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Cisplatin-induced changes in biological activity of blood platelets: thiol-related mechanisms

The effects of cisplatin (cis-diamminedichloroplatinum (II), CDDP) and transplatin (trans-diamminedichloroplatinum(II), TDDP), and their complexes with glutathione (GS–Pt) in vitro on oxygen free radical generation (O2− ⋅), lipid peroxidation and ADP-induced aggregation in pig blood platelets were studied. Incubation of pig blood platelets with cisplatin or transplatin caused a loss of both protein -SH and the thiol groups of GSH. In pig blood platelets exposed to cisplatin or transplatin (20 µM) the GS–Pt complex was formed as a major metabolite. The formation of GS–Pt complexes in platelet cytosol was time dependent and the intracellular content of this complex reached a maximal level after 24 h. GS–Pt complexes were found to induce platelet lipid peroxidation, measured as thiobarbituric acid reactive substance level, and O2−⋅ generation, and it was more active than cisplatin or transplatin alone. Cisplatin and its GS–Pt complex had an inhibitory effect on ADP-induced platelet aggregation. These results showed that GS–Pt complexes affect platelet metabolism and function. It seems that glutathione-associated metabolism of platinum compounds plays an important role in the cytotoxicity and biological activity of these drugs.