title: 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.
authors.affiliation: Centre for Pharmaceutical Research & Development, Ireland.
authors.forename: Bhumika
authors.initials: B
authors.lastname: Thati
authors.forename: Andy
authors.initials: A
authors.lastname: Noble
authors.forename: Bernadette S
authors.initials: BS
authors.lastname: Creaven
authors.forename: Maureen
authors.initials: M
authors.lastname: Walsh
authors.forename: Malachy
authors.initials: M
authors.lastname: McCann
authors.forename: Michael
authors.initials: M
authors.lastname: Devereux
authors.forename: Kevin
authors.initials: K
authors.lastname: Kavanagh
authors.forename: Denise A
authors.initials: DA
authors.lastname: Egan
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry / Q000494:pharmacology; D009369:Neoplasms / Q000473:pathology*; D019384:Nucleic Acid Synthesis Inhibitors / Q000737:chemistry / Q000494:pharmacology; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D012834:Silver / Q000737:chemistry*
chemical_list: C539395:(4-hydroxy-3-nitrocoumarin)bis(phenanthroline)silver(I); D000970:Antineoplastic Agents; D007364:Intercalating Agents; D019384:Nucleic Acid Synthesis Inhibitors; D009942:Organometallic Compounds; D012834:Silver; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3