206-3215 [How to Cite?]
DOI: http://dx.doi.org/10.1039/c2sc20738a
dc.identifier.doihttp://dx.doi.org/10.1039/c2sc20738a
dc.identifier.epage3215
dc.identifier.hkuros205086
dc.identifier.issn2041-6520
2011 Impact Factor: 7.525
dc.identifier.issue11
dc.identifier.openurl
dc.identifier.scopuseid_2-s2.0-84867342140
dc.identifier.spage3206
dc.identifier.urihttp://hdl.handle.net/10722/159380
dc.identifier.volume3
dc.languageeng
dc.publisherRoyal Society of Chemistry. The Journal's web site is located at http://www.rsc.org/publishing/journals/sc/About.asp
dc.publisher.placeUnited Kingdom
dc.relation.ispartofChemical Science
dc.subjectAnticancer compounds
dc.subjectAnticancer drug
dc.subjectBidentate ligands
dc.subjectBlood plasma
dc.subjectCarboplatin
dc.titleActivation of carboplatin and nedaplatin by the N-terminus of human copper transporter 1 (hCTR1)
dc.typeArticle
Author Affiliations
  1. Nanjing University
  2. The University of Hong Kong
  3. University of Edinburgh