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 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.
Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
Markus
M
Knipp
Andrei V
AV
Karotki
Serge
S
Chesnov
Giovanni
G
Natile
Peter J
PJ
Sadler
Viktor
V
Brabec
Milan
M
Vasák
D000970:Antineoplastic Agents / Q000737:chemistry*; D002945:Cisplatin / Q000737:chemistry; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008668:Metallothionein / Q000737:chemistry*; D009944:Organoplatinum Compounds / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D015032:Zinc
D000970:Antineoplastic Agents; D008024:Ligands; D009944:Organoplatinum Compounds; C021267:zinc thionein; D008668:Metallothionein; D015032:Zinc; D002945:Cisplatin