The presence of traces of iron and copper ions during γ-irradiation does not result in clear mutational hot spots in the lacI gene

Wijker, Carola A; Vincent, Maxence S.; Lafleur, M.V.M.

doi:10.1016/s0027-5107(99)00098-6

Cited by 11 publications

(6 citation statements)

References 27 publications

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“…This agent has been shown to promote hydroxyl radical formation from molecular oxygen by redox-cycling and could therefore be considered suitable for stimulating the production of reactive oxygen species. Transition metal cations such as Cu (II) and Fe(II) bind to negatively-charged DNA and have been shown to play an important role in the local formation of • OH radicals [13,14]. One of the consequences of high copper levels in the body is an increase in the rate of radical formation leading to oxidative damage [15].…”

Section: Introductionmentioning

confidence: 99%

In vitro anti-tumour effect of 1,10-phenanthroline-5,6-dione (phendione), [Cu(phendione)3](ClO4)2·4H2O and [Ag(phendione)2]ClO4 using human epithelial cell lines

Deegan¹,

Coyle

McCann

et al. 2006

Chemico-Biological Interactions

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The anti-cancer chemotherapeutic potential of 1,10-phenanthroline-5,6-dione (phendione), [Cu(phendione)(3)](ClO(4))(2).4H(2)O and [Ag(phendione)(2)]ClO(4) were determined using four human cells lines, i.e. two neoplastic (A-498 and Hep-G2) and two non-neoplastic (CHANG and HK-2). All of the phendione derivatives induced a concentration-dependant decrease in the viability of the four cell lines, with [Cu(phendione)(3)](ClO(4))(2).4H(2)O displaying greatest activity. In comparative studies, IC(50) values obtained with the two neoplastic cell lines showed a cytotoxic response which was between 3 and 35 times greater than that observed for the metal-based anti-cancer agent, cisplatin. Furthermore, metal-phendione complexes, rather than simple solvated metal ions, were responsible for the observed cytotoxicity. Despite the high level of potency associated with these compounds they did not display an apparent cyto-selective profile, as they reduced the viability of both neoplastic and non-neoplastic cells. However, selected mechanistic studies showed that phendione and its metal complexes inhibited DNA synthesis which did not appear to be mediated through intercalation. Ames testing highlighted that all three compounds and their phase I metabolites were non-mutagenic, unlike cisplatin. Taken together, these results suggest that phendione and its Cu(II) and Ag(I) complexes may be capable of acting as highly effective anti-cancer therapies, which with careful administration could provide very potent and effective alternatives to cisplatin.

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Section: Introductionmentioning

confidence: 99%

In vitro anti-tumour effect of 1,10-phenanthroline-5,6-dione (phendione), [Cu(phendione)3](ClO4)2·4H2O and [Ag(phendione)2]ClO4 using human epithelial cell lines

Deegan¹,

Coyle

McCann

et al. 2006

Chemico-Biological Interactions

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“…In both cases the concentrations used were in the low micromolar range, and over short incubation times. Other researchers have shown that [Cu(phen) 2 ] 2+ is a biologically active metal-phenanthroline complex (Samuni et al, 1981;Wijker and Lafleur, 1999). This agent has been shown to promote hydroxyl radical formation from molecular oxygen by redox-cycling and could therefore be considered suitable for stimulating the production of reactive oxygen species.…”

mentioning

confidence: 99%

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

Thati¹,

Noble

Creaven

et al. 2009

European Journal of Pharmacology

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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.

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“…Other researchers have shown that [Cu(phen) 2 ] 2+ was a biologically active metal-phenanthroline complex (Samuni et al, 1981;Wijker and Lafleur, 1999). This agent has been shown to promote hydroxyl radical formation from molecular oxygen by redox-cycling and could therefore be considered suitable for stimulating the production of reactive oxygen species.…”

Section: Introductionmentioning

confidence: 99%

“…This agent has been shown to promote hydroxyl radical formation from molecular oxygen by redox-cycling and could therefore be considered suitable for stimulating the production of reactive oxygen species. Transition metal cations such as Cu(II) and Fe(II) bind to negatively-charged DNA and have been shown to play an important role in the local formation of OH radicals (Samuni et al, 1981;Wijker and Lafleur 1999). One of the consequences of high copper levels in the body has been shown to be an increase in the rate of radical formation leading to oxidative damage, resulting in disruption of lipid bilayers due to oxidation and cleavage of vulnerable unsaturated fatty acid residues of phospholipids (Linder, 2001).…”

Section: Introductionmentioning

confidence: 99%

Apoptotic cell death: A possible key event in mediating the in vitro anti-proliferative effect of a novel copper(II) complex, [Cu(4-Mecdoa)(phen)2] (phen=phenanthroline, 4-Mecdoa=4-methylcoumarin-6,7-dioxactetate), in human malignant cancer cells

Thati

Noble

Creaven

et al. 2007

European Journal of Pharmacology

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The central objective of the current study was to investigate the potential in vitro anti-proliferative effect of the parent ligand, 4-methylcoumarin-6,7-dioxyacyeic acid (4-MecdoaH 2 ), and its copper (II) complex, bis(phenanthroline4-methylcoumarin-6,7-dioxacetatocopper(II) ([Cu(4-Mecdoa)(phen) 2 ]) using four human 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 alter proliferation of both human neoplastic renal (A-498) and hepatic (HepG2) cells. Furthermore, non-neoplastic hepatic (CHANG) cells appeared to be less sensitive. However, this effect was not duplicated with nonneoplastic renal (HK-2) cells, a profile shared by cisplatin. The observed anti-proliferative effect appeared to be dose-and time-dependent, and could be attributed to the complex, rather than any of the free components i.e. the 1,10-phenanthroline or coumarin ligand, or the simple metal salt. Furthermore, the complex was shown to decrease DNA synthesis, but did not intercalate with it. Based on IC 50 values, [Cu(4-Mecdoa)(phen) 2 ] was shown to be almost 12 times more potent than cisplatin. 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 could switch between apoptosis and necrosis, and this effect appeared to be concentration-dependent. Additionally, flow cytometric analysis showed that the complex functioned through an alteration in cell cycle progression. Taken together, [Cu(4-Mecdoa)(phen) 2 ] has been shown to be a more potent anti-proliferative agent than either the ligand or cisplatin, and is capable of altering key biochemical events leading to the execution of apoptotic and/or necrotic cell death, suggesting that it is worthy of further investigation.

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The presence of traces of iron and copper ions during γ-irradiation does not result in clear mutational hot spots in the lacI gene

Cited by 11 publications

References 27 publications

In vitro anti-tumour effect of 1,10-phenanthroline-5,6-dione (phendione), [Cu(phendione)3](ClO4)2·4H2O and [Ag(phendione)2]ClO4 using human epithelial cell lines

In vitro anti-tumour effect of 1,10-phenanthroline-5,6-dione (phendione), [Cu(phendione)3](ClO4)2·4H2O and [Ag(phendione)2]ClO4 using human epithelial cell lines

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

Apoptotic cell death: A possible key event in mediating the in vitro anti-proliferative effect of a novel copper(II) complex, [Cu(4-Mecdoa)(phen)2] (phen=phenanthroline, 4-Mecdoa=4-methylcoumarin-6,7-dioxactetate), in human malignant cancer cells

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