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PubMed1979

[Side effects of oral retinoid Ro 10-9359 on the unaffected skin of psoriatic patients: retinoid dermatitis].

Dermatitis occurring as a side effect in psoriatic patients during oral administration of the retinoid acid derivative Ro 10-9359 is described. This so-called retinoid dermatitis exhibits a characteristic disseminated pattern. Sites of predilection are the face, the exterior surface of the upper and the interior surface of the lower arms, the superior thoracic aperture, the back of the hands and the flanks. The lesions present as follicular papules and/or vesicles. The histological picture is that of acute non-specific dermatitis. This retinoid dermatitis was observed in 9 our of 23 patients (39%) treated with Ro 10-9359. Other side effect such as erythema, desquamation, itching and, rarely, a burning sensation showed the same distribution. The characteristic dermatitis, as well as the other side effects mentioned, occur dose-dependently within the normal therapeutic range of Ro 10-9359 for psoriasis (0.5--1 mg/kg bodyweight daily).

Administration, Oral↗
PubMed1993

Fatty acids and retinoids control lipid metabolism through activation of peroxisome proliferator-activated receptor-retinoid X receptor heterodimers.

The nuclear hormone receptors called PPARs (peroxisome proliferator-activated receptors alpha, beta, and gamma) regulate the peroxisomal beta-oxidation of fatty acids by induction of the acyl-CoA oxidase gene that encodes the rate-limiting enzyme of the pathway. Gel retardation and cotransfection assays revealed that PPAR alpha heterodimerizes with retinoid X receptor beta (RXR beta; RXR is the receptor for 9-cis-retinoic acid) and that the two receptors cooperate for the activation of the acyl-CoA oxidase gene promoter. The strongest stimulation of this promoter was obtained when both receptors were exposed simultaneously to their cognate activators. Furthermore, we show that natural fatty acids, and especially polyunsaturated fatty acids, activate PPARs as potently as does the hypolipidemic drug Wy 14,643, the most effective activator known so far. Moreover, we discovered that the synthetic arachidonic acid analogue 5,8,11,14-eicosatetraynoic acid is 100 times more effective than Wy 14,643 in the activation of PPAR alpha. In conclusion, our data demonstrate a convergence of the PPAR and RXR signaling pathways in the regulation of the peroxisomal beta-oxidation of fatty acids by fatty acids and retinoids.

Animals↗
PubMed1995

Retinoid activation of retinoic acid receptors but not of retinoid X receptors promotes cellular differentiation and replication of human cytomegalovirus in embryonal cells.

The susceptibility of human embryonal cell line NT-2/D1 to replicate human cytomegalovirus (hCMV) is dependent on retinoic acid (RA) stimulation. Physiological responses to retinoic acid involve two distinct subfamilies of nuclear receptors, the RA receptors (RARs) and retinoid X receptors (RXRs), which function by activating transcription as heterodimeric or RXR homodimeric complexes from cis-acting DNA response elements. At present, it is not clear whether the association between these two classes of receptors can lead to multiple distinct induction pathways by signalling one or both receptor partners. Here we have determined, by selectively activating endogenous receptors with novel synthetic ligands specific for either RARs or RXRs, what ligand interaction is physiological in the retinoid receptor pathways necessary for inducing replication of hCMV in differentiated embryonal cells. We show that ligand binding to RAR alone is sufficient and that exclusive ligand activation of RXR is insufficient for inducing replication of hCMV. We also find that differentiation and inhibition of NT-2/D1 cell growth are promoted by compounds that signal the RAR pathway. These results provide direct evidence that RAR ligand-mediated physiological responses are separable and distinct from RXR ligand activation functions. Moreover, our results provide insight into a hormone response pathway for cellular differentiation that might be coopted by hCMV in the host.

Cell Differentiation↗
PubMed1993

DNA bending by retinoid X receptor-containing retinoid and thyroid hormone receptor complexes.

Retinoid X receptors (RXR) have been identified as common subunits in the regulation of multiple hormonal signaling pathways. Using circular permutation and phasing analysis of specific response elements, we present evidence that RXR-retinoic acid receptor and RXR-thyroid hormone receptor heterodimer or RXR-RXR homodimer complexes induce directed DNA bends when bound to their cognate response elements. The extent of DNA bending induced by the RXR alpha-containing complexes varied and depended on the structure of the DNA-binding sites and the RXR partners. The overall bending orientation for RXR-containing complexes is directed toward the major groove of the DNA helix at the center of hormone response elements. Our observation implicates DNA bending as a possible mechanism underlying transcriptional regulation of distinct retinoid and thyroid hormone responsive genes.

Base Sequence↗
PubMed2005

DNA methylation of genes linked with retinoid signaling in gastric carcinoma: expression of the retinoid acid receptor beta, cellular retinol-binding protein 1, and tazarotene-induced gene 1 genes is associated with DNA methylation.

BACKGROUND: Hypermethylation of CpG islands has been associated with silencing of various tumor suppressor genes, and the retinoid acid receptor beta (RARbeta), cellular retinol-binding protein 1 (CRBP1), and tazarotene-induced gene 1 (TIG1) genes have been associated with retinoic acid signaling. To the authors' knowledge, little is known regarding the involvement of these three genes in gastric carcinoma (GC). In this study, the authors investigated the methylation status of these genes and analyzed the role of their DNA methylation in GC. METHODS: DNA methylation of 3 retinoic acid-associated genes was analyzed in 42 samples of GC from 42 patients and in 8 GC cell lines by methylation-specific polymerase chain reaction (PCR) analysis. The mRNA expression levels for these three genes were measured by quantitative reverse transcription-PCR. RESULTS: In 7 of 8 GC cell lines, the CRBP1 gene was hypermethylated, and CRBP1 transcription was inactive. In 6 of 8 GC cell lines, the TIG1 gene was hypermethylated, and TIG1 transcription was inactive. Treatment with demethylating agent 5-aza-2'-deoxycytidine restored both CRBP1 and TIG1 transcription. DNA methylation of the RARbeta, CRBP1, and TIG1 genes was detected in 15 of 42 GC samples (36%), 14 of 42 GC samples (33%), and 4 of 42 GC samples (10%), respectively, and in 6 of 30 samples (20%), 0 of 30 samples (0%), and 1 of 30 samples (3%) of corresponding nonneoplastic mucosa. None of the 10 normal gastric mucosa samples from young, healthy individuals demonstrated hypermethylation of any of these genes. DNA methylation of each gene was associated significantly with low mRNA expression of the respective gene. Twenty-four of 42 GC samples (57%) demonstrated hypermethylation of at least 1 of the 3 genes. However, no significant, concordant hypermethylation of these genes was observed. CONCLUSIONS: The results suggested that gastric carcinogenesis involves transcriptional inactivation by aberrant DNA methylation of genes related to retinoid signaling.

Adenocarcinoma↗
PubMedDate not supplied

Potential anti-inflammatory effects of topical retinoids and retinoid analogues.

The topical retinoid tretinoin and topical retinoid analogues such as adapalene and tazarotene help normalize hyperkeratinization in acne vulgaris and have demonstrated significant anti-inflammatory effects in experimental trials. Inhibition of various immune factors, including the activity of leukocytes, the release of proinflammatory cytokines and other mediators, and the expression of transcription factors and toll receptors involved in immunomodulation, has emerged in both in vitro studies and in vivo animal experiments. These multiple mechanisms of action should encourage clinicians to consider these agents in the first-line management of inflammatory acne lesions.

Adapalene↗
PubMed1995

On the role of ligand in retinoid signaling: positive cooperativity in the interactions of 9-cis retinoic acid with tetramers of the retinoid X receptor.

Previously, we have shown that the retinoid X receptor (RXR) forms tetramers with a high affinity and that interactions of the receptor with its ligand, 9-cis retinoic acid (9cRA), result in dissociation of protein tetramers. Here it is shown by fluorescence anisotropy studies that ligand-induced tetramer dissociation displays a pronounced positive cooperativity. The binding affinity of RXR for 9cRA at low saturation levels of the receptor with ligand was found to be significantly weaker than the affinity observed at higher levels of saturation. In addition, the rate of dissociation of 9cRA from RXR was found to be faster at low vs. high saturation levels of the receptor. These data suggest that the observed positive cooperativity of the ligand-induced dissociation of RXR tetramers stems from positive cooperativity in binding of 9cRA by the receptor. Kinetic studies showed that dissociation of RXR tetramers upon ligand binding is a rapid reaction characterized by a t1/2 of 80 ms, which is about 5 orders of magnitude faster than the rate of dissociation in the absence of ligand. The data indicate that the oligomeric state of RXR is tightly regulated by the precise concentrations of 9cRA and that it rapidly responds to changes in the ligand's concentrations. These findings further substantiate the hypothesis that modulation of the oligomeric state of RXR by 9cRA is an important regulatory step in the pathway by which retinoids affect gene transcription.

Fluorescence Polarization↗
PubMed1989

Effect of structural modifications in the C7-C11 region of the retinoid skeleton on biological activity in a series of aromatic retinoids.

A series of conformationally restricted analogues of (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)propenyl ] benzoic acid--(E)-4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2 - propenyl]benzoic acid, (E)-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-bu ten- 2-yl]benzoic acid, trans-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) cyclopropyl]benzoic acid, 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)benzoic acid, 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2- naphthalenecarboxylic acid, 6-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-2- naphthalenecarboxylic acid and 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-5-methyl-2- naphthalenecarboxylic acid--were synthesized and screened for retinoid biological activity. Comparison of the conformers of these analogues generated by molecular mechanics calculations with the biological activity profiles of these compounds indicates that geometric constraints required for high biological activity are imposed on the bridge joining the two aromatic ring systems by the retinoid receptor.

Animals↗
PubMed2002

Stereoselective synthesis of annular 9-cis-retinoids and binding characterization to the retinoid X receptor.

Analogues of 9-cis-retinoic acid incorporating an alicyclic ring between the C19 and C10 positions have been synthesized and evaluated as ligands for the RXRalpha nuclear receptor. The stereocontrolled synthesis of these configurationally constrained retinoids combines a Stille cross-coupling and the Wittig reaction as key bond-forming steps. The palladium-catalyzed cross-coupling reaction of the beta-bromo-alpha,beta-unsaturated aldehydes 5 to dienylstannane 6 is very fast at room temperature, and takes place with preservation of the dienylstannane geometry. A highly stereoselective Wittig reaction afforded the C7-C8 bond connecting the hydrophobic ring to the retinoid side chain. The binding affinities of these compounds for the receptor were determined, and the structural and energetic rationale behind the affinity profile of the cyclic 9-cis-retinoic acid derivatives for the RXRalpha nuclear receptor was characterized by using Molecular Mechanics protocols.

Alitretinoin↗
PubMed2003

Functional specificity of two hormone response elements present on the human apoA-II promoter that bind retinoid X receptor alpha/thyroid receptor beta heterodimers for retinoids and thyroids: synergistic interactions between thyroid receptor beta and upstream stimulatory factor 2a.

DNA binding and mutagenesis in vitro established that the -67/-55 region of the apoA-II (apolipoprotein A-II) promoter contains a thyroid HRE (hormone response element), which strongly binds RXRalpha (retinoid X receptor alpha)/T(3)Rbeta (thyroid receptor beta) heterodimers and weakly T(3)Rbeta homodimers, but does not bind other homo- or heterodimers of RXRalpha or orphan nuclear receptors. Transactivation was abolished by point mutations in the thyroid HRE. In co-transfection experiments of HEK-293 (human embryonic kidney 293) cells, the -911/+29 human apoA-II promoter was transactivated strongly by RXRalpha/T(3)Rbeta heterodimers in the presence of RA (9- cis retinoic acid) or T(3) (tri-iodothyronine). Homopolymeric promoters containing either three copies of the -73/-40 (element AIIAB) or four copies of the -738/-712 (element AIIJ) apoA-II promoter could be transactivated by RXRalpha/T(3)Rbeta heterodimers in COS-7 cells only in the presence of T(3) or RA respectively. RXRalpha/T(3)Rbeta heterodimers and USF2a (upstream stimulatory factor 2a) synergistically transactivated the -911/+29 apoA-II promoter in the presence of T(3). USF2a also enhanced the activity of a GAL4-T(3)Rbeta fusion protein in the presence of T(3) and suppressed the activity of a GAL4-RXRalpha fusion protein in the presence of RA. These findings suggest a functional specificity of the two HREs of the apoA-II promoter for retinoids and thyroids, which is modulated by synergistic or antagonistic interactions between RXRalpha/T(3)Rbeta heterodimers and the ubiquitous transcription factor USF2a.

Alitretinoin↗
PubMed1984

Lack of an effect of dietary retinoids in chemical carcinogenesis of the mouse mammary gland: inverse relationship between mammary tumor cell anaplasia and retinoid efficacy.

Feeding of retinyl acetate (0.2 mM) or N-(4-hydroxyphenyl) retinamide (4-HPR) (1.0 mM) for 27 weeks to female BD2F1 mice previously treated with a series of gastric intubations of 7,12-dimethylbenzanthracene (DMBA), did not significantly affect the incidence of mammary tumors. In the retinyl acetate study, 75 retinyl acetate fed mice developed 31 mammary adenocarcinomas and 19 mammary adenoacanthomas (50 total mammary tumors) while 75 control mice developed 22 mammary adenocarcinomas and 20 mammary adenoacanthomas (42 total mammary tumors). In the 4-HPR study, 74 4-HPR fed mice developed 45 mammary adenocarcinomas and 41 mammary adenoacanthomas (86 total mammary tumors) while 74 control mice developed 29 mammary adenocarcinomas and 44 mammary adenoacanthomas (73 total mammary tumors). Retinoid treatments did not significantly affect body weight gains or mortality rates. These results provide evidence that carcinogen induced mouse mammary gland tumorigenesis in vivo is not influenced by hyperalimentation of dietary retinoids.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2006

Antitumor activity of the retinoid-related molecules (E)-3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid (ST1926) and 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) in F9 teratocarcinoma: Role of retinoic acid receptor gamma and retinoid-independent pathways.

The retinoid-related molecules (RRMs) ST1926 [(E)-3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid] and CD437 (6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid) are promising anticancer agents. We compared the retinoic acid receptor (RAR) trans-activating properties of the two RRMs and all-trans-retinoic acid (ATRA). ST1926 and CD437 are better RARgamma agonists than ATRA. We used three teratocarcinoma cell lines to evaluate the significance of RARgamma in the activity of RRMs: F9-wild type (WT); F9gamma-/-, lacking the RARgamma gene; F9gamma51, aF9gamma-/-derivative, complemented for the RARgamma deficit. Similar to ATRA, ST1926 and CD437 activate cytodifferentiation only in F9-WT cells. Unlike ATRA, ST1926 and CD437 arrest cells in the G2/M phase of the cell cycle and induce apoptosis in all F9 cell lines. Our data indicate that RARgamma and the classic retinoid pathway are not relevant for the antiproliferative and apoptotic activities of RRMs in vitro. Increases in cytosolic calcium are fundamental for apoptosis, in that intracellular calcium chelators abrogate the process. Comparison of the gene expression profiles associated with ST1926 and ATRA in F9-WT and F9gamma-/-indicates that the RRM activates a conspicuous nonretinoid response in addition to the classic and RAR-dependent pathway. The pattern of genes regulated by ST1926 selectively, in a RARgamma-independent manner, provides novel insights into the possible molecular determinants underlying the activity of RRMs in vitro. Furthermore, it suggests that RARgamma-dependent responses are relevant to the activity of RRMs in vivo. Indeed, the receptor hinders the antitumor activity in vivo, in that both syngeneic and immunosuppressed SCID mice bearing F9gamma-/- tumors have increased life spans after treatment with ST1926 and CD437 relative to their F9-WT counterparts.

Adamantane↗
PubMed1999

Overexpression of retinoic acid receptor beta in head and neck squamous cell carcinoma cells increases their sensitivity to retinoid-induced suppression of squamous differentiation by retinoids.

Nuclear retinoic acid receptor beta(RARbeta) expression is suppressed in many head and neck squamous cell carcinomas (HNSCCs), and an inverse relationship was found between squamous differentiation and RARbeta expression in such cells. To investigate the role of RARbeta in HNSCC growth and differentiation, we transfected a retroviral RARbeta2 expression vector (LNSbeta) into HNSCC SqCC/Y1 cells, which do not express endogenous RARbeta but do express RARalpha, RARgamma, and retinoid X receptors. Transfected clones expressing RARbeta2 mRNA and protein exhibited enhanced sensitivity to the suppressive effects of all-trans-retinoic acid (ATRA) on squamous differentiation compared with cells transfected with the LNSX vector only; transglutaminase type I level was suppressed after a 3-day treatment with 10(-10) M ATRA in four of five LNSbeta clones, whereas it was not suppressed in LNSX cells even by 10(-6) M ATRA. Similarly, cytokeratin 1 mRNA level was more suppressed in ATRA-treated LNSbeta clones than it was in LNSX cells. This effect was independent of transrepression of activator protein-1. None of the LNSbeta-transfected clones showed an increased growth inhibition by ATRA, 9-cis-retinoic acid, or the synthetic retinoid 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-naphthale necarboxylic acid. These findings suggest that, in SqCC/Y1 cells, RARbeta mediates suppression of squamous differentiation by ATRA without enhancing its growth-inhibitory effects.

3T3 Cells↗
PubMed1992

Enhanced HIV-1 replication in retinoid-treated monocytes. Retinoid effects mediated through mechanisms related to cell differentiation and to a direct transcriptional action on viral gene expression.

Vitamin A and other retinoids have profound effects on macrophage differentiation and function. Such effects could alter interactions between HIV and tissue macrophages, a principal target cell and reservoir for virus during HIV disease. Indeed, retinoids are used to treat various symptoms associated with HIV infection. We show that levels of virus replication in monocytes cultured 7 days before and continuously after HIV infection in 1 to 10 microM retinoic acid were 10- to 20-fold greater than those of control cells. No direct toxicity (detachment from substrate or cell death) was evident in infected or control monocytes treated with less than or equal to 10 microM retinoic acid. Maximum effects of retinoic acid (50% maximum effect was at 0.8 +/- 0.1 microM) required 5 to 7 days treatment before infection and persisted without additional treatment through more than 4 wk. RT activity in cultures of retinoic acid-treated monocytes reached maximum levels much earlier than those of control cultures, but the minimum tissue culture infectious doses for retinoic acid-treated and untreated monocytes were comparable. Retinoic acid treatment did not affect susceptibility of monocytes to HIV infection. Further, the frequency of infected cells in retinoic acid-treated and control cultures were also comparable: about 20% of cells in each culture expressed HIV proteins or RNA 2 wk after infection. In contrast, levels of HIV-specific RNA and DNA were 3- to 5-fold higher in the retinoic acid-treated over control monocytes 1 wk after infection. That retinoic acid increased levels of HIV gene expression in monocyte cultures without affecting the number of infected cells per culture suggested a transcriptional mechanism for the effect. This was confirmed in the U937 myeloid cell line transfected with HIV LTR linked to a chloramphenicol acetyl transferase reporter gene. Chloramphenicol acetyl transferase activity in lysates of retinoic acid-treated cells were 20-fold higher than that of control cells. These data show that retinoic acid significantly increased HIV replication in monocytes through mechanisms related to cell differentiation and to a direct transcriptional effect on viral gene expression.

Cell Differentiation↗
PubMed1995

Retinoic acid receptors and retinoid binding proteins in endometrial adenocarcinoma: differential expression of cellular retinoid binding proteins in endometrioid tumours.

Retinoic acid is apparently required for the normal differentiation of reproductive epithelium. Cellular abnormalities in retinoid homeostasis could be a factor in the development of endometrial malignancy. We have thus investigated the expression of nuclear retinoic acid receptors (RARs and RXRs) and cellular binding proteins for retinol (CRBP) and retinoic acid (CRABP) in endometrial adenocarcinoma of the endometrioid histological subtype. Ten grade I, II grade 2 and 10 grade 3 tumour samples, as well as 4 samples of severe atypical precancerous endometrial hyperplasia, were studied. No significant difference in expression of RAR-beta was detected in tumour samples compared with normal epithelial cells. RAR-gamma was significantly elevated in grade 1 and 2 carcinomas, but this may be due to greater stromal cell involvement in these lower grade tumours. There was significant elevation of CRBP I mRNA in tumour samples. Furthermore, although undetectable in normal endometrial epithelium, CRABP I was expressed in 3/II grade 2 and 9/10 grade 3 carcinomas, with expression being significantly higher where the primary tumour had invaded more than 50% of the total myometrial thickness. Analysis of 2 epithelial-like endometrial adenocarcinoma cell lines supported the idea that CRABP I expression is characteristic of poorly differentiated endometrial adenocarcinoma. Our data suggest that alterations in mechanisms of retinoid homeostasis are a feature of endometrial adenocarcinoma and may contribute to the severity of disease.

Adenocarcinoma↗
PubMed1996

Retinoids as Ig isotype-switch modulators. The role of retinoids in directing isotype switching to IgA and IgG1 (IgE) in association with IL-4 and IL-5.

The role of retinoids was analyzed in directing isotype switching to IgA and IgG1 (IgE) by LPS-stimulated murine mu(+)B-cells in the presence of two Th2-type cytokines, IL-4 and IL-5. All trans retinoic acid (RA) enhanced the production of IgA at high concentrations (10-100 nM) in the presence of IL-5. Addition of IL-4 to the system modulated the IgA response in a dose-dependent manner. Namely, IL-4 inhibited the response at concentrations higher than 250 u/ml, but showed slight enhancement at lower concentrations (130 u/ml). IL-4 alone, which is considered to be an IgE isotype-switch inducer, strongly enhanced the IgG1 and IgE responses. Addition of IL-5 to the system showed a synergistic effect which could be attenuated by addition of low concentrations of RA (about 1 nM). Thus, the presence of switch modulators such as IL-4 and IL-5, their concentration ratios, and concentrations of retinoids are crucial factors in initiating and directing isotype switching to IgA and IgG1 (IgE).

Animals↗
PubMed1997

Retinoid binding-proteins redirect retinoid metabolism: biosynthesis and metabolism of retinoic acid.

Many tissues and cell types, starting early in embryogenesis, convert retinol (vitamin A) into an active form, all-trans-retinoic acid. This article will discuss a current model of retinol and retinoic acid metabolism that integrates the various reactions which maintain retinoic acid homeostasis, and will also integrate the enzymology with the functions of cellular retinoid binding proteins. These conserved, high-affinity binding proteins enjoy widespread expression throughout all vertebrates and throughout most vertebrate tissues. The binding proteins limit access to retinol and retinoic acid to select enzymes and serve as substrates and affecters of retinoid metabolism.

Journal Article↗