Anti-inflammatory effects of moxifloxacin on IL-8, IL-1β and TNF-α secretion and NFκB and MAP-kinase activation in human monocytes stimulated with Aspergillus fumigatus

Shalit, Itamar; Halperin, Drora; Haite, Debby; Levitov, Avital; Romano, Jacob; Osherov, Nir; Fabian, Ina

doi:10.1093/jac/dki441

Cited by 62 publications

(56 citation statements)

References 21 publications

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“…The inhibitory effect of MXF on cytokine secretion from THP-1 cells also confirms our previous observations of MXF inhibition of the synthesis of proinflammatory cytokines in THP-1 cells and human peripheral blood monocytes stimulated with LPS-phorbol myristate acetate (Weiss et al, 2004) or Aspergillus fumigatus (Shalit et al, 2006). Additionally, MXF inhibited NF-kB and mitogen-activated protein kinase activation in THP-1 cells and in a human respiratory epithelial cell line (Weiss et al, 2004;Werber et al, 2005).…”

Section: Discussionsupporting

confidence: 88%

Moxifloxacin enhances antiproliferative and apoptotic effects of etoposide but inhibits its proinflammatory effects in THP-1 and Jurkat cells

et al. 2006

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Etoposide (VP-16) is a topoisomerase II (topo II) inhibitor chemotherapeutic agent. Studies indicate that VP-16 enhances proinflammatory cytokines secretion from tumour cells, including IL-8, a chemokine associated with proangiogenic effects. Fluoroquinolones inhibit topo II activity in eukaryotic cells by a mechanism different from that of VP-16. The fluoroquinolone moxifloxacin (MXF) has pronounced anti-inflammatory effects in vitro and in vivo. We studied the effects of MXF and VP-16 on purified human topo II activity and further analysed their combined activity on proliferation, apoptosis and caspase-3 activity in THP-1 and Jurkat cells. Moxifloxacin alone slightly inhibited the activity of human topo II; however, in combination with VP-16 it led to a 73% reduction in enzyme activity. VP-16 inhibited cell proliferation in a time and dose-dependent manner. The addition of moxifloxacin for 72 h to low-dose VP-16 doubled its cytotoxic effect in THP-1 and Jurkat cells (1.8-and 2.6-fold decrease in cell proliferation, respectively) (Po0.004). Moxifloxacin given alone did not induce apoptosis but enhanced VP-16-induced apoptosis in THP-1 and Jurkat cells (1.8-and two-fold increase in annexin V positive cells and caspase-3 activity, respectively) (Po0.04). VP-16 induced the release of IL-8 in a time and dose-dependent manner from THP-1 cells. Moxifloxacin completely blocked the enhanced release of IL-8 induced by 0.5 and 1 mg ml À1 VP-16, and decreased IL-8 release from cells incubated for 72 h with 3 mg ml À1 VP-16 (Po0.001). VP-16 enhanced the release of IL-1b and TNF-a from THP-1 cells, whereas the addition of MXF prevented the enhanced cytokine secretion (Po0.001). We conclude that MXF significantly enhances VP-16 cytotoxicity in tumour-derived cells while preventing VP-16-induced proinflammatory cytokine release. This unique combination may have clinical benefits and cytotoxic drug 'sparing effect' and should be further studied in vivo.

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Section: Discussionsupporting

confidence: 88%

Moxifloxacin enhances antiproliferative and apoptotic effects of etoposide but inhibits its proinflammatory effects in THP-1 and Jurkat cells

et al. 2006

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“…Certain fluoroquinolone derivatives have been reported to selectively inhibit PI3Kg [50]; however, lomefloxacin appears to have broader effects on a number of proinflammatory signalling pathways. The findings reported here do, however, provide a mechanistic basis for the independent, empirical observation of the anti-inflammatory therapeutic benefit of moxifloxacin in a TRAPS patient [36], and concurs with other reports of inhibitory effects of moxifloxacin on MAP-kinases and NFkB [47][48][49]. However, it cannot be excluded that the beneficial effects of moxifloxacin in this patient were due to its anti-microbial activity against infections that might otherwise have triggered TRAPS-associated inflammation; furthermore, moxifloxacin and ciprofloxacin were not beneficial in three other TRAPS patients with the C33Y-TNFR1 mutation [36].…”

Section: Discussionsupporting

confidence: 91%

“…In particular, with regard to the effects of fluoroquinolones on pro-inflammatory signaling intermediates, it has been reported that norfloxacin and gemifloxacin reduce NFkB expression and activation [43][44][45], and that garenoxacin inhibits Erk1/2 phosphorylation [46]. Moxifloxacin also inhibits Erk1/2, JNK and NFkB [47][48][49]. Certain derivatives of fluoroquinolones have been reported selectively to inhibit PI3Kg [50].…”

Section: Discussionmentioning

confidence: 99%

A signalome screening approach in the autoinflammatory disease TNF receptor associated periodic syndrome (TRAPS) highlights the anti-inflammatory properties of drugs for repurposing

Todd

Negm

Reps

et al. 2017

Pharmacological Research

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2Abbreviations: BCA, bicinchoninic acid; CV, coefficient of variation; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PBMCs, peripheral blood mononuclear cells; RPPA, reverse phase protein array; SSMD, strictly standardised mean difference; TNFR1, tumour necrosis factor receptor-1; TRAPS, TNF receptor associated periodic syndrome; WT, wild type. 3ABSTRACT: TNF Receptor Associated Periodic Syndrome (TRAPS) is an autoinflammatory disease caused by mutations in TNF Receptor 1 (TNFR1). Current therapies for TRAPS are limited and do not target the pro-inflammatory signalling pathways that are central to the disease mechanism. Our aim was to identify drugs for repurposing as anti-inflammatories based on their ability to down-regulate molecules associated with inflammatory signalling pathways that are activated in TRAPS. This was achieved using rigorously optimised, high through-put cell culture and reverse phase protein microarray systems to screen compounds for their effects on the TRAPS-associated inflammatory signalome. 1360 approved, publically available, pharmacologically active substances were investigated for their effects on 40 signalling molecules associated with pro-inflammatory signalling pathways that are constitutively upregulated in TRAPS. The drugs were screened at four ten-fold concentrations on cell lines expressing both wild-type (WT) TNFR1 and TRAPS-associated C33Y mutant TNFR1, or WT TNFR1 alone; signalling molecule levels were then determined in cell lysates by the reversephase protein microarray. A novel mathematical methodology was developed to rank the compounds for their ability to reduce the expression of signalling molecules in the C33Y-TNFR1 transfectants towards the level seen in the WT-TNFR1 transfectants. Seven high-ranking drugs were selected and tested by RPPA for effects on the same 40 signalling molecules in lysates of peripheral blood mononuclear cells (PBMCs) from C33Y-TRAPS patients compared to PBMCs from normal controls. The fluoroquinolone antibiotic lomefloxacin, as well as others from this class of compounds, showed the most significant effects on multiple pro-inflammatory signalling pathways that are constitutively activated in TRAPS; lomefloxacin dose-dependently significantly reduced expression of 7/40 signalling molecules across the Jak/Stat, MAPK, NF-kB and PI3K/AKT pathways. This study demonstrates the power of signalome screening for identifying candidates for drug repurposing.

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“…These observations confirm our previous studies that demonstrated significant inhibition by MXF of the synthesis of proinflammatory cytokines in THP-1 cells and in human peripheral blood monocytes stimulated with LPS-phorbol myristate acetate (37) or Aspergillus fumigatus (38). The combined effect of MXF on inhibition of VP-16-induced IL-8 and of spontaneous secretion of VEGF from HT-29 cells may be an important aspect of MXF activity.…”

Section: Discussionsupporting

confidence: 91%

Moxifloxacin enhances etoposide-induced cytotoxic, apoptotic and anti-topoisomerase II effects in a human colon carcinoma cell line

Fabian¹

2010

Int J Oncol

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Abstract. Etoposide (VP-16) is a topoisomerase-II (topo II) inhibitor chemotherapeutic agent. Studies have shown that a combination of VP-16 with other drugs demonstrates better clinical responses. The aim of this study was to investigate the effects of moxifloxacin (MXF) and VP-16 on cellular topo II activity in drug-treated cells and evaluate the influence of MXF on the mode of action of VP-16, on proliferation and apoptosis of HT-29 cells. Decatenation assay, band depletion and Western blot analysis, cytotoxic assay (MTT), flow cytometric studies (cell cycle and survivin expression), apoptosis (DAPI-sulforhodamine staining and caspase 3 activity) and IL-8 and VEGF secretion were determined. MXF or VP-16 slightly affected cellular topo II activity in nuclear extracts derived from drug-treated cells while the combination enhanced inhibitory activity and the reduction in band depletion of topo II. VP-16 induced cell cycle arrest at G 2 /M and the appearance of the subG 1 peak which was increased by the addition of MXF. Apoptosis studies (DAPI staining and caspase 3 activity) showed a marked increase in the presence of MXF and VP-16 compared to VP-16 alone. VP-16 induced the release of IL-8, and addition of MXF reduced enhanced release and the spontaneous release of VEGF from the cells. In conclusion, the results suggest that the enhancement in the reduction of topo II activity by the combined MXF/VP-16 treatments was probably due to the increase in the level of the DNA-enzyme cleavable complexes formed by both drugs. The unique combination of MXF/VP-16 may have clinical benefits and a cytotoxic drug 'sparing effect' and should be further studied in vivo.

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Anti-inflammatory effects of moxifloxacin on IL-8, IL-1β and TNF-α secretion and NFκB and MAP-kinase activation in human monocytes stimulated with Aspergillus fumigatus

Abstract: Our results indicate that moxifloxacin acts as an anti-inflammatory agent in monocytic cells stimulated with A. fumigatus conidia. Whether these effects may be protective as in the Candida pneumonia model is unknown and merits in vivo studies in models of pulmonary aspergillosis.

Cited by 62 publications

References 21 publications

Moxifloxacin enhances antiproliferative and apoptotic effects of etoposide but inhibits its proinflammatory effects in THP-1 and Jurkat cells

Moxifloxacin enhances antiproliferative and apoptotic effects of etoposide but inhibits its proinflammatory effects in THP-1 and Jurkat cells

A signalome screening approach in the autoinflammatory disease TNF receptor associated periodic syndrome (TRAPS) highlights the anti-inflammatory properties of drugs for repurposing

Moxifloxacin enhances etoposide-induced cytotoxic, apoptotic and anti-topoisomerase II effects in a human colon carcinoma cell line

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