Aryl hydrocarbon receptor response to indigoids in vitro and in vivo

2004 ◽  
Vol 423 (2) ◽  
pp. 309-316 ◽  
Author(s):  
F Peter Guengerich ◽  
Martha V Martin ◽  
W.Andrew McCormick ◽  
Linh P Nguyen ◽  
Edward Glover ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Aryl Hydrocarbon ◽  
Receptor Response

scholarly journals Increase Paclitaxel Sensitivity to Better Suppress Serous Epithelial Ovarian Cancer via Ablating Androgen Receptor/Aryl Hydrocarbon Receptor-ABCG2 Axis

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 463 ◽  
Author(s):  
Wei-Min Chung ◽  
Yen-Ping Ho ◽  
Wei-Chun Chang ◽  
Yuan-Chang Dai ◽  
Lumin Chen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Androgen Receptor ◽  
Epithelial Ovarian Cancer ◽  
Aryl Hydrocarbon Receptor ◽  
Proximal Promoter ◽  
Luciferase Reporter ◽  
Aryl Hydrocarbon ◽  
Paclitaxel Treatment

Background: Epithelial ovarian cancer (EOC) is one of the most lethal gynecological malignancies and presents chemoresistance after chemotherapy treatment. Androgen receptor (AR) has been known to participate in proliferation. Yet the mechanisms of the resistance of this drug and its linkage to the AR remains unclear. Methods: To elucidate AR-related paclitaxel sensitivity, co-IP, luciferase reporter assay and ChIP assay were performed to identify that AR direct-regulated ABCG2 expression under paclitaxel treatment. IHC staining by AR antibody presented higher AR expression in serous-type patients than other types. AR degradation enhancer (ASC-J9) was used to examine paclitaxel-associated and paclitaxel-resistant cytotoxicity in vitro and in vivo. Results: We found AR/aryl hydrocarbon receptor (AhR)-mediates ABCG2 expression and leads to a change in paclitaxel cytotoxicity/sensitivity in EOC serous subtype cell lines. Molecular mechanism study showed that paclitaxel activated AR transactivity and bound to alternative ARE in the ABCG2 proximal promoter region. To identify AR as a potential therapeutic target, the ASC-J9 was used to re-sensitize paclitaxel-resistant EOC tumors upon paclitaxel treatment in vitro and in vivo. Conclusion: The results demonstrated that activation of AR transactivity beyond the androgen-associated biological effect. This novel AR mechanism explains that degradation of AR is the most effective therapeutic strategy for treating AR-positive EOC serous subtype.

scholarly journals In Silico Identification of an Aryl Hydrocarbon Receptor Antagonist with Biological Activity In Vitro and In Vivo

2014 ◽  
Vol 86 (5) ◽  
pp. 593-608 ◽  
Author(s):  
Ashley J. Parks ◽  
Michael P. Pollastri ◽  
Mark E. Hahn ◽  
Elizabeth A. Stanford ◽  
Olga Novikov ◽  
...  
Keyword(s):  
Biological Activity ◽  
Receptor Antagonist ◽  
Aryl Hydrocarbon Receptor ◽  
In Silico ◽  
Aryl Hydrocarbon ◽  
In Silico Identification ◽  
Aryl Hydrocarbon Receptor Antagonist

Microbial Metabolites of Omeprazole Activate Murine Aryl Hydrocarbon Receptor In Vitro and In Vivo

2014 ◽  
Vol 42 (10) ◽  
pp. 1690-1697 ◽  
Author(s):  
Kazuhiro Shiizaki ◽  
Masanobu Kawanishi ◽  
Takashi Yagi
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Microbial Metabolites ◽  
Aryl Hydrocarbon

scholarly journals Streptococcus gallolyticus Increases Expression and Activity of Aryl Hydrocarbon Receptor-Dependent CYP1 Biotransformation Capacity in Colorectal Epithelial Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Rahwa Taddese ◽  
Rian Roelofs ◽  
Derk Draper ◽  
Xinqun Wu ◽  
Shaoguang Wu ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Aryl Hydrocarbon Receptor ◽  
Specific Inhibitor ◽  
Intestinal Bacteria ◽  
Opportunistic Pathogen ◽  
Dependent Manner ◽  
Aryl Hydrocarbon ◽  
Streptococcus Gallolyticus

ObjectiveThe opportunistic pathogen Streptococcus gallolyticus is one of the few intestinal bacteria that has been consistently linked to colorectal cancer (CRC). This study aimed to identify novel S. gallolyticus-induced pathways in colon epithelial cells that could further explain how S. gallolyticus contributes to CRC development.Design and ResultsTranscription profiling of in vitro cultured CRC cells that were exposed to S. gallolyticus revealed the specific induction of oxidoreductase pathways. Most prominently, CYP1A and ALDH1 genes that encode phase I biotransformation enzymes were responsible for the detoxification or bio-activation of toxic compounds. A common feature is that these enzymes are induced through the Aryl hydrocarbon receptor (AhR). Using the specific inhibitor CH223191, we showed that the induction of CYP1A was dependent on the AhR both in vitro using multiple CRC cell lines as in vivo using wild-type C57bl6 mice colonized with S. gallolyticus. Furthermore, we showed that CYP1 could also be induced by other intestinal bacteria and that a yet unidentified diffusible factor from the S. galloltyicus secretome (SGS) induces CYP1A enzyme activity in an AhR-dependent manner. Importantly, priming CRC cells with SGS increased the DNA damaging effect of the polycyclic aromatic hydrocarbon 3-methylcholanthrene.ConclusionThis study shows that gut bacteria have the potential to modulate the expression of biotransformation pathways in colonic epithelial cells in an AhR-dependent manner. This offers a novel theory on the contribution of intestinal bacteria to the etiology of CRC by modifying the capacity of intestinal epithelial or (pre-)cancerous cells to (de)toxify dietary components, which could alter intestinal susceptibility to DNA damaging events.

scholarly journals Inhibition of dioxin effects on bone formation in vitro by a newly described aryl hydrocarbon receptor antagonist, resveratrol

2000 ◽  
Vol 167 (1) ◽  
pp. 183-195 ◽  
Author(s):  
SU Singh ◽  
RF Casper ◽  
PC Fritz ◽  
B Sukhu ◽  
B Ganss ◽  
...  
Keyword(s):  
Periodontal Disease ◽  
Aryl Hydrocarbon Receptor ◽  
Cigarette Smoke ◽  
Bone Cell ◽  
Nodule Formation ◽  
Antifungal Compound ◽  
Type I ◽  
Aryl Hydrocarbon

Aryl hydrocarbon receptor (AhR) ligands are environmental contaminants found in cigarette smoke and other sources of air pollution. The prototypical compound is TCDD (2,3,7, 8-tetrachlorodibenzo-p-dioxin), also known as dioxin. There is an increasing body of knowledge linking cigarette smoking to osteoporosis and periodontal disease, but the direct effects of smoke-associated aryl hydrocarbons on bone are not well understood. Through the use of resveratrol (3,5,4'-trihydroxystilbene), a plant antifungal compound that we have recently demonstrated to be a pure AhR antagonist, we have investigated the effects of TCDD on osteogenesis. It was postulated that TCDD would inhibit osteogenesis in bone-forming cultures and that this inhibition would be antagonized by resveratrol. We employed the chicken periosteal osteogenesis (CPO) model, which has been shown to form bone in vitro in a pattern morphologically and biochemically similar to that seen in vivo, as well as a rat stromal cell bone nodule formation model. In the CPO model, alkaline phosphatase (AP) activity was reduced by up to 50% (P<0.01 vs control) in the presence of 10(-9) M TCDD and these effects were reversed by 10(-6) M resveratrol (P<0.05 vs TCDD alone). TCDD-mediated inhibition of osteogenesis was restricted primarily to the osteoblastic differentiation phase (days 0-2) as later addition did not appear to have any effects. Message levels for important bone-associated proteins (in the CPO model) such as collagen type I, osteopontin, bone sialoprotein and AP were inhibited by TCDD, an effect that was antagonized by resveratrol. Similar findings were obtained using the rat stromal bone cell line. TCDD (at concentrations as low as 10(-10)M) caused an approximately 33% reduction in AP activity, which was abrogated by 3. 5x10(-7) M resveratrol. TCDD also induced a marked reduction in mineralization ( approximately 75%) which was completely antagonized by resveratrol. These data suggest that AhR ligands inhibit osteogenesis probably through inhibition of osteodifferentiation and that this effect can be antagonized by resveratrol. Since high levels of AhR ligands are found in cigarette smoke, and further since smoking is an important risk factor in both osteoporosis and periodontal disease, it may be postulated that AhR ligands are the component of cigarette smoke linking smoking to osteoporosis and periodontal disease. If so, resveratrol could prove to be a promising preventive or therapeutic agent for smoking-related bone loss.

Carbidopa is an activator of aryl hydrocarbon receptor with potential for cancer therapy

2017 ◽  
Vol 474 (20) ◽  
pp. 3391-3402 ◽  
Author(s):  
Jiro Ogura ◽  
Seiji Miyauchi ◽  
Kazumi Shimono ◽  
Shengping Yang ◽  
Sathisha Gonchigar ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Liver Cancer ◽  
Aryl Hydrocarbon Receptor ◽  
Cancer Cells ◽  
Inhibitory Effect ◽  
Anticancer Effect ◽  
Liver Cancer Cells ◽  
Aryl Hydrocarbon

Carbidopa is used with l-DOPA (l-3,4-dihydroxyphenylalanine) to treat Parkinson's disease (PD). PD patients exhibit lower incidence of most cancers including pancreatic cancer, but with the notable exception of melanoma. The decreased cancer incidence is not due to l-DOPA; however, the relevance of Carbidopa to this phenomenon has not been investigated. Here, we tested the hypothesis that Carbidopa, independent of l-DOPA, might elicit an anticancer effect. Carbidopa inhibited pancreatic cancer cell proliferation both in vitro and in vivo. Based on structural similarity with phenylhydrazine, an inhibitor of indoleamine-2,3-dioxygenase-1 (IDO1), we predicted that Carbidopa might also inhibit IDO1, thus providing a molecular basis for its anticancer effect. The inhibitory effect was confirmed using human recombinant IDO1. To demonstrate the inhibition in intact cells, AhR (aryl hydrocarbon receptor) activity was monitored as readout for IDO1-mediated generation of the endogenous AhR agonist kynurenine in pancreatic and liver cancer cells. Surprisingly, Carbidopa did not inhibit but instead potentiated AhR signaling, evident from increased CYP1A1 (cytochrome P450 family 1 subfamily A member 1), CYP1A2, and CYP1B1 expression. In pancreatic and liver cancer cells, Carbidopa promoted AhR nuclear localization. AhR antagonists blocked Carbidopa-dependent activation of AhR signaling. The inhibitory effect on pancreatic cancer cells in vitro and in vivo and the activation of AhR occurred at therapeutic concentrations of Carbidopa. Chromatin immunoprecipitation assay further confirmed that Carbidopa promoted AhR binding to its target gene CYP1A1 leading to its induction. We conclude that Carbidopa is an AhR agonist and suppresses pancreatic cancer. Hence, Carbidopa could potentially be re-purposed to treat pancreatic cancer and possibly other cancers as well.

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