Pregnane X Receptor and Cancer: Context-Specificity is Key

Pondugula, Satyanarayana R.; Pávek, Petr; Mani, Sridhar

doi:10.11131/2016/101198

Cited by 58 publications

(56 citation statements)

References 141 publications

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“…It is possible to alleviate chemoresistance in some cases if a clinical anticancer drug can antagonize the drug-activated hPXR at therapeutic concentrations during combination chemotherapy. Our results are specifically relevant to cancers where hPXR activation contributes to chemoresistance via the upregulation of hPXR target genes (https://www.oncomine.org) (Pondugula and Mani, 2013;Pondugula et al, 2016).…”

Section: Discussionmentioning

confidence: 89%

“…Previous studies have shown that elevated levels of PXR-mediated expression of drug-metabolizing enzymes and drug-efflux pumps in cancer cells contribute to increased resistance toward chemotherapy drugs (Pondugula and Mani, 2013;Planque et al, 2016;Pondugula et al, 2016). For instance, the activation of hPXR-mediated expression of drug-metabolizing enzymes and drug-efflux pumps decreases the sensitivity of human colon cancer cells, including LS174T cells, to several chemotherapy drugs such as SN-38 [the active metabolite of irinotecan (C 22 H 20 N 2 O 5 )] (Pondugula et al, 2016). Because BEL inhibited the hPXR agonist-activated expression of CYP3A4 and MDR1 in LS174 cells, we determined whether BEL inhibits RIF-induced resistance to SN-38.…”

Section: Resultsmentioning

confidence: 99%

“…It is known that the regulation of PXR-dependent reporter gene activity using transfected cells does not always correlate with the regulation of endogenous hPXR target gene expression (Luo et al, 2002;Cui et al, 2008). It is also known that PXR activity can be regulated in a tissue-specific (Robbins and Chen, 2014) and contextdependent (Pondugula et al, 2016) manner with in the same cells. Our reporter gene results show a differential effect of BEL on PXR in a cell-dependent manner.…”

Section: Belinostat Antagonizes Hpxr Target Gene Expressionmentioning

confidence: 99%

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Belinostat, at Its Clinically Relevant Concentrations, Inhibits Rifampicin-Induced CYP3A4 and MDR1 Gene Expression

et al. 2019

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Activation of pregnane X receptor (PXR) by clinical compounds during multidrug chemotherapy results in upregulation of the expression of PXR target genes, including cytochrome p450 3A4 (CYP3A4) and multidrug resistance protein 1 (MDR1), leading to chemoresistance. It is possible to overcome the PXR‐mediated chemoresistance by downregulating the upregulated PXR target genes by inhibiting the activated PXR. However, a selective and less‐toxic PXR antagonist has yet to be developed. In this regard, a clinical anticancer drug, with selective PXR antagonistic activity at its less‐toxic concentrations, would be beneficial. We sought to determine whether belinostat, a clinically‐used histone deacetylase inhibitor, inhibits the PXR target gene expression at its clinically relevant plasma concentrations (< ~100 μM) in human hepatocytes (primary hepatocytes & hepatocells) and intestinal cells (LS174T colon cancer cells). Rifampicin, an agonist of human PXR, was used to activate PXR. Cell viability and CYQUANT cell proliferation assays were performed to determine cytotoxicity and cell proliferation, respectively. Quantitative RT‐PCR assays were conducted to study the gene expression. CYP3A4 p450‐Glo and Rhodamine‐123 intracellular accumulation assays were performed to determine the function of CYP3A4 and MDR1, respectively. Belinostat, at its unbound therapeutic plasma concentrations (< ~5 μM) did not affect the viability of LS174T cells and the hepatocytes. Belinostat (1 & 3 μM) not only inhibited rifampicin‐induced gene expression of CYP3A4 and MDR1, but also attenuated rifampicin‐induced activity of CYP3A4 and MDR1. However, belinostat alone did not affect CYP3A4 or MDR1 gene expression. These results suggest that belinostat does not affect the basal expression of PXR target genes but downregulates the upregulated PXR target genes by inhibiting the ligand‐activated PXR. Notably, belinostat, at its PXR inhibiting concentrations, decreased rifampicin‐induced proliferation of LS174T cells, suggesting that belinostat suppresses PXR‐mediated proliferation of the cancer cells. Interestingly, belinostat failed to inhibit rodent PXR agonist pregnenolone‐16 alpha‐carbonitrile (PCN)‐induced expression of CYP3A1 (the rat analog of human CYP3A4) in rat primary hepatocytes, suggesting that belinostat exhibits species‐specific inhibition of PXR at unbound plasma therapeutic concentrations. Taken together, these results are consistent with the conclusion that belinostat, at its less‐toxic and clinically relevant unbound plasma concentrations, inhibits the ligand‐activated human PXR target gene expression. Future studies will determine the mechanisms of belinostat inhibition of PXR, and belinostat sensitization of the cancer cells to chemotherapy drugs with PXR agonistic activity. Support or Funding Information The authors would like to thank Drs. Coleman, Schwartz, and Tao for sharing their research facilities. This work was supported by the Auburn University Research Initiative in Cancer Grant, Animal Health and Disease Research Grant...

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Section: Discussionmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Belinostat Antagonizes Hpxr Target Gene Expressionmentioning

confidence: 99%

See 1 more Smart Citation

Belinostat, at Its Clinically Relevant Concentrations, Inhibits Rifampicin-Induced CYP3A4 and MDR1 Gene Expression

et al. 2019

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“…CYP3A4 is probably the most important CYP enzyme for metabolism of chemicals, and for this reason, the induction and variability of CYP3A4 are important modifying factors in a large number of chemical‐induced toxicities, especially regarding pharmaceuticals . For example, anticancer therapy‐related adverse effects have been associated with CYP3A4 variability due to induction and genetic polymorphisms in breast, prostate, gynaecological and colorectal cancers , and consequently, the interest of using nuclear receptor activation and target gene induction as biomarkers for revealing potential risks and for the translation into successful treatments of diseases has grown during the recent years .…”

Section: The Central Role Of Xenobiotic Receptors and Cyp Induction Imentioning

confidence: 99%

Cytochrome P450 Induction and Xeno‐Sensing Receptors Pregnane X Receptor, Constitutive Androstane Receptor, Aryl Hydrocarbon Receptor and Peroxisome Proliferator‐Activated Receptor α at the Crossroads of Toxicokinetics and Toxicodynamics

Hakkola

Bernasconi

Coecke

et al. 2018

Basic Clin Pharma Tox

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Pregnane X receptor (PXR), constitutive androstane receptor (CAR), aryl hydrocarbon receptor (AHR) and peroxisome proliferator-activated receptor α (PPARα) are ligand-activated transcription factors that regulate expression of many xenobiotic-metabolizing enzymes including several cytochrome P450 (CYP) enzymes. Many xenobiotics induce CYP enzymes through these intracellular receptors and consequently affect toxicokinetics and possible metabolic activation of the receptor ligands and other xenobiotics utilizing similar metabolic pathways. However, it is now apparent that the xenobiotic receptors regulate also many endogenous functions and signalling pathways, and xenobiotic exposure thus may dysregulate an array of fundamental cell functions. This MiniReview surveys and discusses the multifaceted roles of xenobiotic receptors, for which CYP induction may serve as the first alert and possibly a biomarker for exposure to xenobiotics. With the current emergence of the adverse outcome pathway (AOP) concept, these receptors are being and will be assigned as molecular initiating events or key events in numerous discrete toxicity pathways.

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“…The activation of AhR by bacterial-derived tryptophan metabolites elicits anti-inflammatory and tumor-suppressive effects in the colon [63–66]. PXR also regulates cell proliferation, metastasis, and inflammation [67]; as such, bacterial metabolites of tryptophan that activate this receptor may affect the development and severity of colonic inflammation and colon cancer.…”

Section: Tryptophan Metabolitesmentioning

confidence: 99%

Gut Microbiome and Colon Cancer: Role of Bacterial Metabolites and Their Molecular Targets in the Host

Bhutia

Ogura

Sivaprakasam

et al. 2017

Curr Colorectal Cancer Rep

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Purpose of review The relationship between colonic bacteria and the host is symbiotic, but how communication between the two partners occurs is just beginning to be understood at the molecular level. Here, we highlight specific products of bacterial metabolism that are present in the colonic lumen and their molecular targets in the host that facilitate this communication. Recent findings Colonic epithelial cells and mucosal immune cells express several cell-surface receptors and nuclear receptors that are activated by specific bacterial metabolites, which impact multiple signaling pathways and expression of many genes. In addition, some bacterial metabolites also possess the ability to cause epigenetic changes in these cells via inhibition of selective enzymes involved in the maintenance of histone acetylation and DNA methylation patterns. Summary Colonic bacteria communicate with their host with selective metabolites that interact with host molecular targets. This chemical communication underlies a broad range of the biology and function of colonic epithelial cells and mucosal immune cells, which protect against inflammation and carcinogenesis in the colon under normal physiological conditions.

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Pregnane X Receptor and Cancer: Context-Specificity is Key

Cited by 58 publications

References 141 publications

Belinostat, at Its Clinically Relevant Concentrations, Inhibits Rifampicin-Induced CYP3A4 and MDR1 Gene Expression

Belinostat, at Its Clinically Relevant Concentrations, Inhibits Rifampicin-Induced CYP3A4 and MDR1 Gene Expression

Cytochrome P450 Induction and Xeno‐Sensing Receptors Pregnane X Receptor, Constitutive Androstane Receptor, Aryl Hydrocarbon Receptor and Peroxisome Proliferator‐Activated Receptor α at the Crossroads of Toxicokinetics and Toxicodynamics

Gut Microbiome and Colon Cancer: Role of Bacterial Metabolites and Their Molecular Targets in the Host

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