Studies on cellular accumulation of satraplatin and its major metabolite JM118 and their interactions with glutathione

Hana Kostrhunova, Jana Kasparkova, Dan Gibson, Viktor Brabec*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Before the active form of a Pt drug reaches its major pharmacological target in the cell nucleus, the Pt complex has to accumulate in cells, and during its transportation into cells and inside cells, it reacts with various biomolecules. Satraplatin is the first orally administered Pt drug under active clinical investigation. The major metabolite of this PtIV complex is its PtII analogue (JM118), which also has significant anticancer properties. Here we report the role of active transport in cellular entry of satraplatin and JM118 and interactions of these Pt complexes with glutathione. The results reveal that the organic cation transporters may play a more important role in the mechanism of cytotoxicity of JM118 than in the cytotoxicity of cisplatin. In contrast, satraplatin is a poor substrate of these transporters. In addition, satraplatin reacts with glutathione with the rate markedly lower than JM118 and cisplatin. Interestingly, satraplatin can be activated by glutathione allowing it to react with DNA, although to a much lower extent than in the case of another PtIV drug tetraplatin.

Original languageEnglish
Pages (from-to)2093-2102
Number of pages10
JournalMolecular Pharmaceutics
Volume7
Issue number6
DOIs
StatePublished - 6 Dec 2010

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