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Mechanistic insights into antitumor effects of new dinuclear cis Pt(II) complexes containing aromatic linkers
L. Zerzankova, H. Kostrhunova, M. Vojtiskova, O. Novakova, T. Suchankova, M. Lin, Z. Guo, J. Kasparkova, V. Brabec
Language English Country England, Great Britain
Document type Comparative Study, Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- DNA Adducts chemistry metabolism MeSH
- Cisplatin chemistry metabolism pharmacology MeSH
- HeLa Cells MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- DNA Damage drug effects physiology MeSH
- Antineoplastic Agents chemistry metabolism pharmacology MeSH
- Cross-Linking Reagents chemistry metabolism pharmacology MeSH
- Cell Survival drug effects physiology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Comparative Study MeSH
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, {[cis-Pt(NH(3))(2)Cl](2)(4,4'-methylenedianiline)}(2+) (1) and {[cis-Pt(NH(3))(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 1 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.
References provided by Crossref.org
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- $a 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, {[cis-Pt(NH(3))(2)Cl](2)(4,4'-methylenedianiline)}(2+) (1) and {[cis-Pt(NH(3))(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 1 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.
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