Role of cell cycle events and apoptosis in mediating the anti-cancer activity of a silver(I) complex of 4-hydroxy-3-nitro-coumarin-bis(phenanthroline) in human malignant cancer cells

Abstract

The central objective of the current study was to investigate the potential in vitro anti-proliferative effect of 4-hydroxy-3-nitro-coumarin (hncH), and the mixed-ligand silver (I) complex of 4-oxy-3-nitro-coumarin-bis(phenanthroline), [Ag(hnc)(phen)(2)] using four human-derived model cell lines. In addition, selected mechanistic studies were carried out using the most sensitive of the four cell lines. Results obtained show that the complex could decrease the proliferation of all four cell lines including neoplastic renal and hepatic, namely A-498 and HepG(2) cells, respectively, along with two non-neoplastic renal and hepatic cell lines, HK-2 and Chang, respectively. Furthermore, non-neoplastic hepatic cells (Chang) appeared to be less sensitive to the effect of the complex, but this effect was not replicated in the non-neoplastic renal (HK-2) cells. Based on IC(50) values [Ag(hnc)(phen)(2)] was shown to be almost four times more potent than cisplatin, using HepG(2) cells. In addition, the observed anti-proliferative effect was shown to be both dose- and time-dependent. Furthermore, the complex was shown to decrease DNA synthesis, but did not intercalate with it. Moreover, there was no evidence that P-glycoprotein-mediated multi-drug resistance was likely to decrease anti-proliferative activity. Cytological stains, analysis of genomic DNA, and biochemical assays [caspase-3 and -9 and cleaved poly(ADP-ribose)-polymerase protein] showed that cell death appeared to result from apoptosis, with the possibility of secondary necrosis. Additionally, flow cytometric analysis showed that the complex functioned through an alteration in cell cycle progression. Taken together, [Ag(hnc)(phen)(2)] has been shown to be a more potent anti-proliferative agent than cisplatin, capable of altering key biochemical events leading to cell death. Additional mechanistic studies are underway to probe more fully its mechanism of action.

7,8-Dihydroxycoumarin inhibits A549 human lung adenocarcinoma cell proliferation by inducing apoptosis via suppression of Akt/NF-κB signaling

“…Bhattacharyya et al reported that coumarin enhances pro-apoptotic p53, PCNA, Bad, Bax, apoptotic protease activating factor (Apaf), cyt c, caspase-3 and caspase-9 expression in melanoma (skin cancer) cells, and inhibits the anti-apoptotic factors Akt, Bcl-2, Bcl-xL and NF-κB (15). Thati et al also identified that coumarin derivatives enhance the malignancy of pro-apoptotic factors caspase-3 and -9 (16). …”

Anticancer and antifungal activity of copper(II) complexes of quinolin-2(1H)-one-derived Schiff bases

“…Our previous work has focussed on the synthesis and therapeutic applications of a series of silver and copper complexes of coumarin-derived ligands [24][25][26][27][28][29]. More recently we have focused our research efforts on the preparation of a series of coumarinand quinolin-2(1H)-one-triazole-derived Schiff bases and their Cu(II) complexes [30,31].…”

Gold(III) compounds-mediated inhibition of lung cancer cell proliferation

“…The chemotherapeutic potential of 1,10-phenanthroline and three of its transition metal complexes was determined on two different cancer cells by Deegan et al [48] and they suggested that phen and three metal-phen complexes may have been successful therapeutics. A silver(I) complex of phenanthroline was found to be more potent than cisplatin on HepG2 cells [49]. Gold(III) complexes with bidentate ligands based on the 1,10-phenanthroline and 2,2′-bipyridine scaffolds showed promising anticancer activity against a variety of tumor cell lines [50].…”