Activation of intestinal human pregnane X receptor (PXR) has recently been proposed as a promising strategy for the chemoprevention of inflammation-induced colon cancer. The present study was aimed at evaluating the effect of rifaximin, a non-absorbable antibiotic, in inhibiting angiogenesis in a model of human colorectal epithelium and investigating the role of PXR in its mechanism of action. Caco-2 cells were treated with rifaximin (0.1, 1.0 and 10.0 μM) in the presence or absence of ketoconazole (10 μM) and assessed for cell proliferation, migration and expression of proliferating cell nuclear antigen (PCNA). The release of vascular endothelial growth factor (VEGF) and nitric oxide (NO), expression of Akt, mechanistic target of rapamycin (mTOR), p38 mitogen activated protein kinases (MAPK), nuclear factor κB (NF-κB) and metalloproteinase-2 and -9 (MMP-2 and -9) were also evaluated. Treatment with rifaximin 0.1, 1.0 and 10.0 μM caused significant and concentration-dependent reduction of cell proliferation (-25, -40 and -68%), cell migration (-18, -30 and -46%) and PCNA expression (-29, -53 and -76%) in the Caco-2 cells vs. untreated cells. Treatment downregulated VEGF secretion (-32, -45 and -72%), NO release (-40, -69 and -87%), VEGFR-2 expression (-33, -58 and -65%) and MMP-2 (-25, -62 and -87%) and MMP-9 expression (-38, -56 and -78%) vs. untreated cells. Rifaximin treatment also resulted in a concentration-dependent decrease in the phosphorylation of Akt (-50, -75 and -86%), mTOR (-38, -56 and -78%), p38MAPK (-24, -62 and -71%) and inhibition of HIF-1α (-65, -82 and -92%), p70S6K (-27, -55 and -85%) and NF-κB (-29, -55 and -61%). Ketoconazole (PXR antagonist) treatment inhibited these effects. These findings demonstrated that rifaximin causes PXR-mediated inhibition of angiogenic factors in Caco-2 cell line and may be a promising anticancer tool.

Rifaximin, a non-absorbable antibiotic, inhibits the release of pro-angiogenic mediators in colon cancer cells through a pregnane X receptor-dependent pathway / Esposito, Giuseppe; Gigli, Stefano; Seguella, Luisa; Nobile, Nicola; d'Alessandro, Alessandra; Pesce, Marcella; Capoccia, Elena; Steardo, Luca; Cirillo, Carla; Cuomo, Rosario; Sarnelli, Giovanni. - In: INTERNATIONAL JOURNAL OF ONCOLOGY. - ISSN 1019-6439. - ELETTRONICO. - 49:2(2016), pp. 639-645. [10.3892/ijo.2016.3550]

Rifaximin, a non-absorbable antibiotic, inhibits the release of pro-angiogenic mediators in colon cancer cells through a pregnane X receptor-dependent pathway

ESPOSITO, GIUSEPPE
;
GIGLI, STEFANO;Seguella Luisa;CAPOCCIA, ELENA;STEARDO, LUCA;
2016

Abstract

Activation of intestinal human pregnane X receptor (PXR) has recently been proposed as a promising strategy for the chemoprevention of inflammation-induced colon cancer. The present study was aimed at evaluating the effect of rifaximin, a non-absorbable antibiotic, in inhibiting angiogenesis in a model of human colorectal epithelium and investigating the role of PXR in its mechanism of action. Caco-2 cells were treated with rifaximin (0.1, 1.0 and 10.0 μM) in the presence or absence of ketoconazole (10 μM) and assessed for cell proliferation, migration and expression of proliferating cell nuclear antigen (PCNA). The release of vascular endothelial growth factor (VEGF) and nitric oxide (NO), expression of Akt, mechanistic target of rapamycin (mTOR), p38 mitogen activated protein kinases (MAPK), nuclear factor κB (NF-κB) and metalloproteinase-2 and -9 (MMP-2 and -9) were also evaluated. Treatment with rifaximin 0.1, 1.0 and 10.0 μM caused significant and concentration-dependent reduction of cell proliferation (-25, -40 and -68%), cell migration (-18, -30 and -46%) and PCNA expression (-29, -53 and -76%) in the Caco-2 cells vs. untreated cells. Treatment downregulated VEGF secretion (-32, -45 and -72%), NO release (-40, -69 and -87%), VEGFR-2 expression (-33, -58 and -65%) and MMP-2 (-25, -62 and -87%) and MMP-9 expression (-38, -56 and -78%) vs. untreated cells. Rifaximin treatment also resulted in a concentration-dependent decrease in the phosphorylation of Akt (-50, -75 and -86%), mTOR (-38, -56 and -78%), p38MAPK (-24, -62 and -71%) and inhibition of HIF-1α (-65, -82 and -92%), p70S6K (-27, -55 and -85%) and NF-κB (-29, -55 and -61%). Ketoconazole (PXR antagonist) treatment inhibited these effects. These findings demonstrated that rifaximin causes PXR-mediated inhibition of angiogenic factors in Caco-2 cell line and may be a promising anticancer tool.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/870601
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