Cytotoxicity, cellular uptake, glutathione and DNA interactions of an antitumor large-ring Pt II chelate complex incorporating the cis-1,4-diaminocyclohexane carrier ligand
Language English Country Great Britain, England Media print
Document type Comparative Study, Journal Article, Research Support, Non-U.S. Gov't
Grant support
Howard Hughes Medical Institute - United States
PubMed
19782655
DOI
10.1016/j.bcp.2009.09.019
PII: S0006-2952(09)00798-9
Knihovny.cz E-resources
- MeSH
- Cell Membrane drug effects metabolism MeSH
- Cyclohexylamines chemistry metabolism pharmacology MeSH
- DNA, Neoplasm metabolism MeSH
- Glutathione metabolism MeSH
- HeLa Cells MeSH
- Rabbits MeSH
- Humans MeSH
- Ligands MeSH
- Cell Line, Tumor MeSH
- Drug Carriers chemistry metabolism toxicity MeSH
- DNA Repair drug effects physiology MeSH
- Organoplatinum Compounds metabolism toxicity MeSH
- Antineoplastic Agents chemistry metabolism pharmacology MeSH
- Cattle MeSH
- Platinum Compounds chemistry metabolism toxicity MeSH
- Animals MeSH
- Check Tag
- Rabbits MeSH
- Humans MeSH
- Cattle MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Comparative Study MeSH
- Names of Substances
- 1,4-diaminocyclohexane MeSH Browser
- Cyclohexylamines MeSH
- DNA, Neoplasm MeSH
- Glutathione MeSH
- Ligands MeSH
- Drug Carriers MeSH
- Organoplatinum Compounds MeSH
- platinum chloride MeSH Browser
- Antineoplastic Agents MeSH
- Platinum Compounds MeSH
Earlier studies have described promising antitumor activity of a large-ring chelate complex [PtCl(2)(cis-1,4-DACH)] (DACH=diaminocyclohexane). Encouraging antitumor activity of this analogue of cisplatin prompted us to perform studies focused on the mechanistic basis of pharmacological effects of this complex. Four early steps in the mechanism of biological activity of cisplatin have been delineated: cell entry, reactions with sulfur-containing compounds, platinum-DNA binding along with processing platinated DNA by proteins (enzymes) and DNA repair. Here, we describe comparative experiments (involving also cisplatin) revealing: (i) improved cytotoxicity (3.4-5.4-fold) of [PtCl(2)(cis-1,4-DACH)] in human tumor ovarian cell lines; (ii) enhanced cellular uptake (approximately 1.5-fold) of [PtCl(2)(cis-1,4-DACH)]; (iii) somewhat enhanced rate of reactions of [PtCl(2)(cis-1,4-DACH)] with glutathione (approximately 1.5-fold), but a similar rate of reactions with metallothionenin-2; (iv) enhanced rate of DNA binding of [PtCl(2)(cis-1,4-DACH)] in cell-free media (approximately 2-fold); (v) similar sequence preference of DNA binding of [PtCl(2)(cis-1,4-DACH)] in cell-free media; (vi) identical DNA interstrand cross-linking efficiency (6%); (vii) similar bending (32 degrees) and enhanced local unwinding (approximately 1.5-fold) induced in DNA by the major 1,2-GG-intrastrand cross-link; (viii) markedly enhanced inhibiting effects of DNA adducts of [PtCl(2)(cis-1,4-DACH)] on processivity of DNA polymerase; and (ix) a slightly lower efficiency of DNA repair systems to remove the adducts of [PtCl(2)(cis-1,4-DACH)] from DNA.
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