Abstract
We synthesized, characterized and tested in a panel of cancer cell lines, nine new bipyridine gold(III) dithiocarbamate-containing complexes. In vitro studies demonstrated that compounds 1, 2, 4, 5, 7 and 8 were the most cytotoxic in prostate, breast, ovarian cancer cell lines and in Hodgkin lymphoma cells with IC50 values lower than the reference drug cisplatin. The most active compound 1 was more active than cisplatin in ovarian (A2780cis and 2780CP-16) and breast cancer cisplatin-resistant cells. Compound 1 determined an alteration of the cellular redox homeostasis leading to increased ROS levels, a decrease in the mitochondrial membrane potential, cytochrome-c release from the mitochondria and activation of caspases 9 and 3. The ROS scavenger NAC suppressed ROS generation and rescued cells from damage. Compound 1 resulted more active in tumor cells than in normal human Mesenchymal stromal cells. Gold compounds were active independent of p53 status: exerted cytotoxic effects on a panel of non-small cell lung cancer cell lines with different p53 status and in the ovarian A2780 model where the p53 was knocked out. In conclusion, these promising results strongly indicate the need for further preclinical evaluation to test the clinical potential of these new gold(III) complexes.
Highlights
The breakthrough of the anticancer properties of cisplatin cis-[Pt(NH3)2Cl2] around 1965, promoted very much attention in the area of metal-based anticancer agents [1]
Gold(III) mixed ligands complexes 1–9 were identified via the presence of the stretching bands around 3030 and 2925 cm-1 for ν(C–H) the aromatic and ν(C–H) saturated aliphatic methyl and ethyl groups of coordinated ligands respectively
C = S stretching with medium intensity around 1070 and 970 cm-1 for compounds 1–9 is an additional evidence of the formation of mixed ligands compounds
Summary
The breakthrough of the anticancer properties of cisplatin cis-[Pt(NH3)2Cl2] around 1965, promoted very much attention in the area of metal-based anticancer agents [1]. The anticancer effects observed for cisplatin suggested that platinum and non-platinum metal-based compounds might be as valuable as organic anticancer drugs [2, 3]. The extensive clinical success of platinum compounds has improved the synthesis of other platinum and nonplatinum metallodrugs that might demonstrate different cytotoxic properties and characterized by a different prototype of anticancer specificities, active against cisplatin-resistant tumor cells and with an encouraging toxicological profile. Due to the structural similarity, the square planar gold(III) complexes have been qualified as appropriate candidates for the potential anticancer activity evaluation [3, 11,12,13,14]
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