Reaction of Zn7metallothionein with cis- and trans-[Pt(N-donor)2Cl2] anticancer complexes: trans-Pt(II) complexes retain their N-donor ligands

Intrinsic and acquired resistance are major drawbacks of platinum-based cancer therapy. The protein superfamily of cysteine- and ZnII-rich proteins, metallothioneins (MT), efficiently inactivate these antitumor drugs because of the strong reactivity of platinum compounds with S-donor molecules. In t...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2007-08, Vol.50 (17), p.4075-4086
Main Authors: Knipp, Markus, Karotki, Andrei V, Chesnov, Serge, Natile, Giovanni, Sadler, Peter J, Brabec, Viktor, Vasák, Milan
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemistry
Cisplatin - chemistry
Drug Resistance, Neoplasm
Humans
Kinetics
Ligands
Metallothionein - chemistry
Organoplatinum Compounds - chemistry
Spectrometry, Mass, Electrospray Ionization
Structure-Activity Relationship
Zinc
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Summary:Intrinsic and acquired resistance are major drawbacks of platinum-based cancer therapy. The protein superfamily of cysteine- and ZnII-rich proteins, metallothioneins (MT), efficiently inactivate these antitumor drugs because of the strong reactivity of platinum compounds with S-donor molecules. In this study the reactions of human Zn7MT-2 with twelve cis/trans-[Pt(N-donor)2Cl2] compounds and [Pt(dien)Cl]Cl, including new generation drugs, were investigated and the products characterized. A comparison of reaction kinetics revealed that trans-PtII compounds react faster with Zn7MT-2 than cis-PtII compounds. The characterization of the products showed that while all ligands in cis-PtII compounds were replaced by cysteine thiolates, trans-PtII compounds retained their N-donor ligands, thus remaining in a potentially active form. These results provide an increased understanding of the role of MT in the acquired resistance to platinum-based anticancer drugs.
ISSN:0022-2623