Studies on Cellular Accumulation of Satraplatin and Its Major Metabolite JM118 and Their Interactions with Glutathione

Publikace: MOLECULAR PHARMACEUTICS 7, 2093-2102 Autoři: Kostrhunova, H., Kasparkova, J., Gibson, D., Brabec, V. Rok: 2010

Abstrakt

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 Pt-IV complex is its Pt-II 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 Pt-IV drug tetraplatin.