In vitro binding of an orally active platinum antitumor drug, JM216 to metallothionein.

Abstract

The in vitro binding of an orally active anticancer drug JM216 to metallothionein is firstly investigated in this paper. It is revealed that a redox reaction following a substitution reaction from JM216 with rabbit liver Zn7MT-II is presented. The reaction feature, the metal binding stoichiometry and the oxidation states of platinum and sulfur in the products are studied by UV-visible, chromatography and X-ray photoelectron spectroscopy methods. Parts of MT are oxidized to precipitate products with intra and intermolecular CyS-SCy disulfides linkages. Pt(IV) is reduced to its Pt(II) counterpart. And the reduced Pt(II) replace the metal ions in native MTs. Meanwhile it can also cause the dimerization of MT. Increasing the reaction ratio of JM216 to MT leads to a concomitant increase in the apparent yield of the precipitate and dimeric products and the elevation of the binding stoichiometry of Pt to the protein. Based on the experimental data, the reaction mechanism between JM216 and Zn7MT-II in vitro are discussed.