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Fertility and Sterility Jul 2014To investigate the impact of liarozole on transforming growth factor-β3 (TGF-β3) expression, TGF-β3 controlled profibrotic cytokines, and extracellular matrix...
OBJECTIVE
To investigate the impact of liarozole on transforming growth factor-β3 (TGF-β3) expression, TGF-β3 controlled profibrotic cytokines, and extracellular matrix formation in a three-dimensional (3D) leiomyoma model system.
DESIGN
Molecular and immunohistochemical analysis in a cell line evaluated in a three-dimensional culture.
SETTING
Laboratory study.
PATIENT(S)
None.
INTERVENTION(S)
Treatment of leiomyoma and myometrial cells with liarozole and TGF-β3 in a three-dimensional culture system.
MAIN OUTCOME MEASURE(S)
Quantitative real-time reverse-transcriptase polymerase chain reaction and Western blotting to assess fold gene and protein expression of TGF-β3 and TGF-β3 regulated fibrotic cytokines: collagen 1A1 (COL1A1), fibronectin, and versican before and after treatment with liarozole, and confirmatory immunohistochemical stains of treated three-dimensional cultures.
RESULT(S)
Both TGF-β3 gene and protein expression were elevated in leiomyoma cells compared with myometrium in two-dimensional and 3D cultures. Treatment with liarozole decreased TGF-β3 gene and protein expression. Extracellular matrix components versican, COL1A1, and fibronectin were also decreased by liarozole treatment in 3D cultures. Treatment of 3D cultures with TGF-β3 increased gene expression and protein production of COL1A1, fibronectin, and versican.
CONCLUSION(S)
Liarozole decreased TGF-β3 and TGF-β3-mediated extracellular matrix expression in a 3D uterine leiomyoma culture system.
Topics: Antineoplastic Agents, Hormonal; Cell Culture Techniques; Collagen Type I; Collagen Type I, alpha 1 Chain; Down-Regulation; Extracellular Matrix; Female; Fibronectins; Humans; Imidazoles; Leiomyoma; Myometrium; Transforming Growth Factor beta3; Tumor Cells, Cultured; Uterine Neoplasms; Versicans
PubMed: 24825427
DOI: 10.1016/j.fertnstert.2014.03.042 -
The Journal of Investigative Dermatology Jan 2021Inhibition of CYP450-mediated retinoic acid (RA) metabolism by RA metabolism blocking agents increases endogenous retinoids and is an alternative to retinoid therapy.... (Review)
Review
Inhibition of CYP450-mediated retinoic acid (RA) metabolism by RA metabolism blocking agents increases endogenous retinoids and is an alternative to retinoid therapy. Currently available RA metabolism blocking agents (i.e., liarozole and talarozole) tend to have fewer adverse effects than traditional retinoids but lack target specificity. Substrate-based inhibitor DX314 has enhanced selectivity for RA-metabolizing enzyme CYP26B1 and may offer an improved treatment option for keratinization disorders such as congenital ichthyosis and Darier disease. In this study, we used RT-qPCR, RNA sequencing, pathway, upstream regulator, and histological analyses to demonstrate that DX314 can potentiate the effects of all-trans-RA in healthy and diseased reconstructed human epidermis. We unexpectedly discovered that DX314, but not all-trans-RA or previous RA metabolism blocking agents, appears to protect epidermal barrier integrity. In addition, DX314-induced keratinization and epidermal proliferation effects are observed in a rhino mice model. Altogether, the results indicate that DX314 inhibits all-trans-RA metabolism with minimal off-target activity and shows therapeutic similarity to topical retinoids in vitro and in vivo. Findings of a barrier-protecting effect require further mechanistic study but may lead to a unique strategy in barrier-reinforcing therapies. DX314 is a promising candidate compound for further study and development in the context of keratinization disorders.
Topics: Benzothiazoles; Cell Differentiation; Cytochrome P-450 Enzyme Inhibitors; Epidermis; Humans; Keratinocytes; Retinoic Acid 4-Hydroxylase; Skin Diseases; Triazoles
PubMed: 32505549
DOI: 10.1016/j.jid.2020.05.090 -
The British Journal of Dermatology Jan 2014Oral liarozole, a retinoic acid metabolism-blocking agent, may be an alternative to systemic retinoid therapy in patients with lamellar ichthyosis. (Randomized Controlled Trial)
Randomized Controlled Trial
Oral liarozole in the treatment of patients with moderate/severe lamellar ichthyosis: results of a randomized, double-blind, multinational, placebo-controlled phase II/III trial.
BACKGROUND
Oral liarozole, a retinoic acid metabolism-blocking agent, may be an alternative to systemic retinoid therapy in patients with lamellar ichthyosis.
OBJECTIVE
To demonstrate the efficacy and safety of once-daily oral liarozole in the treatment of moderate/severe lamellar ichthyosis.
METHODS
This was a double-blind, multinational, parallel phase II/III trial (NCT00282724). Patients aged ≥ 14 years with moderate/severe lamellar ichthyosis [Investigator's Global Assessment (IGA) score ≥ 3] were randomized 3 : 3 : 1 to receive oral liarozole (75 or 150 mg) or placebo once daily for 12 weeks. Assessments included: IGA; a five-point scale for erythema, scaling and pruritus severity; Short Form-36 health survey; Dermatology Life Quality Index (DLQI); and safety parameters. The primary efficacy variable was response rate at week 12 (responder: ≥ 2-point decrease in IGA from baseline).
RESULTS
Sixty-four patients were enrolled. At week 12, 11/27 (41%; liarozole 75 mg), 14/28 (50%; liarozole 150 mg) and one out of nine (11%; placebo) patients were responders; the difference between groups (liarozole 150 mg vs. placebo) was not significant (P = 0.056). Mean IGA and scaling scores decreased from baseline in both liarozole groups at weeks 8 and 12 vs. placebo; erythema and pruritus scores were similar between treatment groups. Improvement in DLQI score was observed in both liarozole groups. Treatment with liarozole for 12 weeks was well tolerated.
CONCLUSIONS
The primary efficacy variable did not reach statistical significance, possibly owing to the small sample size following premature termination. However, once-daily oral liarozole, 75 and 150 mg, improved scaling and DLQI and was well tolerated in patients with moderate/severe lamellar ichthyosis.
Topics: Administration, Oral; Adolescent; Adult; Aged; Dermatologic Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Ichthyosis, Lamellar; Imidazoles; Male; Middle Aged; Treatment Outcome; Young Adult
PubMed: 24102348
DOI: 10.1111/bjd.12626 -
The Journal of Investigative Dermatology Aug 1996Metabolic inactivation of all-trans retinoic acid to 4-hydroxy retinoic acid occurs via a cytochrome P-450 enzyme. We investigated the effects of liarozole on the...
Metabolic inactivation of all-trans retinoic acid to 4-hydroxy retinoic acid occurs via a cytochrome P-450 enzyme. We investigated the effects of liarozole on the retinoic acid 4-hydroxylase activity of human epidermis and its ability to modify in vivo human skin responses to retinoic acid and all-trans retinol. Retinoic acid 4-hydroxylase activity induced in vivo by 4 d treatment with retinoic acid (0.1%) was inhibited in vitro by liarozole in a concentration-dependent manner. Comparable micromolar concentrations of liarozole were extracted from stratum corneum-free epidermis treated with 3% liarozole. Retinoic acid levels in liarozole-treated skin increased to 19 +/- 5 ng/g wet wt (mean +/- SEM, p < 0.002, n = 17) at 18 h and to 6 +/- 2 ng/g wet wt (p = 0.38, n = 17) at 48 h as compared to vehicle (not detectable). At 48 h, retinoic acid 4-hydroxylase activity was induced 9-fold over vehicle (p < 0.03, n = 8). At 96 h, no significant erythema or increased epidermal thickness was found when either retinoic acid (0.001%), all-trans retinol (0.0250%), or liarozole (3%) was applied individually, but when 0.001% retinoic acid and 3% liarozole were applied together, both erythema and increased epidermal thickness occurred. In contrast, 0.025% all-trans retinol and 3% liarozole together caused increased epidermal thickness but no erythema. These data demonstrate that, at doses used here, liarozole, although an effective inhibitor of retinoic acid 4-hydroxylase, cannot function alone like a retinoid in vivo, probably because of retinoic acid 4-hydroxylase induction. In the presence of a low dose retinoic acid or all-trans retinol, however, liarozole can amplify human skin responses to each retinoid in a manner characteristic of the retinoid at a higher dose (erythema and hyperplasia with retinoic acid; no erythema but hyperplasia with all-trans retinol).
Topics: Androgen Antagonists; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Drug Synergism; Epidermis; Humans; Imidazoles; Retinoic Acid 4-Hydroxylase; Skin; Tretinoin; Vitamin A
PubMed: 8757760
DOI: 10.1111/1523-1747.ep12329579 -
Acta Dermato-venereologica 2009Lamellar ichthyosis is a keratinization disorder caused by TGM1, Ichthyin and several other gene mutations. A new treatment option is liarozole, which blocks the... (Randomized Controlled Trial)
Randomized Controlled Trial
Lamellar ichthyosis is a keratinization disorder caused by TGM1, Ichthyin and several other gene mutations. A new treatment option is liarozole, which blocks the cytochrome P450 (CYP26)-mediated catabolism of endogenous all-trans retinoic acid. This study focuses on the expression of retinoid-related genes in ichthyotic epidermis before and after treatment with oral liarozole. We first compared the mRNA expression of cellular retinoic acid binding protein II (CRABPII), keratin (KRT) 2 and 4, CYP26A1 and B1, and two markers of inflammation (interleukin-1alpha and tumours necrosis factor (TNF)-alpha) in shave biopsies from 11 genetically defined, untreated patients and 12 age- and sex-matched healthy controls, finding no overt differences between the groups, besides elevated CRABPII expression. We then studied the biomarkers before and after 4 weeks of treatment with liarozole (75 or 150 mg/day), which produced a better therapeutic response in patients with Ichthyin (n=3) than in those with TGM1 (n=6) mutations. A significant decrease in the mRNA expression of KRT2 and TNF-alpha, and trends toward increased expression of KRT4 and CYP26A1 were observed in liarozole-treated patients, consistent with an increased retinoid stimulation of epidermis. However, there were no dose-related responses and the results of the immunostaining did not always parallel the mRNA findings. The results suggest that liarozole exerts a therapeutic effect in lamellar ichthyosis by mildly affecting the expression of retinoid- regulated genes in epidermis.
Topics: Administration, Oral; Adolescent; Adult; Aged; Biomarkers; Dermatologic Agents; Double-Blind Method; Female; Humans; Ichthyosis, Lamellar; Imidazoles; Interleukin-1alpha; Male; Middle Aged; Polymerase Chain Reaction; RNA, Messenger; Receptors, Retinoic Acid; Skin; Tretinoin; Tumor Necrosis Factor-alpha
PubMed: 19197536
DOI: 10.2340/00015555-0573 -
BMC Cancer Jan 2007Liarozole fumarate (liarozole--R85246) is a novel compound with characteristics of both aromatase inhibitor (AI) and a retinoic acid metabolism blocking agent (RAMBA)....
BACKGROUND
Liarozole fumarate (liarozole--R85246) is a novel compound with characteristics of both aromatase inhibitor (AI) and a retinoic acid metabolism blocking agent (RAMBA). Our objective was to determine the effects of liarozole alone or in combination with tamoxifen on the N-methyl-N-nitrosourea (MNU)-induced rat mammary carcinoma model, as well as on the uterus in ovariectomized immature rats.
METHODS
(1) Tumor burden experiments: Animals bearing one or more tumors greater than 10 mm in diameter were treated for 56 consecutive days with 20 mg/kg or 80 mg/kg of liarozole by oral gavage, tamoxifen 100 mug/kg by subcutaneous injection, or a combination of liarozole and tamoxifen. At the end of the treatment period, total cumulative tumor volume as well as retinoic acid levels were measured. (2) Uterotrophic assay and proliferation experiments: 21-day-old ovariectomized (OVX) Sprague-Dawley rats were treated with 20 mg/kg or 80 mg/kg of liarozole by oral gavage, tamoxifen 1 mg/kg by subcutaneous injection, and combination of both for 4 consecutive days. At the end of the treatment period, uterine weight, epithelial lining cell height and indices of proliferation cell nuclear antigen (PCNA) were measured.
RESULTS
The tumor burden experiments in rats bearing estrogen receptor (ER) positive mammary tumours showed that liarozole has a marked anti-tumour effect. In combination with tamoxifen, liarozole had neither an additive nor an antagonistic effect. However, liarozole markedly reduced the uterotrophic effects induced by tamoxifen.
CONCLUSION
Liarozole's antitumor effects on ER positive mammary tumors and its protective effect on the uterus merit further studies to confirm its clinical value in combination with tamoxifen in ER positive postmenopausal breast cancer. Liarozole and other retinomimetics might also be suitable chemoprevention drugs in combination with tamoxifen because of their favorable toxicity profile.
Topics: Animals; Breast Neoplasms; Cell Proliferation; Disease Models, Animal; Drug Therapy, Combination; Female; Imidazoles; Methylnitrosourea; Ovariectomy; Rats; Rats, Sprague-Dawley; Tamoxifen; Uterus
PubMed: 17266767
DOI: 10.1186/1471-2407-7-26 -
Fertility and Sterility Dec 2012To study the influence of liarozole on leiomyoma cell proliferation and extracellular matrix (ECM) gene expression in immortalized leiomyoma cells.
OBJECTIVE
To study the influence of liarozole on leiomyoma cell proliferation and extracellular matrix (ECM) gene expression in immortalized leiomyoma cells.
DESIGN
Laboratory study.
SETTING
University hospital.
PATIENT(S)
None.
INTERVENTION(S)
Tissue culture, real-time reverse transcription-polymerase chain reaction, Western blot.
MAIN OUTCOME MEASURE(S)
Proliferation, messenger RNA (mRNA), and ECM protein expression.
RESULT(S)
Proliferation of leiomyoma cells was inhibited by treatment with liarozole at suprapharmacologic concentrations. The mRNA and protein expression of COL1A1, COL4A2, versican, fibromodulin, and fibronectin was increased in untreated leiomyoma cells compared with untreated patient-matched myometrial cells. Extracellular matrix mRNA expression was decreased in a dose-dependent manner in leiomyoma cells treated with pharmacologic concentrations of liarozole. In addition, myometrial cells treated with liarozole demonstrated no statistically significant alteration in ECM regulation.
CONCLUSION(S)
Liarozole inhibited ECM protein production at pharmacologic concentrations in immortalized human leiomyoma cells. Retinoic acid metabolic blocking agents represent a potential therapeutic drug family for human leiomyomas.
Topics: Antineoplastic Agents, Hormonal; Cell Proliferation; Dose-Response Relationship, Drug; Extracellular Matrix; Extracellular Matrix Proteins; Female; Humans; Imidazoles; Leiomyoma; Tretinoin; Tumor Cells, Cultured; Uterine Neoplasms
PubMed: 22925684
DOI: 10.1016/j.fertnstert.2012.07.1132 -
The British Journal of Dermatology Jan 1997Liarozole, a novel imidazole derivative, inhibits the cytochrome P450-dependent 4-hydroxylation of retinoic acid, resulting in increased tissue levels of retinoic acid.... (Clinical Trial)
Clinical Trial
Liarozole, a novel imidazole derivative, inhibits the cytochrome P450-dependent 4-hydroxylation of retinoic acid, resulting in increased tissue levels of retinoic acid. Twelve male patients with ichthyosis were given oral liarozole, 150 mg twice daily, in an open study for 12 weeks. Immunohistochemical parameters of inflammation, epidermal proliferation and differentiation were assessed before and after treatment. Extent and severity of the skin lesions was markedly reduced in all patients. Clinical side-effects were reminiscent of those with synthetic retinoids. No relevant changes were found in the haematological, urinary and biochemical parameters. Immunohistochemical assessment showed a statistically significant induction of keratin 4 after liarozole treatment in 10 of 12 patients. In two of these patients keratin 13 was induced. This open study showed that oral liarozole treatment was efficacious and well tolerated in the treatment of different types of ichthyosis. The immunohistochemical results suggest a retinoid mechanism as the mode of action.
Topics: Adolescent; Adult; Aged; Androgen Antagonists; Cytochrome P-450 Enzyme Inhibitors; Follow-Up Studies; Humans; Ichthyosis; Imidazoles; Keratins; Male; Middle Aged; Prospective Studies; Severity of Illness Index
PubMed: 9039298
DOI: No ID Found -
Toxicology and Applied Pharmacology Apr 2024Cytochrome P450 enzymes (CYPs) play a crucial role in the metabolism and synthesis of various compound classes. While drug-metabolizing CYP enzymes are frequently...
Cytochrome P450 enzymes (CYPs) play a crucial role in the metabolism and synthesis of various compound classes. While drug-metabolizing CYP enzymes are frequently investigated as anti-targets, the inhibition of CYP enzymes involved in adrenal steroidogenesis is not well studied. The steroidogenic enzyme CYP17A1 is a dual-function enzyme catalyzing hydroxylase and lyase reactions relevant for the biosynthesis of adrenal glucocorticoids and androgens. Inhibition of CYP17A1-hydroxylase leads to pseudohyperaldosteronism with subsequent excessive mineralocorticoid receptor activation, hypertension and hypokalemia. In contrast, specific inhibition of the lyase function might be beneficial for the treatment of prostate cancer by decreasing adrenal androgen levels. This study combined in silico and in vitro methods to identify drugs inhibiting CYP17A1. The most potent CYP17A1 inhibitors identified are serdemetan, mocetinostat, nolatrexed, liarozole, and talarozole. While some of these drugs are currently under investigation for the treatment of various cancers, their potential for the treatment of prostate cancer is yet to be explored. The DrugBank database was screened for CYP17A1 inhibitors, to increase the awareness for the risk of drug-induced pseudohyperaldosteronism and to highlight drugs so far unknown for their potential to cause side effects resulting from CYP17A1 inhibition.
PubMed: 38688424
DOI: 10.1016/j.taap.2024.116945 -
Substrate specificity and ligand interactions of CYP26A1, the human liver retinoic acid hydroxylase.Molecular Pharmacology Aug 2011All-trans-retinoic acid (atRA) is the active metabolite of vitamin A. atRA is also used as a drug, and synthetic atRA analogs and inhibitors of retinoic acid (RA)... (Comparative Study)
Comparative Study
All-trans-retinoic acid (atRA) is the active metabolite of vitamin A. atRA is also used as a drug, and synthetic atRA analogs and inhibitors of retinoic acid (RA) metabolism have been developed. The hepatic clearance of atRA is mediated primarily by CYP26A1, but design of CYP26A1 inhibitors is hindered by lack of information on CYP26A1 structure and structure-activity relationships of its ligands. The aim of this study was to identify the primary metabolites of atRA formed by CYP26A1 and to characterize the ligand selectivity and ligand interactions of CYP26A1. On the basis of high-resolution tandem mass spectrometry data, four metabolites formed from atRA by CYP26A1 were identified as 4-OH-RA, 4-oxo-RA, 16-OH-RA and 18-OH-RA. 9-cis-RA and 13-cis-RA were also substrates of CYP26A1. Forty-two compounds with diverse structural properties were tested for CYP26A1 inhibition using 9-cis-RA as a probe, and IC(50) values for 10 inhibitors were determined. The imidazole- and triazole-containing inhibitors [S-(R*,R*)]-N-[4-[2-(dimethylamino)-1-(1H-imidazole-1-yl)propyl]-phenyl]2-benzothiazolamine (R116010) and (R)-N-[4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]-2-benzothiazolamine (R115866) were the most potent inhibitors of CYP26A1 with IC(50) values of 4.3 and 5.1 nM, respectively. Liarozole and ketoconazole were significantly less potent with IC(50) values of 2100 and 550 nM, respectively. The retinoic acid receptor (RAR) γ agonist CD1530 was as potent an inhibitor of CYP26A1 as ketoconazole with an IC(50) of 530 nM, whereas the RARα and RARβ agonists tested did not significantly inhibit CYP26A1. The pan-RAR agonist 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid and the peroxisome proliferator-activated receptor ligands rosiglitazone and pioglitazone inhibited CYP26A1 with IC(50) values of 3.7, 4.2, and 8.6 μM, respectively. These data demonstrate that CYP26A1 has high ligand selectivity but accepts structurally related nuclear receptor agonists as inhibitors.
Topics: Animals; Cell Line; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Humans; Ketoconazole; Ligands; Liver; Mixed Function Oxygenases; Protease Inhibitors; Rats; Retinoic Acid 4-Hydroxylase; Substrate Specificity; Tretinoin
PubMed: 21521770
DOI: 10.1124/mol.111.072413