Increased sensitivity to quinolone antibacterials can be engineered in human topoisomerase IIα by selective mutagenesis

Hammonds, Timothy R.; Foster, Simon R.; Maxwell, Anthony

doi:10.1006/jmbi.2000.3892

Cited by 19 publications

(16 citation statements)

References 36 publications

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“…In order to investigate further the unexplained increase in cell death induced by high concentrations of genistein in RINm5F cells, the cells were exposed to the drug in the presence of ciprofloxacin. This reagent does not interact with tyrosine kinases but, rather, it binds to DNA topoisomerase enzymes ( Elsea et al ., 1997 ; Hammonds et al ., 2000 ). Over periods up to 24 h, ciprofloxacin did not cause any direct loss of RINm5F cell viability (Figure 5) nor did it alter the extent of cell death induced by NaF (not shown).…”

Section: Resultsmentioning

confidence: 99%

“…Ciprofloxacin is a quinolone antibiotic that binds to mammalian DNA topoisomerase II at a site which overlaps the binding site for genistein ( Elsea et al ., 1997 ; Hammonds et al ., 2000 ). Binding of ciprofloxacin does not cause any loss of enzyme activity ( Elsea et al ., 1997 ; Hammonds et al ., 2000 ) whereas the interaction of genistein with topoisomerase II leads to loss of the DNA ligase activity of the enzyme.…”

Section: Discussionmentioning

confidence: 99%

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Effects of tyrosine kinase inhibitors on cell death induced by sodium fluoride and pertussis toxin in the pancreatic β‐cell line, RINm5F

Elliott

Scarpello

Morgan

2001

British J Pharmacology

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1 Sodium¯uoride causes apoptosis of pancreatic b-cells and this response is enhanced by pretreatment with pertussis toxin. In the present study, tyrosine kinase inhibitors were used to investigate the mechanisms of action of NaF and pertussis toxin in the b-cell line, RINm5F. 2 Exposure of RINm5F cells to low concentrations of genistein or tyrphostin A25 resulted in signi®cant inhibition of cell death induced by 5 mM NaF. Higher concentrations (425 mM) were cytotoxic in the absence of NaF but, paradoxically, the combination of genistein and NaF induced less cell death than when each agent was used alone. 3 The increase in cell death induced by 100 mM genistein was markedly inhibited by cipro¯oxacin, a drug which binds to topoisomerase II. Etoposide (which inhibits topoisomerase II but has no e ect on tyrosine kinase activity) also caused an increase in RINm5F cell death. Neither etoposide nor cipro¯oxacin altered the response to 5 mM NaF. 4 Pertussis toxin markedly enhanced the extent of RINm5F cell death induced by NaF and this e ect was completely prevented by 25 mM genistein. The inhibition caused by genistein was not a ected by cipro¯oxacin but was reproduced by a structurally dissimilar tyrosine kinase inhibitor, herbimycin A. 5 The results demonstrate that RINm5F b-cells express a pertussis toxin sensitive pathway that is antiapoptotic. The activity of this pathway is most evident in cells exposed to pro-apoptotic stimuli where the e ects of pertussis toxin can be blocked by inhibitors of tyrosine kinase enzymes. A genisteinsensitive tyrosine kinase does not appear to be involved in RINm5F cell survival under basal conditions.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effects of tyrosine kinase inhibitors on cell death induced by sodium fluoride and pertussis toxin in the pancreatic β‐cell line, RINm5F

Elliott

Scarpello

Morgan

2001

British J Pharmacology

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“…Antibacterial fluoroquinolones are a class of antibacterial agents that are commonly used to treat human and animal infections. The treatment of bacterial infection inhibits bacterial DNA gyrase by a mechanism similar to that of certain antitumor drugs against mammalian topoisomerase II [17]. Some antibacterial fluoroquinolones, such as ciprofloxacin, ofloxacin and norfloxacin, also demonstrate a slight interaction with mammalian topoisomerase II, although these antibacterials are much more selective for bacterial DNA gyrase [18].…”

Section: Discussionmentioning

confidence: 99%

Trimethoxy-benzaldehyde levofloxacin hydrazone inducing the growth arrest and apoptosis of human hepatocarcinoma cells

et al. 2013

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BackgroundIn order to search for new structural modification strategies on fluoroquinolones, we have designed and synthesized a series of fluoroquinolone derivatives by linking various hydrazine compounds to the C-3 carboxyl group of levofloxacin and assessed their anticancer activities. Several novel levofloxacin derivatives displayed potent cytotoxicity against the tested cancer cell lines in vitro. In the present study, we investigated the effect of 1-Cyclopropyl-6-fluoro-4-oxo-7- piperazin-1, 4-dihydro- quinoline- 3-carboxylic acid benzo [1,3] dioxol-5- ylmethylene- hydrazide (QNT11) on the apoptosis of human hepatocarcinoma cells in vitro.MethodsThe inhibition effects of QNT11 on cell proliferation were examined by MTT assay. Cell apoptosis was determined by TUNEL and DNA agarose gel electrophoresis method. The topoisomerase ΙΙ activity was measured by agarose gel electrophoresis using Plasmid pBR322 DNA as the substrate. Cell cycle progression was analyzed using flow cytometry in conjunction with ethanol fixation and propidium iodide staining. Mitochondrial membrane potential (△ψm) was measured by high content screening image system. The caspase-9, caspase-8, caspase-3, Bcl-2, Bax, CDK1, Cyclin B1and cytochrome c protein expressions were detected by Western blot analysis.ResultsQNT11 showed selective cytotoxicity against Hep3B, SMMC-7721, MCF-7 and HCT-8 cell lines with IC50 values of 2.21 μM, 2.38 μM, 3.17 μM and 2.79 μM, respectively. In contrast, QNT11 had weak cytotoxicity against mouse bone marrow mesenchymal stem cells (BMSCs) with IC50 value of 7.46 μM. Treatment of Hep3B cells with different concentrations of QNT11 increased the percentage of the apoptosis cells significantly, and agarose gel electrophoresis revealed the ladder DNA bands typical of apoptotic cells, with a decrease in the mitochondrial membrane potential. Compared to the control group, QNT11 could influence the DNA topoisomerase IIactivity and inhibit the religation of DNA strands, thus keeping the DNA in fragments. There was a significant increase of cytochrome c in the cytosol after 24 h of treatment with QNT11 and a decrease in the mitochondrial compartment. Observed changes in cell cycle distribution by QNT11 treated might be caused by insufficient preparation for G2/M transition. In addition, QNT11 increased the protein expression of Bax, caspase-9, caspase-8, caspase-3, as well as the cleaved activated forms of caspase-9, caspase-8 and caspase-3 significantly, whereas the expression of Bcl-2 decreased.ConclusionsOur results showed that QNT11 as a fluoroquinolone derivative exerted potent and selectively anticancer activity through the mechanism of eukaryotic topoisomerase II poisoning. The growth inhibition was in large part mediated via apoptosis-associated mitochondrial dysfunction and regulation of Bcl-2 signaling pathways.

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“…The treatment of bacterial infection inhibits bacterial DNA gyrase by a mechanism similar to that of certain antitumor drugs against mammalian topoisomerase II [17] . Some antibacterial fluoroquinolones, such as ciprofloxacin, ofloxacin and norfloxacin, also demonstrate a slight interaction with mammalian topoisomerase II, although these antibacterials are much more selective for bacterial DNA gyrase [18] .…”

Section: Wwwchinapharcom Shi Zy Et Almentioning

confidence: 99%

“…These findings provide evidence that QNT4 is a poisonous inhibitor for topoisomerase II [21] . QNT4 binds the reversible complex between DNA and topoisomerase II, preventing the dissociation of the DNA-topoisomerase II complex and thereby inducing DNA damage [22,23] . It has been reported that one of the key responses of fluoroquinolone-induced DNA damage is the expression of tumor suppressor protein p53, causing apoptosis of the treated cells [24,25] .…”

Section: Wwwchinapharcom Shi Zy Et Almentioning

confidence: 99%

Piperonal ciprofloxacin hydrazone induces growth arrest and apoptosis of human hepatocarcinoma SMMC-7721 cells

Shi

Kang

et al. 2012

Acta Pharmacol Sin

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Aim: To investigate the cytotoxic effects of piperonal ciprofloxacin hydrazone (QNT4), a novel antibacterial fluoroquinolone derivative, against human hepatocarcinoma SMMC-7721 cells. Methods: Human hepatocarcinoma cells (SMMC-7721), human breast adenocarcinoma cells (MCF-7) and human colon adenocarcinoma cells (HCT-8) were tested. The effects of QNT4 on cell proliferation were examined using MTT assay. Cell apoptosis was determined using Hoechst 33258 fluorescence staining, TUNEL assay and agarose gel electrophoresis. The topoisomerase II activity was measured using agarose gel electrophoresis with the DNA plasmid pBR322 as the substrate. Mitochondrial membrane potential (∆ψm) was measured using a high content screening imaging system. Protein expression of caspase-9, caspase-8, caspase-3, p53, Bcl-2, Bax, and cytochrome c was detected with Western blot analysis. Results: Treatment with QNT4 (0.625-10 μmol/L) potently inhibited the proliferation of the cancer cells in time-and dose-dependent manners (the IC 50 value at 24 h in SMMC-7721 cells, MCF-7 cells and HCT-8 cells was 2.956±0.024, 3.710±0.027, and 3.694±0.030 μmol/L, respectively). Treatment of SMMC-7721 cells with QNT4 (0.2146, 2.964, and 4.600 μmol/L) for 24 h dose-dependently increased the percentage of apoptotic cells, elicited characteristic DNA "ladder" bands, and decreased the mitochondrial membrane potential. QNT4 dose-dependently increased topoisomerase II-mediated DNA breaks while inhibiting DNA relegation, thus keeping the DNA in fragments. Treatment of SMMC-7721 cells with QNT4 significantly increased cytochrome c in the cytosol, and decreased cytochrome c in the mitochondrial compartment. QNT4 (3-7.39 μmol/L) significantly increased the protein expression of p53, Bax, caspase-9, caspase-3, and the cleaved activated forms of caspase-9 and caspase-3 in SMMC-7721 cells. In contrast, the expression of Bcl-2 was decreased, while caspase-8 had no significant change. Conclusion: QNT4 induced the apoptosis of SMMC-7721 cells via inhibiting topoisomerase II activity and modulating mitochondrialdependent pathways.

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Increased sensitivity to quinolone antibacterials can be engineered in human topoisomerase IIα by selective mutagenesis

Cited by 19 publications

References 36 publications

Effects of tyrosine kinase inhibitors on cell death induced by sodium fluoride and pertussis toxin in the pancreatic β‐cell line, RINm5F

Effects of tyrosine kinase inhibitors on cell death induced by sodium fluoride and pertussis toxin in the pancreatic β‐cell line, RINm5F

Trimethoxy-benzaldehyde levofloxacin hydrazone inducing the growth arrest and apoptosis of human hepatocarcinoma cells

Piperonal ciprofloxacin hydrazone induces growth arrest and apoptosis of human hepatocarcinoma SMMC-7721 cells

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