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, Silvia; Seguella, Luisa; Nobile, Nicola; D’Alessandro, Alessandra; Pesce, Marcella; Capoccia, Elena; Steardo, Luca; Cirillo, Carla; Cuomo, Rosario; Sarnelli, Giovanni

doi:10.3892/ijo.2016.3550

Cited by 19 publications

(16 citation statements)

References 27 publications

(26 reference statements)

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“…We detected that meclizine markedly inhibited phosphorylation of ERK and p38 triggered by RANKL. These results were in line with previous studies, suggesting that meclizine attenuates ERK phosphorylation in chondrocytes and rifaximin acts as a PXR agonist similar to meclizine significantly blocked p38 phosphorylation ( Matsushita et al, 2013 ; Esposito et al, 2016 ). Moreover, our data showed that meclizine obviously repressed RANKL-induced expression of NFATc1 and c-Fos, and subsequently inhibited the activation of osteoclast-derived marker genes, including cathepsin K and MMP9 , which can straightly degrade collagens in hard tissues ( Takayanagi, 2007b ).…”

Section: Discussionsupporting

confidence: 93%

Meclizine Prevents Ovariectomy-Induced Bone Loss and Inhibits Osteoclastogenesis Partially by Upregulating PXR

Guo

et al. 2017

Front. Pharmacol.

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Pregnane X receptor (PXR) which belongs to the nuclear hormone receptor superfamily plays vital roles in several biological functions, especially in the inflammatory procedure. Besides that, PXR is revealed by recent studies to have essential effects on bone tissue. As an agonist of PXR, meclizine is a piperazine-derived histamine H1 antagonist, and has been frequently used for prevention and treatment of vomiting and nausea. Because osteoclastogenesis is characterized by the activation of inflammation-related signaling pathways, we speculated that meclizine may affect formation and function of osteoclast. In the present study, we explored the effect of meclizine on RANKL-induced osteoclastogenesis both in vivo and in vitro. In primary bone marrow-derived macrophages (BMMs), meclizine reduced osteoclast formation and bone resorption in a dose-dependent manner, while knockdown of PXR with siRNA partially abrogated the osteoclastogenesis inhibition of meclizine. On the one hand, at the molecular level, meclizine attenuated RANKL-induced activation of c-Fos, NFATc1, nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPKs), including ERK and p38, but not JNK. Meanwhile, meclizine reduced the expression of osteoclast-specific genes, including TRAP, MMP9, Cathepsin K and NFATc1. On the other hand, meclizine decreased OVX-induced bone loss by repressing osteoclast activity. In conclusion, our results indicated that meclizine inhibits osteoclastogenesis via regulation of several RANKL signaling pathways and PXR was involved in the processes. Therefore, meclizine may be considered as a novel therapeutic candidate for osteoclast-related diseases.

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Section: Discussionsupporting

confidence: 93%

Meclizine Prevents Ovariectomy-Induced Bone Loss and Inhibits Osteoclastogenesis Partially by Upregulating PXR

Guo

et al. 2017

Front. Pharmacol.

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“…In Caco2 CRC cells, Rifaximin reduces PCNA protein levels and consequently decreases cell proliferation, also reducing mediators of cell migration and angiogenesis [69]. Rifaximin inhibits the activation of AKT, NF-κB, and p70S6K, leading to a reduction in HIF-1α levels and inhibition of the p38 MAPK signaling pathway [70]. Imperatorin, one of the major active coumarins found in the root of Imperata cylindrica Beauv with many pharmacological activities including anti-inflammatory, anti-coagulant, and anti-proliferative effects, was reported to greatly reduce HIF-1α levels by decreasing hypoxia in various types of tumors.…”

Section: Role Of the P38 Mapk Signaling Pathway In The Response To Otmentioning

confidence: 99%

The p38 MAPK Signaling Activation in Colorectal Cancer upon Therapeutic Treatments

Pranteda¹,

Piastra²,

Stramucci³

et al. 2020

IJMS

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Pharmacological treatment of colorectal carcinoma currently proceeds through the administration of a combination of different chemotherapeutic agents. In the case of rectal carcinoma, radiation therapy also represents a therapeutic strategy. In an attempt at translating much-needed new targeted therapy to the clinics, p38 mitogen activated protein kinase (MAPK) inhibitors have been tested in clinical trials involving colorectal carcinoma patients, especially in combination with chemotherapy; however, despite the high expectations raised by a clear involvement of the p38 MAPK pathway in the response to therapeutic treatments, poor results have been obtained so far. In this work, we review recent insights into the exact role of the p38 MAPK pathway in response to currently available therapies for colorectal carcinoma, depicting an intricate scenario in which the p38 MAPK node presents many opportunities, as well as many challenges, for its perspective exploitation for clinical purposes.

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“…This process works first by the release of VEGF, which then activates the Nuclear Factor Kappa B (NF-κB) pathway leading to an increase in nitric oxide synthase and thus nitric oxide. Nitric oxide then stimulates angiogenesis of new blood vessels needed by cancer cells to thrive [ 58 ]. Esposito et al (2016) found that PXR activation could inhibit this process via its inhibition of the NF-κB pathway leading to decreased levels of NO.…”

Section: Pxr and Breast Cancermentioning

confidence: 99%

Associations between Pregnane X Receptor and Breast Cancer Growth and Progression

Creamer

Sloan

Dennis

et al. 2020

Cells

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Pregnane X receptor (PXR, NR1I2) is a member of the ligand-activated nuclear receptor superfamily. This receptor is promiscuous in its activation profile and is responsive to a broad array of both endobiotic and xenobiotic ligands. PXR is involved in pivotal cellular detoxification processes to include the regulation of genes that encode key drug-metabolizing cytochrome-P450 enzymes, oxidative stress response, as well as enzymes that drive steroid and bile acid metabolism. While PXR clearly has important regulatory roles in the liver and gastrointestinal tract, this nuclear receptor also has biological functions in breast tissue. In this review, we highlight current knowledge of PXR’s role in mammary tumor carcinogenesis. The elevated level of PXR expression in cancerous breast tissue suggests a likely interface between aberrant cell division and xeno-protection in cancer cells. Moreover, PXR itself exerts positive effect on the cell cycle, thereby predisposing tumor cells to unchecked proliferation. Activation of PXR also plays a key role in regulating apoptosis, as well as in acquired resistance to chemotherapeutic agents. The repressive role of PXR in regulating inflammatory mediators along with the existence of genetic polymorphisms within the sequence of the PXR gene may predispose individuals to developing breast cancer. Further investigations into the role that PXR plays in driving tumorigenesis are needed.

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

Cited by 19 publications

References 27 publications

Meclizine Prevents Ovariectomy-Induced Bone Loss and Inhibits Osteoclastogenesis Partially by Upregulating PXR

Meclizine Prevents Ovariectomy-Induced Bone Loss and Inhibits Osteoclastogenesis Partially by Upregulating PXR

The p38 MAPK Signaling Activation in Colorectal Cancer upon Therapeutic Treatments

Associations between Pregnane X Receptor and Breast Cancer Growth and Progression

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