Mechanistic insights into antitumor effects of new dinuclear cis Pt(II) complexes containing aromatic linkers.
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.
Zerzankova
Lenka
L
Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, CZ-61265 Brno, Czech Republic.
Kostrhunova
Hana
H
Vojtiskova
Marie
M
Novakova
Olga
O
Suchankova
Tereza
T
Lin
Miaoxin
M
Guo
Zijian
Z
Kasparkova
Jana
J
Brabec
Viktor
V
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002945:Cisplatin / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D006367:HeLa Cells; D006801:Humans
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D002945:Cisplatin