Activation of intestinal human PXR has been recently proposed as a promising strategy for the chemoprevention of inflammation-induced colon cancer. Rifaximin is a non-absorbable antibiotic with PXR-inducer properties that has been shown to exert anti-inflammatory activities. The up-regulation of vascular endothelial growth factor (VEGF) and nitric oxide (NO) represents a pivotal mechanism in the carcinogenesis, likely because of their involvement in the angiogenic process. Some evidence proved the inhibitory effect of rifaximin on NO production during inflammatory bowel diseases. We aimed at evaluating the effect of rifaximin in human colorectal cancer cell line (Caco-2) and at investigating its mechanism of action, with focus on pregnane X receptor (PXR). To this aim we measured 1/ the release of pro-angiogenic factors as VEGF and NO; 2/ the expression of Akt, mTOR, p38 mitogen activated protein kinases (MAPK) and NF-kappaB; 3/ cell migration and the expression of metalloproteinase MMP-2 and 9 after treatment with rifaximin in the presence or absence of ketokonazole, as inhibitor of PXR. According to previous report we showed that rifaximin significantly inhibits cell migration and proliferation, but we also demonstrated its ability to dose-dependently inhibit the release of VEGF and NO. The mechanism of action involves the synergic inhibition of both Akt/mTOR and NF-kappaB signaling and was significantly reverted by the PXR-antagonist ketoconazole. This study suggests a new pharmacological effect of rifaximin, that together with its safety profile, pave the way to identifies 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.

D'ALESSANDRO, ALESSANDRA;PESCE, MARCELLA;CUOMO, ROSARIO;SARNELLI, GIOVANNI
2016

Abstract

Activation of intestinal human PXR has been recently proposed as a promising strategy for the chemoprevention of inflammation-induced colon cancer. Rifaximin is a non-absorbable antibiotic with PXR-inducer properties that has been shown to exert anti-inflammatory activities. The up-regulation of vascular endothelial growth factor (VEGF) and nitric oxide (NO) represents a pivotal mechanism in the carcinogenesis, likely because of their involvement in the angiogenic process. Some evidence proved the inhibitory effect of rifaximin on NO production during inflammatory bowel diseases. We aimed at evaluating the effect of rifaximin in human colorectal cancer cell line (Caco-2) and at investigating its mechanism of action, with focus on pregnane X receptor (PXR). To this aim we measured 1/ the release of pro-angiogenic factors as VEGF and NO; 2/ the expression of Akt, mTOR, p38 mitogen activated protein kinases (MAPK) and NF-kappaB; 3/ cell migration and the expression of metalloproteinase MMP-2 and 9 after treatment with rifaximin in the presence or absence of ketokonazole, as inhibitor of PXR. According to previous report we showed that rifaximin significantly inhibits cell migration and proliferation, but we also demonstrated its ability to dose-dependently inhibit the release of VEGF and NO. The mechanism of action involves the synergic inhibition of both Akt/mTOR and NF-kappaB signaling and was significantly reverted by the PXR-antagonist ketoconazole. This study suggests a new pharmacological effect of rifaximin, that together with its safety profile, pave the way to identifies a promising anticancer tool.
File in questo prodotto:
File Dimensione Formato  
Int J Oncol Vol49 No2 Pg639 2016.pdf

non disponibili

Tipologia: Altro materiale allegato
Licenza: Accesso privato/ristretto
Dimensione 750.2 kB
Formato Adobe PDF
750.2 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/633248
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 15
  • ???jsp.display-item.citation.isi??? 15
social impact