Cytotoxicity, cellular uptake, glutathione and DNA interactions of an antitumor large-ring PtII chelate complex incorporating the cis-1,4-diaminocyclohexane carrier ligand

International audienceEarlier studies have described promising antitumor activity of a large-ring chelate complex [PtCl(-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(-1,4-DACH)] in human tumor ovarian cell lines; (ii) enhanced cellular uptake (∼1.5-fold) of [PtCl(-1,4-DACH)]; (iii) somewhat enhanced rate of reactions of [PtCl(-1,4-DACH)] with glutathione (∼1.5-fold), but a similar rate of reactions with metallothionenin-2; (iv) enhanced rate of DNA binding of [PtCl(-1,4-DACH)] in cell-free media (∼2-fold); (v) similar sequence preference of DNA binding of [PtCl(-1,4-DACH)] in cell-free media; (vi) identical DNA interstrand crosslinking efficiency (6%); (vii) similar bending (32 °) and enhanced local unwinding (∼1.5-fold) induced in DNA by the major 1,2-GG-intrastrand crosslink; (viii) markedly enhanced inhibiting effects of DNA adducts of [PtCl(-1,4-DACH)] on processivity of DNA polymerase; and (ix) a slightly lower efficiency of DNA repair systems to remove the adducts of [PtCl(-1,4-DACH)] from DNA

DNA Binding Studies and Cytotoxicity of a Dinuclear PtII Diazapyrenium- Based Metallo-supramolecular Rectangular Box

The interaction with native DNA of a 2,7-diazapyrenium-based ligand 1 and its PtII rectangular metallacycle 2 is explored through circular and linear dichroism and fluorescence spectroscopies. The metal-free ligand 1 binds through intercalation, with a binding constant of approximately 5*105m-1, whereas the metallacycle 2 binds and bends the DNA with a binding constant of 7*106m-1. PCR assays show that metallo-supramolecular box 2 interferes with DNA transactions in vitro whereas the intercalator 1 does not. The metallacycle is active against four human cancer cell lines, with IC50 values ranging between 3.1 and 19.2 mm and shows similar levels of efficacy, but a different spectrum of activity, to cisplatin

Differences in the cellular response and signaling pathways between cisplatin and monodentate organometallic Ru(II) antitumor complexes containing a terphenyl ligand

The new monofunctional Ru(II)-arene complex [(η6-arene)Ru(II)(en)Cl]+, where en = 1,2-diaminoethane and the arene is para-terphenyl (complex 1) exhibits promising cytotoxic effects in human tumor cells including those resistant to conventional cisplatin (J. Med. Chem.2008, 51, 5310). The present study is focused on the cellular pharmacology of 1 to elucidate more deeply the mechanisms underlying its antitumor effects. We have identified several cellular mechanisms induced by 1 in human ovarian carcinoma cells, including inhibition of DNA synthesis, overexpression and activation of p53, expression of proapoptotic proteins p21WAF1 and Bax, G0/G1 arrest, and nuclear fragmentation as a result of apoptotic, and, to a much lower extent, also necrotic processes. Thus, 1 inhibits growth of the cancer cells through induction of apoptotic cell death and G0/G1 cell cycle arrest. Further investigations have shown that 1 induces apoptosis by regulating the expression of Bcl-2 family proteins. There were significant differences in cellular responses to the treatment with 1 and with conventional cisplatin, particularly in the kinetics and the extent of these responses. In addition, the distinct p53 activation profile of 1 compared with cisplatin provides an explanation for the activity of this ruthenium drug against cisplatin-resistant cells. Hence complex 1 may provide an alternative therapy in patients with acquired cisplatin resistance, particularly with respect to its very low mutagenicity and different mode of action compared to platinum antitumor drugs in clinical use