In vitro screening of inhibition of PPAR-γ activity as a first step in identification of potential breast carcinogens

2015 ◽  
Vol 34 (11) ◽  
pp. 1106-1118 ◽  
Author(s):  
TI Kopp ◽  
J Lundqvist ◽  
RK Petersen ◽  
A Oskarsson ◽  
K Kristiansen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ethylene Glycol ◽  
Ethyl Acetate ◽  
Organic Solvents ◽  
Inhibitory Effect ◽  
Aromatase Activity ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Screening Assay ◽  
Ppar Γ

Alcohol consumption and increased estrogen levels are major risk factors for breast cancer, and peroxisome proliferator-activated receptor γ (PPAR-γ) plays an important role in alcohol-induced breast cancer. PPAR-γ activity is inhibited by ethanol, leading to increased aromatase activity and estrogen biosynthesis ultimately leading to breast cancer. If other organic solvents inhibit PPAR-γ activity, they should also lead to increased oestrogen biosynthesis and thus be potential breast carcinogens. Ten commonly used hydrophilic organic solvents were first tested in a cell-based screening assay for inhibitory effects on PPAR-γ transactivation. The chemicals shown to inhibit PPAR-γ were tested with vectors encoding PPAR-γ with deleted AB domains and only the ligand-binding domain to rule out unspecific toxicity. Next, the effects on biosynthesis of estradiol, testosterone and oestrone sulphate were measured in the H295R steroidogenesis assay after incubation with the chemicals. Ethylene glycol, ethyl acetate, and dimethyl sulphoxide inhibited PPAR-γ transactivation in a dose-dependent manner. The inhibitory effect on PPAR-γ was specific for PPAR-γ since the AB domain of PPAR-γ was required for the inhibitory effect. In the second step, ethylene glycol significantly increased production of oestradiol by 19% ( p < 0.05) and ethyl acetate inhibited production of testosterone ( p < 0.05). We here show that screening of 10 commonly used organic solvents for the ability to inhibit PPAR-γ transactivation followed by a well-established steroidogenesis assay for production of sex hormones in exposed H295 R cells may provide a screening tool for potential breast carcinogens. This initial screening thus identified ethylene glycol and possibly ethyl acetate as potential breast carcinogens.

Lipopolysaccharide inhibits the expression of resistin in adipocytes

2013 ◽  
Vol 51 (3) ◽  
pp. 287-299 ◽  
Author(s):  
Xinxin Xiang ◽  
Wenjiao An ◽  
Changtao Jiang ◽  
Jing Zhao ◽  
Xian Wang ◽  
...  
Keyword(s):  
Lipid A ◽  
Ex Vivo ◽  
Underlying Mechanism ◽  
Inhibitory Effect ◽  
Pharmacological Intervention ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Resistin Mrna

Resistin is an adipocytokine leading to insulin resistance. Endotoxin/lipopolysaccharide (LPS) has been reported to decrease the expression of resistin mRNA and protein in both lean and db/db obese mice, although the underlying mechanism remains unclear. Several models such as ex vivo culture of adipose tissues, primary rat adipocytes and 3T3-L1 adipocytes were used to further characterize the effect of LPS on the expression of resistin. LPS attenuated both the resistin mRNA and protein in a time- and dose-dependent manner. In the presence of actinomycin D, LPS failed to reduce the half-life of resistin mRNA, suggesting a transcriptional mechanism. The lipid A fraction is crucial for the inhibition of resistin expression induced by LPS. Pharmacological intervention of c-Jun N-terminal kinase (JNK) reversed the inhibitory effect of LPS. LPS down-regulated CCAAT/enhancer-binding protein α (C/EBP-α; CEBPA) and peroxisome proliferator-activated receptor γ (PPAR-γ; PPARG), while activation of C/EBP-α or PPAR-γ by either over-expressing these transcriptional factors or by rosiglitazone, an agonist of PPAR-γ, blocked the inhibitory effect of LPS on resistin. C/EBP homologous protein (CHOP-10; DDIT3) was up-regulated by LPS, while a CHOP-10 antisense oligonucleotide reversed the decrement of resistin protein induced by LPS. Taken together, these results suggest that LPS inhibits resistin expression through a unique signaling pathway involving toll-like receptor 4, JNK, CHOP-10 and C/EBP-α/PPAR-γ.

scholarly journals Andrographis paniculata and Its Main Bioactive Ingredient Andrographolide Decrease Alcohol Drinking and Seeking in Rats Through Activation of Nuclear PPARγ Pathway

2021 ◽  
Author(s):  
Serena Stopponi ◽  
Yannick Fotio ◽  
Carlo Cifani ◽  
Hongwu Li ◽  
Carolina L Haass-Koffler ◽  
...  
Keyword(s):  
Oral Administration ◽  
Alcohol Drinking ◽  
Andrographis Paniculata ◽  
Peroxisome Proliferator ◽  
Herbaceous Plant ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Treatment Administration ◽  
Dried Extract

Abstract Background and aims Andrographis paniculata is an annual herbaceous plant which belongs to the Acanthaceae family. Extracts from this plant have shown hepatoprotective, anti-inflammatory and antidiabetic properties, at least in part, through activation of the nuclear receptor Peroxisome Proliferator-Activated Receptor-gamma (PPAR γ). Recent evidence has demonstrated that activation of PPARγ reduces alcohol drinking and seeking in Marchigian Sardinian (msP) alcohol-preferring rats. Methods The present study evaluated whether A. paniculata reduces alcohol drinking and relapse in msP rats by activating PPARγ. Results Oral administration of an A. paniculata dried extract (0, 15, 150 mg/kg) lowered voluntary alcohol consumption in a dose-dependent manner and achieved ~65% reduction at the dose of 450 mg/kg. Water and food consumption were not affected by the treatment. Administration of Andrographolide (5 and 10 mg/kg), the main active component of A. paniculata, also reduced alcohol drinking. This effect was suppressed by the selective PPARγ antagonist GW9662. Subsequently, we showed that oral administration of A. paniculata (0, 150, 450 mg/kg) prevented yohimbine- but not cues-induced reinstatement of alcohol seeking. Conclusions Results point to A. paniculata-mediated PPARγactivation as a possible therapeutic strategy to treat alcohol use disorder.

scholarly journals Quercetin Is a Flavonoid Breast Cancer Resistance Protein Inhibitor with an Impact on the Oral Pharmacokinetics of Sulfasalazine in Rats

Pharmaceutics ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 397
Author(s):  
Yoo-Kyung Song ◽  
Jin-Ha Yoon ◽  
Jong Kyu Woo ◽  
Ju-Hee Kang ◽  
Kyeong-Ryoon Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Resistance Protein ◽  
Fold Increase ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Cancer Resistance ◽  
Concentration Dependent Manner ◽  
Resistance Protein

The potential inhibitory effect of quercetin, a major plant flavonol, on breast cancer resistance protein (BCRP) activity was investigated in this study. The presence of quercetin significantly increased the cellular accumulation and associated cytotoxicity of the BCRP substrate mitoxantrone in human cervical cancer cells (HeLa cells) in a concentration-dependent manner. The transcellular efflux of prazosin, a stereotypical BCRP substrate, was also significantly reduced in the presence of quercetin in a bidirectional transport assay using human BCRP-overexpressing cells; further kinetic analysis revealed IC50 and Ki values of 4.22 and 3.91 μM, respectively. Moreover, pretreatment with 10 mg/kg quercetin in rats led to a 1.8-fold and 1.5-fold increase in the AUC8h (i.e., 44.5 ± 11.8 min∙μg/mL vs. 25.7 ± 9.98 min∙μg/mL, p < 0.05) and Cmax (i.e., 179 ± 23.0 ng/mL vs. 122 ± 23.2 ng/mL, p < 0.05) of orally administered sulfasalazine, respectively. Collectively, these results provide evidence that quercetin acts as an in vivo as well as in vitro inhibitor of BCRP. Considering the high dietary intake of quercetin as well as its consumption as a dietary supplement, issuing a caution regarding its food–drug interactions should be considered.

scholarly journals The Inhibitory Effect of (−)-Epigallocatechin-3-Gallate on Breast Cancer Progression via Reducing SCUBE2 Methylation and DNMT Activity

Molecules ◽  
2019 ◽  
Vol 24 (16) ◽  
pp. 2899 ◽  
Author(s):  
Jie Sheng ◽  
Weilin Shi ◽  
Hui Guo ◽  
Wenlin Long ◽  
Yuxin Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Inhibitory Effect ◽  
Breast Cancer Progression ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Complement Protein ◽  
Epidermal Growth Factor Domain ◽  
Potential Implication ◽  
Egcg Treatment

Epigenetic modifications are important mechanisms responsible for cancer progression. Accumulating data suggest that (−)-epigallocatechin-3-gallate (EGCG), the most abundant catechin of green tea, may hamper carcinogenesis by targeting epigenetic alterations. We found that signal peptide-CUB (complement protein C1r/C1s, Uegf, and Bmp1)-EGF (epidermal growth factor) domain-containing protein 2 (SCUBE2), a tumor suppressor gene, was hypermethylated in breast tumors. However, it is unknown whether EGCG regulates SCUBE2 methylation, and the mechanisms remain undefined. This study was designed to investigate the effect of EGCG on SCUBE2 methylation in breast cancer cells. We reveal that EGCG possesses a significantly inhibitory effect on cell viability in a dose- and time-dependent manner and presents more effects than other catechins. EGCG treatment resulted in enhancement of the SCUBE2 gene, along with elevated E-cadherin and decreased vimentin expression, leading to significant suppression of cell migration and invasion. The inhibitory effect of EGCG on SCUBE2 knock-down cells was remarkably alleviated. Further study demonstrated that EGCG significantly decreased the SCUBE2 methylation status by reducing DNA methyltransferase (DNMT) expression and activity. In summary, this study reported for the first time that SCUBE2 methylation can be reversed by EGCG treatment, finally resulting in the inhibition of breast cancer progression. These results suggest the epigenetic role of EGCG and its potential implication in breast cancer therapy.

scholarly journals Rosiglitazone Inhibits Adrenocortical Cancer Cell Proliferation by Interfering with the IGF-IR Intracellular Signaling

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-11 ◽  
Author(s):  
Giulia Cantini ◽  
Adriana Lombardi ◽  
Elisabetta Piscitelli ◽  
Giada Poli ◽  
Elisabetta Ceni ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Phosphatidyl Inositol ◽  
Inhibitory Effect ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Adrenocortical Cancer ◽  
Peroxisome Proliferator Activated Receptor ◽  
Igf I

Rosiglitazone (RGZ), a thiazolidinedione ligand of the peroxisome proliferator-activated receptor (PPAR)-γ, has been recently described as possessing antitumoral properties. We investigated RGZ effect on cell proliferation in two cell line models (SW13 and H295R) of human adrenocortical carcinoma (ACC) and its interaction with the signaling pathways of the activated IGF-I receptor (IGF-IR). We demonstrate a high expression of IGF-IR in the two cell lines and in ACC. Cell proliferation is stimulated by IGF-I in a dose- and time-dependent manner and is inhibited by RGZ. The analysis of the main intracellular signaling pathways downstream of the activated IGF-IR, phosphatidyl inositol 3-kinase (PI3K)-Akt, and extracellular signal-regulated kinase (ERK1/2) cascades reveals that RGZ rapidly interferes with the Akt and ERK1/2 phosphorylation/activation which mediates IGF-I stimulated proliferation. In conclusion, our results suggest that RGZ exerts an inhibitory effect on human ACC cell proliferation by interfering with the PI3K/Akt and ERK1/2 signaling pathways downstream of the activated IGF-IR.

scholarly journals Progesterone inhibits glucocorticoid-dependent aromatase induction in human adipose fibroblasts

1998 ◽  
Vol 158 (3) ◽  
pp. 401-407 ◽  
Author(s):  
M Schmidt ◽  
C Renner ◽  
G Loffler
Keyword(s):  
Adipose Tissue ◽  
Active Sites ◽  
Premenopausal Women ◽  
Human Adipose Tissue ◽  
Inhibitory Effect ◽  
Pcr Analysis ◽  
Aromatase Activity ◽  
Dependent Manner ◽  
Physiological Concentration ◽  
Intact Cells

In fibroblasts derived from human adipose tissue, aromatase induction is observed after exposure to 1 microM cortisol in the presence of serum or platelet-derived growth factor (PDGF). Progesterone suppresses this induction in a dose-dependent manner, 10 microM resulting in complete inhibition. A reduced cortisol concentration (0.1 microM) concomitantly reduces the progesterone concentration required for effective inhibition (10-100 nM). This effect of progesterone is specific, as neither the release of cellular enzymes nor aromatase induction by dibutyryl-cAMP, which acts independently from cortisol, are affected. However, the inhibitory effect of progesterone requires its presence throughout the induction period. Kinetic studies in intact cells reveal a reduced number of aromatase active sites upon progesterone treatment, whereas progesterone at near-physiological concentration (100 nM) does not inhibit aromatase activity in isolated microsomes. Semi-quantitative reverse transcriptase PCR analysis shows reduced amounts of aromatase mRNA in progesterone-treated cells, indicating specific inhibition of the glucocorticoid-dependent pathway of aromatase induction. The inhibitory effect of progesterone is not blocked by the anti-progestin ZK114043, excluding action via progesterone receptors and indicating competition for the glucocorticoid receptor. Progesterone must be considered a potential physiological inhibitor of glucocorticoid-dependent aromatase induction in adipose tissue. It is proposed that it is a suppressor of aromatase induction in adipose tissue in premenopausal women.

Use of the Peroxisome Proliferator-Activated Receptor (PPAR) γ Ligand Troglitazone as Treatment for Refractory Breast Cancer: A Phase II Study

2003 ◽  
Vol 79 (3) ◽  
pp. 391-397 ◽  
Author(s):  
Harold J. Burstein ◽  
George D. Demetri ◽  
Elisabetta Mueller ◽  
Pasha Sarraf ◽  
Bruce M. Spiegelman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ

PPAR-γ agonists inhibit toll-like receptor-mediated activation of dendritic cells via the MAP kinase and NF-κB pathways

Blood ◽  
2005 ◽  
Vol 106 (12) ◽  
pp. 3888-3894 ◽  
Author(s):  
Silke Appel ◽  
Valdete Mirakaj ◽  
Anita Bringmann ◽  
Markus M. Weck ◽  
Frank Grünebach ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Map Kinase ◽  
Lymphocyte Activation ◽  
Human Monocyte ◽  
Inhibitory Effect ◽  
Peroxisome Proliferator ◽  
Toll Like Receptor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Cytokines And Chemokines

Dendritic cells (DCs) play an important role in initiating and maintaining primary immune responses. However, mechanisms involved in the resolution of these responses are elusive. We analyzed the effects of 15d-PGJ2 and the synthetic peroxisome proliferator-activated receptor (PPAR)-γ ligand troglitazone (TGZ) on the immunogenicity of human monocyte-derived DCs upon stimulation with toll-like receptor (TLR) ligands. Activation of PPAR-γ resulted in a reduced stimulation of DCs via the TLR ligands 2, 3, 4, and 7, characterized by down-regulation of costimulatory and adhesion molecules and reduced secretion of cytokines and chemokines involved in T-lymphocyte activation and recruitment. MCP-1 (monocyte chemotactic protein-1) production was increased due to PPAR-γ activation. Furthermore, TGZ-treated DCs showed a significantly reduced capacity to stimulate T-cell proliferation, emphasizing the inhibitory effect of PPAR-γ activation on TLR-induced DC maturation. Western blot analyses revealed that these inhibitory effects on TLR-induced DC activation were mediated via inhibition of the NF-κB and mitogen-activated protein (MAP) kinase pathways while not affecting the PI3 kinase/Akt signaling. Our data demonstrate that inhibition of the MAP kinase and NF-κB pathways is critically involved in the regulation of TLR and PPAR-γ-mediated signaling in DCs.

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