Cytotoxicity, cellular uptake, glutathione and DNA interactions of an antitumor large-ring Pt-II chelate complex incorporating the cis-1,4-diaminocyclohexane carrier ligand
Earlier studies have described promising antitumor activity of a large-ring chelate complex [PtCl2(cis-1,4-DACH)l (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 [PtCl2(cis-1,4-DACH)] in human tumor ovarian cell lines; (ii) enhanced cellular uptake (similar to 1.5-fold) of [PtCl2(cis-1,4-DACH)]; (iii) somewhat enhanced rate of reactions of [PtCl2(cis-1,4-DACH)] with glutathione (similar to 1.5-fold), but a similar rate of reactions with metallothionenin-2; (iv) enhanced rate of DNA binding of [PtCl2(cis-1,4-DACH)] in cell-free media (similar to 2-fold); (v) similar sequence preference of DNA binding of [PtCl2(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 (similar to 1.5-fold) induced in DNA by the major 1,2-GG-intrastrand cross-link; (viii) markedly enhanced inhibiting effects of DNA adducts of [PtCl2(cis-1,4-DACH)] on processivity of DNA polymerase; and (ix) a slightly lower efficiency of DNA repair systems to remove the adducts of [PtCl2(cis-1,4-DACH)] from DNA. (C) 2009 Elsevier Inc. All rights reserved.