Activation of Intestinal Human Pregnane X Receptor Protects against Azoxymethane/Dextran Sulfate Sodium–Induced Colon Cancer

Cheng, Jie; Fang, Zhong Ze; Nagaoka, Kenjiro; Okamoto, Minoru; Qu, Aijuan; Tanaka, Naoki; Kimura, Shioko; Gonzalez, Frank J.

doi:10.1124/jpet.114.215913

Cited by 24 publications

(18 citation statements)

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“…Cheng et al (16) studied the anti-inflammatory effect of rifaximin in a colitis model and showed that rifaximin acted on human PXR and caused NF-κB inhibition. Another study demonstrated that rifaximin induced specific activation of PXR in PXR-humanized mice and mediated the inflammation, cancer cell proliferation and pro-apoptotic events in colon cancer (25). The results from the present study are in line with these reports and further show that rifaximin is a potent inhibitor of the release of angiogenic mediators.…”

Section: Discussionsupporting

confidence: 91%

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

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et al. 2016

International Journal of Oncology

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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, cell migration and PCNA expression in the Caco-2 cells vs. untreated cells. Treatment downregulated VEGF secretion, NO release, VEGFR-2 expression, MMP-2 and MMP-9 expression vs. untreated cells. Rifaximin treatment also resulted in a concentration-dependent decrease in the phosphorylation of Akt, mTOR, p38MAPK and inhibition of hypoxia-inducible factor 1-α (HIF-1α), p70S6K and NF-κB. 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. IntroductionColorectal cancer (CRC) represents one of the major causes of morbidity and mortality throughout the world and is the third most common form of human cancer worldwide (1,2). Like other forms of cancer, CRC is characterized by angiogenesis, which is a crucial event in promoting cancer growth, progression and metastasis (3). Among the various signaling molecules involved in the angiogenic process, vascular endothelial growth factor (VEGF) and nitric oxide (NO) are thought to be the key signaling molecules responsible for neo-vascularization (4-6). Once hypersecreted, VEGF binds to its type 2 receptor (VEGFR-2) and mediates the regulation of different pathways in the target cells, mainly the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway (7,8) and the phosphop38 mitogen activated protein kinase (MAPK)-dependent activation of nuclear factor κB (NF-κB) (9,10). Activation of the NF-κB and Akt/mTOR pathways increases the levels of the inducible nitric oxide synthase (iNOS) isoform, leading to the release and accumulation of nitric oxide (NO) that acts as a pro-angiogenic stimulus on the blood vessels and favors neo-vascularization in solid tumors (5,11). Thus, targeting the angiogenic and mitogenic pathways is a rational and potentially effective strategy in the treatment of CRC (12).Rifaximin is a semi-synthetic antibiotic largely used fo...

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Section: Discussionsupporting

confidence: 91%

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

Esposito

Gigli

Seguella

et al. 2016

International Journal of Oncology

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“…PXR also inhibited HT29 xenograft tumor growth in mice as a result of cell cycle arrest at G0/G1 phase along with elevated p21 expression and inhibited E2F1 expression. A similar tumor suppressor role for PXR was observed in a very recent study of colon cancer (Cheng et al, 2014). Treatment with rifaximin, which selectively activates intestinal PXR, significantly decreased the number of colon tumors induced by azoxymethane (AOM)/dextran sulfate sodium (DSS) in PXR-humanized mice, but not in wild-type or PXR-null mice (Cheng et al, 2014).…”

Section: Differential Role Of Pxr In Cancersupporting

confidence: 81%

“…A similar tumor suppressor role for PXR was observed in a very recent study of colon cancer (Cheng et al, 2014). Treatment with rifaximin, which selectively activates intestinal PXR, significantly decreased the number of colon tumors induced by azoxymethane (AOM)/dextran sulfate sodium (DSS) in PXR-humanized mice, but not in wild-type or PXR-null mice (Cheng et al, 2014). Additionally, rifaximin treatment increased the survival rate of PXR-humanized mice compared to wild-type or PXR-null mice.…”

Section: Differential Role Of Pxr In Cancersupporting

confidence: 81%

Pregnane X Receptor and Cancer: Context-Specificity is Key

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Pávek

Mani

2016

Nuclear Receptor Research

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Pregnane X receptor (PXR) is an adopted orphan nuclear receptor that is activated by a wide-range of endobiotics and xenobiotics, including chemotherapy drugs. PXR plays a major role in the metabolism and clearance of xenobiotics and endobiotics in liver and intestine via induction of drug-metabolizing enzymes and drug-transporting proteins. However, PXR is expressed in several cancer tissues and the accumulating evidence strongly points to the differential role of PXR in cancer growth and progression as well as in chemotherapy outcome. In cancer cells, besides regulating the gene expression of enzymes and proteins involved in drug metabolism and transport, PXR also regulates other genes involved in proliferation, metastasis, apoptosis, anti-apoptosis, inflammation, and oxidative stress. In this review, we focus on the differential role of PXR in a variety of cancers, including prostate, breast, ovarian, endometrial, and colon. We also discuss the future directions to further understand the differential role of PXR in cancer, and conclude with the need to identify novel selective PXR modulators to target PXR in PXR-expressing cancers.

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“…Interestingly, this report also indicated that expression of PXR is reduced in human colon cancer tissues, albeit using a relatively small sample size (Ouyang et al, 2010). A tumor-suppressive role of PXR was further supported by another report where intestine-specific activation of PXR by rifaximin significantly reduced azoxymethane/dextran sulfate sodium-induced colon cancer in human PXR transgenic but not WT or PXR 2/2 mice, possibly through the PXR-NF-kB axis (Cheng et al, 2014).…”

Section: Downloaded Frommentioning

confidence: 58%

The Roles of Xenobiotic Receptors: Beyond Chemical Disposition

et al. 2018

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Over the past 20 years, the ability of the xenobiotic receptors to coordinate an array of drug-metabolizing enzymes and transporters in response to endogenous and exogenous stimuli has been extensively characterized and well documented. The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are the xenobiotic receptors that have received the most attention since they regulate the expression of numerous proteins important to drug metabolism and clearance and formulate a central defensive mechanism to protect the body against xenobiotic challenges. However, accumulating evidence has shown that these xenobiotic sensors also control many cellular processes outside of their traditional realms of xenobiotic metabolism and disposition, including physiologic and/or pathophysiologic responses in energy homeostasis, cell proliferation, inflammation, tissue injury and repair, immune response, and cancer development. This review will highlight recent advances in studying the noncanonical functions of xenobiotic receptors with a particular focus placed on the roles of CAR and PXR in energy homeostasis and cancer development.

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Activation of Intestinal Human Pregnane X Receptor Protects against Azoxymethane/Dextran Sulfate Sodium–Induced Colon Cancer

Cited by 24 publications

References 24 publications

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

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

Pregnane X Receptor and Cancer: Context-Specificity is Key

The Roles of Xenobiotic Receptors: Beyond Chemical Disposition

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