Hydroxystilbenes and methoxystilbenes activate human aryl hydrocarbon receptor and induce CYP1A genes in human hepatoma cells and human hepatocytes

Pastorková, Barbora; Vrzalová, Aneta; Bachleda, Petr; Dvořák, Zdeněk

doi:10.1016/j.fct.2017.03.008

Cited by 21 publications

(14 citation statements)

References 62 publications

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“…Further studies showed that the human cytochrome P450 1A1 (CYP1A1) is mainly involved in the DMU-212 metabolic pathway [75,86]. The dose-dependent induction of CYP1A1 and CYP1A2 mRNAs was noted after treatment of primary human hepatocytes cells with DMU-212 [75]. This metabolic activation is probably involved in anticancer activity, while it was found that the lack of the expression of CYP1A1 is associated with lower activity of DMU-212 [86].…”

Section: Short Story About Dmu-212-when Synthetic Chemistry Achieved mentioning

confidence: 99%

“…In 2005, McErlane et al suggested that DMU-212 is inactive until it undergoes aromatic hydroxylation (by CYP1A1) and O-demethylation (by CYP1B1) to generate two active metabolites, DMU-214 (referred as a tyrosine kinase inhibitor) and DMU-291 (apoptosis inducer), respectively [85]. Further studies showed that the human cytochrome P450 1A1 (CYP1A1) is mainly involved in the DMU-212 metabolic pathway [75,86]. The dose-dependent induction of CYP1A1 and CYP1A2 mRNAs was noted after treatment of primary human hepatocytes cells with DMU-212 [75].…”

Section: Short Story About Dmu-212-when Synthetic Chemistry Achieved mentioning

confidence: 99%

“…In general, AhR regulates the expression of numerous cytochrome CYP450 genes, including members of the CYP1 family, CYP1A1, and CYP1A2 [67]. It was found that DMU-212 induced AhR activation in HepG2 stably transfected line AZ-AhR [75]. In contrast, another study showed that DMU-214 at a concentration of 0.25 µM might decrease the level of the AhR nuclear fraction and thus, exert the inhibitory effect on CYP1A1 [86].…”

Section: Short Story About Dmu-212-when Synthetic Chemistry Achieved mentioning

confidence: 99%

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More Than Resveratrol: New Insights into Stilbene-Based Compounds

et al. 2020

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The concept of a scaffold concerns many aspects at different steps on the drug development path. In medicinal chemistry, the choice of relevant “drug-likeness” scaffold is a starting point for the design of the structure dedicated to specific molecular targets. For many years, the chemical uniqueness of the stilbene structure has inspired scientists from different fields such as chemistry, biology, pharmacy, and medicine. In this review, we present the outstanding potential of the stilbene-based derivatives. Naturally occurring stilbenes, together with powerful synthetic chemistry possibilities, may offer an excellent approach for discovering new structures and identifying their therapeutic targets. With the development of scientific tools, sophisticated equipment, and a better understanding of the disease pathogenesis at the molecular level, the stilbene scaffold has moved innovation in science. This paper mainly focuses on the stilbene-based compounds beyond resveratrol, which are particularly attractive due to their biological activity. Given the “fresh outlook” about different stilbene-based compounds starting from stilbenoids with particular regard to isorhapontigenin and methoxy- and hydroxyl- analogues, the update about the combretastatins, and the very often overlooked and underestimated benzanilide analogues, we present a new story about this remarkable structure.

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Section: Short Story About Dmu-212-when Synthetic Chemistry Achieved mentioning

confidence: 99%

Section: Short Story About Dmu-212-when Synthetic Chemistry Achieved mentioning

confidence: 99%

Section: Short Story About Dmu-212-when Synthetic Chemistry Achieved mentioning

confidence: 99%

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More Than Resveratrol: New Insights into Stilbene-Based Compounds

et al. 2020

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“…HepaRG cells simulate hepatocytes in that PXR ligands can also induce target genes in similar but not identical manner [19][20][21] . AhR agonists transcriptionally induce target genes, CYP1A1 and CYP1A2, in both hepatocytes 22 and intestinal cells (LS180) 23 . As shown in Fig.…”

Section: Characterization Of Fkk Compound(s) Gene Expression Assay Prmentioning

confidence: 99%

Targeting the Pregnane X Receptor Using Microbial Metabolite Mimicry

Dvořák

Kopp

Costello

et al. 2019

Preprint

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The human pregnane X receptor (PXR), a master regulator of drug metabolism, has important roles in intestinal homeostasis and abrogating inflammation. Existing PXR ligands have substantial off-target toxicity. Based on prior work that established microbial (indole) metabolites as PXR ligands, we proposed microbial metabolite mimicry as a novel strategy for drug discovery that allows to exploit previously unexplored parts of chemical space. Here we report functionalized indole-derivatives as firstin-class PXR selective non-cytotoxic agonists, as a proof-of-concept for microbial metabolite mimicry.The lead compound, FKK6, binds directly to PXR protein in solution, induces PXR specific target gene expression in, cells, human organoids, and mice. FKK6 significantly represses pro-inflammatory cytokine production cells and abrogates inflammation in humanized mice. The development of FKK6 demonstrates for the first time that microbial metabolite mimicry is a viable strategy for drug discovery and opens the door to mine underexploited regions of chemical space.

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“…Among several methoxystilbenes studied, 3,4,5,4 -tetramethoxystilbene (DMU-212) seems to be one of the most potent drivers of cytotoxicity and apoptosis. DMU-212 has been shown to exert pro-apoptotic activity in several cancer cell lines, including transformed fibroblasts, liver, colon, hypopharynx, breast, prostate, and ovarian ones [14][15][16][17][18][19][20][21][22][23]. Biotransformation studies of DMU-212 have revealed its conversion to five metabolites: 3 -hydroxy-3,4,5,4 -tetramethoxystilbene (DMU-214), 4 -hydroxy-3,4,5-trimethoxystilbene (DMU-281), 4-hydroxy-3,5,4 -trimethoxystilbene (DMU-291), 4,4 -dihydroxy-3,5-dimethoxystilbene (DMU-295) and 3-hydroxy-4,5,4 -trimethoxystilbene (DMU-807) [17], (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

The Effect of 3′-Hydroxy-3,4,5,4′-Tetramethoxy -stilbene, the Metabolite of the Resveratrol Analogue DMU-212, on the Motility and Proliferation of Ovarian Cancer Cells

Nowicki

Skupin-Mrugalska

Józkowiak

et al. 2020

IJMS

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Targeting tumor cell motility and proliferation is an extremely important challenge in the prevention of metastasis and improving the effectiveness of cancer treatment. We recently published data revealing that DMU-214, the metabolite of firmly cytotoxic resveratrol analogue DMU-212, exerted significantly higher biological activity than the parent compound in ovarian cancer cells. The aim of the present study was to assess the molecular mechanism of the potential anti-migration and anti-proliferative effect of DMU-214 in ovarian cancer cell line SKOV-3. We showed that DMU-214 reduced the migratory capacity of SKOV-3 cells. The microarray analysis indicated ontology groups of genes involved in processes of negative regulation of cell motility and proliferation. Furthermore, we found DMU-214 triggered changes in expression of several migration- and proliferation-related genes (SMAD7, THBS1, IGFBP3, KLF4, Il6, ILA, SOX4, IL15, SRF, RGCC, GPR56) and proteins (GPR56, RGCC, SRF, SMAD7, THBS1), which have been shown to interact to each other to reduce cell proliferation and motility. Our study showed for the first time that DMU-214 displayed anti-migratory and anti-proliferative activity in SKOV-3 ovarian cancer cells. On the basis of whole transcriptome analysis of these cells, we provide new insight into the role of DMU-214 in inhibition of processes related to metastasis.

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Hydroxystilbenes and methoxystilbenes activate human aryl hydrocarbon receptor and induce CYP1A genes in human hepatoma cells and human hepatocytes

Cited by 21 publications

References 62 publications

More Than Resveratrol: New Insights into Stilbene-Based Compounds

More Than Resveratrol: New Insights into Stilbene-Based Compounds

Targeting the Pregnane X Receptor Using Microbial Metabolite Mimicry

The Effect of 3′-Hydroxy-3,4,5,4′-Tetramethoxy -stilbene, the Metabolite of the Resveratrol Analogue DMU-212, on the Motility and Proliferation of Ovarian Cancer Cells

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