Thioredoxins are small redox proteins and have the active sites of Cys-Xaa-Yaa-Cys; they are overexpressed by many different cancer cells. Cisplatin and Pt(II) analogues could bind to the active sites and inhibit the activities of the proteins, as demonstrated by other researchers. Platinum(IV) anticancer drugs are often regarded as prodrugs, but their interactions with thioredoxins have not been studied. In this work, 3,6-dioxa-1,8-octanedithiol (dithiol) was chosen as a model compound for the active sites of thioredoxins, and its reactions with cis-[Pt(NH3)(2)Cl-4] and trans-[PtCl2(CN)(4)](2-) (cisplatin prodrug and a Model complex) were studied. The pK(a) values for the dithiol were characterized to be 8.7 +/- 0.2 and 9.6 +/- 0.2 at 25.0 degrees C and an ionic strength of 1.0 M. The reaction kinetics was followed by a stopped-flow spectrophotometer over a wide pH range. An overall second-order rate law was established, -d[Pt(IV)]/dt = k'[Pt(IV)][dithiol], where k' stands for the observed second-order rate constants. Values of k' increased several orders of magnitude when the solution pH was increased from 3 to 9. A stoichiometry of Delta[Pt(IV)]/Delta[dithiol] = 1:1 derived for the reduction process and product analysis by mass spectrometry indicated that the dithiol was oxidized to form an intramolecular disulfide, coinciding with the nature of thioredoxin proteins. All of the reaction features are rationalized in terms of a reaction mechanism, involving three parallel rate-determining steps depending on the pH of the reaction medium. Rate constants for the rate-determining steps were evaluated. It can be concluded that Pt(IV) anticancer prodrugs can oxidize the reduced thioredoxins, and the oxidation mechanism is similar to those of the oxidations of biologically important reductants by some reactive oxygen species (ROS) such as hypochlorous acid/hypochlorite and chloramines.