Mechanistic insights into antitumor effects of new dinuclear cis Pt-II complexes containing aromatic linkers

Autoři: Zerzankova, L., Kostrhunova, H., Vojtiskova, M., Novakova, O., Suchankova, T., Lin, MX., Guo, ZJ., Kasparkova, J., Brabec, V.
Rok: 2010


The primary objective was to understand more deeply the molecular mechanism underlying different antitumor effects of dinuclear Pt-II complexes containing aromatic linkers of different length, ([cisPt( NH3)(2)Cl](2)(4,4'-methylenedianiline)}(2+) (1) and {[cis-Pt(NH3)(2)Cl](2)(alpha,alpha'-diamino-p-xylene)}(2+) (2). These complexes belong to a new generation of promising polynuclear platinum drugs resistant to decomposition by sulfur nucleophiles which hampers clinical use of bifunctional polynuclear trans Pt-II complexes hitherto tested. Results obtained with the aid of methods of molecular biophysics and pharmacology reveal differences and new details of DNA modifications by I and 2 and recognition of these modifications by cellular components. The results indicate that the unique properties of DNA interstrand cross-links of this class of polynuclear platinum complexes and recognition of these cross-links may play a prevalent role in antitumor effects of these metallodrugs. Moreover, the results show for the first time a strong specific recognition and binding of high-mobility-group-domain proteins, which are known to modulate antitumor effects of clinically used platinum drugs, to DNA modified by a polynuclear platinum complex. (C) 2010 Elsevier Inc. All rights reserved.