Mechanistic insights into toxic effects of a benzotriazolate-bridged dinuclear platinum(II) compound in tumor cells

Publikace: INORGANICA CHIMICA ACTA 393, 204-211 Autoři: Olivova, R., Stepankova, J., Muchova, T., Novohradsky, V., Novakova, O., Vrana, O., Kasparkova, J., Brabec, V. Rok: 2012


We examined toxicity in tumor cells as well as some early phases of the mechanism underlying biological properties of benzotriazolate (Btaz)-bridged dinuclear Pt-II complex ([{cis-Pt(NH3)(2)Cl}(2)(mu-Btaz-H)]Cl (1)). This dinuclear bifunctional Pt-II complex utilizes rigid aromatic ring of azole as a linker between two Pt atoms, featuring at the same time non-bridging chloride ions as leaving groups. The results of the present work demonstrate that the toxicity of 1 in several human tumor cell lines was lower than that of conventional cisplatin. The results obtained are consistent with the idea, and support the postulate that deactivation of 1 by sulfur-containing compounds is a significant factor contributing to reduced DNA binding of 1 in cells and subsequently to its reduced cytotoxicity. In addition, the observations that DNA adducts of 1 and cisplatin distort DNA conformation differently and that monofunctional DNA adducts of 1 are converted to more toxic bifunctional cross-links considerably more slowly in comparison with cisplatin may contribute to the reduced cytoxicity of 1. The results of the present work afford further details on the mechanism underlying biological effects of bifunctional polynuclear Pt-II compounds and should provide a more rational basis for the design of new antitumor metallodrugs and chemotherapeutic strategies. (C) 2012 Elsevier B. V. All rights reserved.