Conformation and recognition of DNA damaged by antitumor cis-dichlorido platinum(II) complex of CDK inhibitor bohemine
Language English Country France Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
24675180
DOI
10.1016/j.ejmech.2014.03.041
PII: S0223-5234(14)00254-2
Knihovny.cz E-resources
- Keywords
- Antitumor, Bohemine, CDK inhibitor, DNA, DNA polymerization, Glutathione, Platinum, RNA polymerase II,
- MeSH
- Antineoplastic Agents chemical synthesis chemistry pharmacology MeSH
- DNA drug effects metabolism MeSH
- Transcription, Genetic drug effects MeSH
- HeLa Cells MeSH
- Humans MeSH
- Molecular Conformation MeSH
- Molecular Structure MeSH
- Organoplatinum Compounds chemical synthesis chemistry pharmacology MeSH
- Polymerization drug effects MeSH
- DNA Damage MeSH
- CDC2 Protein Kinase antagonists & inhibitors MeSH
- Purines chemistry pharmacology MeSH
- RNA Polymerase II antagonists & inhibitors genetics MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Antineoplastic Agents MeSH
- bohemine MeSH Browser
- DNA MeSH
- Organoplatinum Compounds MeSH
- CDC2 Protein Kinase MeSH
- Purines MeSH
- RNA Polymerase II MeSH
A substitution of the ammine ligands of cisplatin, cis-[Pt(NH3)2Cl2], for cyclin dependent kinase (CDK) inhibitor bohemine (boh), [2-(3-hydroxypropylamino)-6-benzylamino-9-isopropylpurine], results in a compound, cis-[Pt(boh)2Cl2] (C1), with the unique anticancer profile which may be associated with some features of the damaged DNA and/or its cellular processing (Travnicek Z et al. (2003) J Inorg Biochem94, 307-316; Liskova B (2012) Chem Res Toxicol25, 500-509). A combination of biochemical and molecular biology techniques was used to establish mechanistic differences between cisplatin and C1 with respect to the DNA damage they produce and their interactions with critical DNA-binding proteins, DNA-processing enzymes and glutathione. The results show that replacement of the NH3 groups in cisplatin by bohemine modulates some aspects of the mechanism of action of C1. More specifically, the results of the present work are consistent with the thesis that, in comparison with cisplatin, effects of other factors, such as: (i) slower rate of initial binding of C1 to DNA; (ii) the lower efficiency of C1 to form bifunctional adducts; (iii) the reduced bend of longitudinal DNA axis induced by the major 1,2-GG intrastrand cross-link of C1; (iv) the reduced affinity of HMG domain proteins to the major adduct of C1; (v) the enhanced efficiency of the DNA adducts of C1 to block DNA polymerization and to inhibit transcription activity of human RNA pol II and RNA transcription; (vi) slower rate of the reaction of C1 with glutathione, may partially contribute to the unique activity of C1.
Institute of Biophysics Academy of Sciences of The Czech Republic v v i CZ 61265 Brno Czech Republic
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