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PubMed1990

Differentiation of F9 embryonal carcinoma cells by synthetic retinoids: amplitude of plasminogen activator production does not depend on retinoid potency or affinity for F9 nuclear retinoic acid receptors.

Retinoic acid and analogues (retinoids) are able to induce the differentiation of F9 murine embryonal carcinoma stem cells into endoderm-like cells. The secretion of plasminogen activator (PA) which accompanies this differentiation is a good index of the biological response of F9 cells to retinoids. We have previously reported that the potency of a series of natural and synthetic retinoids, evaluated by the concentration which provokes half-maximal induction of PA, correlates well with the affinity of these compounds for the endogenous F9 nuclear retinoic acid receptors, but not for the cytosolic retinoic acid binding protein, CRABP. In this paper we show that various retinoids differ, not only in terms of potency, i.e. the dilution at which they are active, but also in terms of the amount of PA that they induce. This parameter, called amplitude, is used to quantify the extent of PA induction by a given retinoid relative to retinoic acid. The amplitude parameters of synthetic retinoids are found to vary over a wide range and are independent of both potency and binding affinity for F9 retinoic acid receptors. It is proposed that the amplitude of the biological response to a given retinoid is the resultant of three factors: (i) the total or partial agonist character of the retinoid; (ii) the binding spectrum of the retinoid for the various types of retinoic acid receptors; (iii) the chemical and metabolic stability of the retinoid in the test system.

Animals↗
PubMed1996

Identification and characterization of a versatile retinoid response element (retinoic acid receptor response element-retinoid X receptor response element) in the mouse tissue transglutaminase gene promoter.

Tissue transglutaminase (transglutaminase type II) is an intracellular protein cross-linking enzyme that accumulates in connective tissue and in cells undergoing apoptosis. Retinoids regulate the transcription of the mouse tissue transglutaminase gene via activation of regulatory elements contained within 4 kilobases of the 5'-end of the gene. Co-transfection studies with retinoid receptor expression vectors in CV-1 cells demonstrated that the mouse tissue transglutaminase promoter is activated by ligand activation of either retinoic acid receptor-retinoid X receptor (RAR.RXR) heterodimers or RXR homodimers. Optimal induction is achieved with retinoid receptor panagonists; partial activation can also be achieved with either RAR-specific or RXR-specific retinoids. Retinoid-dependent activation of the tissue transglutaminase promoter depends on both a proximal regulatory region containing sequences highly conserved between the human and the mouse tissue transglutaminase promoters and a distal region that includes a 30-base pair retinoid response element (mTGRRE1). mTGRRE1 contains three hexanucleotide half-sites (two canonical and one non-canonical) in a DR7/DR5 motif that bind both RAR*RXR heterodimers and RXR homodimers. These studies suggest that retinoid-dependent expression of the mouse tissue transglutaminase gene is mediated by a versatile tripartite retinoid response element located 1.7 kilobases upstream of the transcription start site.

3T3 Cells↗
PubMed1996

Pattern of retinoid-induced teratogenic effects: possible relationship with relative selectivity for nuclear retinoid receptors RAR alpha, RAR beta, and RAR gamma.

Retinoic acid, an oxidative metabolite of vitamin A, is involved in the control of many biological processes including embryonic development. Excess as well as deficiency of retinoids were found to be teratogenic. The effects of retinoids in normal as well as abnormal development may be mediated by two members of retinoid receptors, the RAR's and RXR's, which exhibit a specific temporal and spatial expression during development. The significance of the retinoid receptors was investigated here by studying the teratogenic effects of retinoid ligands with relative selectivity for binding and transactivation of the retinoic acid receptors RAR alpha, RAR beta and RAR gamma. Pregnant NMRI mice were administered 5 or 15 mg/kg of CD 336 (Am 580) (alpha-ligand), CD 2019 (beta-ligand), CD 437 (gamma-ligand) or 37.5 mg/kg all-trans-retinoic acid in 25% Cremophor EL on day 8.25 or day 11 of gestation by gastric intubation. External, visceral and skeletal malformations were observed on day 18 of gestation. The order of teratogenic potency was: alpha-ligand > beta-ligand > gamma-ligand. In addition, these retinoids also produced a different spectrum of defects. The alpha-ligand induced the most varied defects including severe ear, mandible, and limb malformations. The beta-ligand induced defects of the urinary system and liver in greater frequency than expected from its relative potency. The gamma-ligand preferentially induced ossification deficiencies and defects of the sternebrae and vertebral body. Our results show that these three retinoids, which were previously demonstrated to exhibit retinoid-like activities in several systems, exert differing teratogenic activities, in regard to both potency and regioselectivity: we hypothesize that the relative selectivity for binding and transactivation of the three retinoic acid receptors could possibly be related to the differences of teratogenic effects observed in this study. The low potency of the gamma-ligand may lead the way to interesting new retinoids with improved therapeutic ratio.

Abnormalities, Drug-Induced↗
PubMed1995

Enhanced efficacy of combinations of retinoic acid- and retinoid X receptor-selective retinoids and alpha-interferon in inhibition of cervical carcinoma cell proliferation.

Retinoic acid receptors and retinoid X receptors form heterodimers, bind to retinoic acid response elements, and transactivate the transcription of retinoid-responsive genes. Two synthetic retinoids [4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)benzoic acid (TTAB) and 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-naphthale n ecarboxylic acid (TTNN)], which preferentially bind retinoic acid receptors, inhibited the proliferation of cervical carcinoma ME180 cells by 50% at 0.2 nM and 0.2 microM, respectively. In contrast, two other retinoids [2-(4-carboxyphenyl)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)-1,3-dithiane (SR11203) and 4-(2-methyl-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)propenyl)benzoic acid (SR11217)], which preferentially bind retinoic X receptors, inhibited growth by only 12 and 18% at 1 microM, respectively. The combination of suboptimal concentrations of TTAB (0.1 nM) or TTNN (10 nM) with each of the retinoic X receptor-selective retinoids at 1 microM showed more than additive effects on cell proliferation, especially with SR11217. Further increases in proliferation inhibition were observed when IFN-alpha (100 units/ml) was added to these retinoid combinations. Activation of transcription of a reporter gene linked 3' to the retinoic acid receptor beta retinoic acid response element in transiently transfected cells also exhibited additive effects when the cells were treated with combinations of TTAB or TTNN with SR11217. This additive activation of transcription may be the reason why the combination of retinoids is more effective than each retinoid alone. The results also suggest that the use of combinations of retinoids and IFN-alpha may lead to enhanced antitumor effects.

Cell Division↗
PubMed1994

Retinoid-resistant estrogen receptor-negative human breast carcinoma cells transfected with retinoic acid receptor-alpha acquire sensitivity to growth inhibition by retinoids.

Retinoids mediate their actions via RARs (retinoic acid receptors) and RXRs (retinoid X receptors). Each class of these nuclear retinoid receptors is further subdivided into three species, namely alpha, beta, and gamma. Recent studies demonstrate that estrogen receptor (ER)-positive human breast carcinoma (HBC) cell lines and tumor samples exhibit significantly higher levels of RAR alpha than their ER-negative counterparts. ER-positive HBC cell lines are sensitive to, and ER-negative cell lines are resistant to, growth inhibitory effects of retinoic acid (RA). We previously demonstrated that the expression of functional ERs in an established ER-negative cell line resulted in higher levels of RAR alpha and sensitivity to growth inhibition by RA. To further investigate the major role of RAR alpha in retinoid-mediated inhibition of growth, we transfected RAR alpha cDNA in two RA-resistant ER-negative HBC cell lines. Analyses of different clonal populations of RAR alpha transfectants from each cell line revealed growth inhibition by retinoids. Utilizing RAR- and RXR-class selective retinoids, we further demonstrated that only the RAR alpha-selective retinoids mediated the growth inhibition in these cells, while the RXR-selective retinoids were biologically inert. We thus provide evidence that the molecular mechanisms of retinoid inhibition of HBC proliferation predominantly involve RAR alpha.

Base Sequence↗
PubMed1995

Retinoid refractoriness occurs during lung carcinogenesis despite functional retinoid receptors.

Retinoids have demonstrated activity in the prevention of second primary tumors in patients with non-small cell lung cancer (NSCLC). They also contribute to the normal growth and differentiation of human bronchial epithelial (HBE) cells. Because retinoids mediate their actions through retinoid nuclear receptors (RARs and RXRs), aberrant signaling through retinoid receptors could contribute to lung carcinogenesis. Using a lung carcinogenesis model consisting of normal, premalignant, and malignant HBE cells, we examined all-trans retinoic acid (t-RA)-induced changes in cellular growth. These studies revealed that t-RA treatment inhibited the growth of normal HBE cells, but premalignant and malignant HBE cells were relatively resistant to t-RA. Coincident with the development of retinoid refractoriness, basal expression of the retinoic acid nuclear receptor beta (RAR-beta) increased. Analysis of receptor function by gel shift and transient transfection assays of normal, premalignant, and malignant HBE cells demonstrated that receptor-DNA binding and transcriptional activation properties were intact in the t-RA-refractory malignant HBE cells. To compare these findings to NSCLCs in patients, we investigated retinoid receptor expression in NSCLC biopsies. A subset of the tumors expressed RAR-beta, reflecting the RAR-beta expression observed in the malignant HBE cells in culture. These findings demonstrate that retinoid receptor function was intact in the t-RA-refractory malignant HBE cell line, suggesting that the defect in retinoid signaling in this lung carcinogenesis model is not intrinsic to the retinoid receptors.

Animals↗
PubMed2004

Breast cancer progression in MCF10A series of cell lines is associated with alterations in retinoic acid and retinoid X receptors and with differential response to retinoids.

In most breast carcinomas and in breast cancer cell lines, retinoic acid receptor beta (RARbeta) is lost or down-regulated, whereas retinoic acid receptor alpha and gamma (RARalpha, gamma) and retinoid X receptors (RXRalpha, beta, gamma) are variably expressed. Little is known about alterations of the above receptors in hyperplastic and premalignant stages of breast cancer development. In this study, we employed the MCF10A series of breast epithelial cell lines (the parental and benign MCF10A, premalignant MCF10AT, and malignant MCF10CA1a) to assess whether in the course of their malignant transformation specific alterations in RARalpha, beta, gamma and RXRalpha, beta, gamma expression occur and whether they may affect the sensitivity of cells to retinoids. Malignant properties of the above cell lines were estimated by the nude mice xenograft transplantation assay. Among the above receptors most significant alterations occurred in RARbeta2, which was detected in the normal breast epithelial cells both, at mRNA and protein levels, but expressed in the MCF10A cell lines at mRNA level only. The transformation of benign MCF10A cells into premalignant MCF10AT and malignant MCF10CA1a was also associated with increase in RARalpha, RARgamma, RXRalpha, and RXRbeta proteins expression. All-trans retinoic acid (atRA), 9-cis retinoic acid (9cRA), and 4-(hydroxyphenyl) retinamide (4-HPR) induced RARbeta2 protein expression exclusively in the benign MCF10A cells and the former two retinoids, mRNA expression in MCF10A and MCF10AT cells, but not in malignant, MCF10CA1a cells, suggesting that the loss of inducible RARbeta expression is associated with the progression and malignant transformation of MCF10A cells. Retinoids also variable decreased the RARalpha, RARgamma and RXRalpha protein expression preferentially in the premalignant and malignant, but not in benign MCF10A cells. Among the above retinoids, 4-HPR was most efficacious in inhibiting the growth of the three cell lines and this apparently was not dependent on the levels of the RARbeta2 transcriptional activation. Thus, our data support the hypothesis that breast epithelial cells in the course of their progression and malignant transformation may differentially respond to retinoids and that not only RARbeta, but RARalpha, gamma and/or RXRalpha, beta may also serve as potential targets for retinoids in breast cancer prevention and therapy trials.

Animals↗
PubMed1995

Diminished teratogenicity of retinoid X receptor-selective synthetic retinoids.

One feature that contraindicates the wide therapeutic use of retinoids is their teratogenicity. Synthetic retinoids are distinguishable from each other on the basis of their partial or exclusive preference in binding and activation of all-trans retinoic acid receptors (RARs) or retinoid X receptors (RXRs). Using mouse embryo limb bud cells in micromass cultures as a bioassay, we examined the inhibitory activities of a number of standard and novel retinoids on chondrogenic cell differentiation. Transient cotransfection of HeLa cells was used to measure the ability of each retinoid to induce transcription of a reporter gene by activating RAR alpha, RAR beta, RAR gamma, or RXR alpha chimeric constructs. All retinoids in this study that activated RARs to any degree in the cotransfection assay also inhibited chondrogenesis in vitro, whereas retinoids that were either specific for RXR or inactive in the cotransfection assay did not. The activity of RAR-selective agonists and the inactivity of RXR-specific agonists in the cotransfection assay correlated well with the relative teratogenicity of six of the representative retinoids studied when orally administered at day 11 to pregnant ICR mice.

Animals↗
PubMed2004

Altered localization of retinoid X receptor alpha coincides with loss of retinoid responsiveness in human breast cancer MDA-MB-231 cells.

To understand the mechanism of retinoid resistance, we studied the subcellular localization and function of retinoid receptors in human breast cancer cell lines. Retinoid X receptor alpha (RXR alpha) localized throughout the nucleoplasm in retinoid-sensitive normal human mammary epithelial cells and in retinoid-responsive breast cancer cell line (MCF-7), whereas it was found in the splicing factor compartment (SFC) of the retinoid-resistant MDA-MB-231 breast cancer cell line and in human breast carcinoma tissue. In MDA-MB-231 cells, RXR alpha was not associated with active transcription site in the presence of ligand. Similarly, ligand-dependent RXR homo- or heterodimer-mediated transactivation on RXR response element or RARE showed minimal response to ligand in MDA-MB-231 cells. Infecting MDA-MB-231 cells with adenoviral RXR alpha induced nucleoplasmic overexpression of RXR alpha and resulted in apoptosis upon treatment with an RXR ligand. This suggests that nucleoplasmic RXR alpha restores retinoid sensitivity. Epitope-tagged RXR alpha and a C-terminus deletion mutant failed to localize to the SFC. Moreover, RXR alpha localization to the SFC was inhibited with RXR alpha C-terminus peptide. This peptide also induced ligand-dependent transactivation on RXRE. Therefore, the RXR alpha C terminus may play a role in the intranuclear localization of RXR alpha. Our results provide evidence that altered localization of RXR alpha to the SFC may be an important factor for the loss of retinoid responsiveness in MDA-MB-231 breast cancer cells.

Adenoviridae↗
PubMed2003

Sensitivity of human tumor cells to retinoids or combined treatment with retinoids and ionizing radiation is not dependent on RAR-beta 2 induction.

PURPOSE: The nuclear retinoic acid receptor beta 2 (RAR-beta2) is supposed to be a prognostic marker of retinoid sensitivity in patients after retinoid treatment. Therefore, we investigated the role of RAR-beta2 induction with respect to clonogenic survival of different human tumor cells under retinoid treatment alone or in combination with irradiation. MATERIAL AND METHODS: The retinoid responsiveness of seven human tumor cell lines (HTB35, HTB43, SCC4, SCC9, MDA-MB231, HCT116, and CaSki) as well as one normal human skin fibroblast (HSF6) as control cells was analyzed by colony formation assay under retinoid and retinoid/radiation treatment. Basic mRNA levels of all retinoic acid receptors as well as the treatment-dependent modulation of mRNA and protein levels of RAR-beta were analyzed by RT-PCR and Western blot analysis under the different treatment conditions. RESULTS: It could be shown that the clonogenic inactivation of tumor cells under retinoid treatment alone or in combination with irradiation was not correlated with the induction of RAR-beta on mRNA and protein level, respectively. The control cells (HSF6), however, demonstrated an induction. CONCLUSION: The responsiveness of human tumor cells to retinoid treatment alone and particularly to combined treatment with irradiation is not necessarily associated with an induction of RAR-beta2 as it has been postulated so far. Thus, loss of RAR-beta induction in tumors does not seem to be a good prognostic factor for successful retinoid/radiation therapy, since RAR-beta-deficient tumors may also present strong retinoid responsiveness.

Antineoplastic Agents↗
PubMedDate not supplied

Effect of retinoids on dermal inflammation and on arachidonic acid mobilization and metabolism in murine 3T6 fibroblasts retinoids, arachidonate release and metabolism.

Retinoids have shown anti-inflammatory activity in some animal models and human diseases, although the mechanism by which retinoids elicit this activity is unknown. In this study, retinoids significantly attenuated, in a dose-dependent fashion, murine ear oedema induced by phorbol 12-myristate 13-acetate (PMA) or oxazolone. Dexamethasone inhibited both oedemas whereas ketoprofen reduced only that induced by PMA. PMA application or oxazolone-induced contact hypersensitivity markedly increased production of eicosanoids such as 6-keto-PGF1 alpha or LTB4. The anti-oedematous effects of retinoids were accompanied by inhibition of tissue eicosanoid levels. Besides, retinoids showed toxic effects on culture fibroblasts caused by an irritant effect on plasma membrane. However, when we used subtoxic doses, we demonstrated that retinoids in vitro could inhibited arachidonate mobilization and eicosanoid biosynthesis induced in fibroblast cultures by PMA, calcium ionophore A23187 or bradykinin. Thus, this paper reports the ability of retinoids to inhibit skin inflammatory processes induced by tumour promotors or immunological stimuli. Moreover, we have demonstrated that retinoids at non-cytotoxic doses may inhibit eicosanoid generation and arachidonic acid mobilization in 3T6 fibroblasts.

3T3 Cells↗
PubMed2003

Pharmacological doses of some synthetic retinoids can modulate both the aryl hydrocarbon receptor and retinoid receptor pathways.

Retinoids have been demonstrated to have pharmacological application in the areas of dermatology and oncology. In addition to the natural retinoids such as all-trans-retinoic acid and 9-cis-retinoic acid, many new potential retinoid drugs have been synthesized, including retinoic acid receptor (RAR)-subtype selective agonists, retinoid X receptor (RXR)-selective agonists, RAR-selective antagonists, anti-AP1-specific retinoids and retinoids that induce apoptosis. Recent studies demonstrate that some retinoids, in addition to modulating the RAR/RXR pathway, are also capable at pharmacological concentrations of binding to aryl hydrocarbon receptor (AhR) and activating the AhR/AhR nuclear translocator pathway. Future studies are necessary to ascertain the consequences, if any, of activation of the AhR signaling pathway by pharmacological doses of specific retinoids.

Animals↗
PubMed1993

Cellular metabolism and activation of retinoids: roles of cellular retinoid-binding proteins.

Vitamin A and related molecules--the retinoids--play essential roles in vision, growth, reproduction, and cellular differentiation beginning in early development. Retinoic acid, a key regulatory retinoid formed intracellularly through the oxidation of retinol, functions as ligand for a family of nuclear retinoic acid receptors that regulate transcription from target genes. Metabolic events are critical to maintaining physiological concentrations of retinoic acid. In the cytoplasm, retinol, retinaldehyde, and retinoic acid are associated with retinoid-binding proteins, most of which are approximately 15-kDa proteins belonging to the fatty acid-binding protein/cellular retinol-binding protein family. The ligand binding properties and molecular features of these proteins have been well characterized. Recent experiments have highlighted the importance of the cellular retinoid-binding proteins in controlling the concentration of free retinoids and in directing protein-bound retinoids to key enzymes responsible for their metabolism. For example, the cellular retinol-binding protein, CRBP, has been implicated in retinol uptake, retinol esterification, mobilization of retinyl esters, and the initial oxidation of retinol to retinaldehyde. The ligands bound to other retinoid-binding proteins have also been shown to be available for enzymatic transformation. The new knowledge of the various ways these cytoplasmic proteins buffer the concentration of ligand, control their distribution, and determine their metabolism by specific enzymes is contributing to an improved understanding of the physiological control of retinoid action.

Animals↗
PubMed1996

Retinoid induction of CRABP II mRNA in human dermal fibroblasts: use as a retinoid bioassay.

Cellular retinoic acid binding protein II (CRABP II) mRNA is selectively induced by all-trans retinoic acid in human skin and dermal fibroblasts. In order to determine whether this response can be used as a reliable measure of retinoid potency and activity, we treated human skin fibroblasts for 24 h with increasing concentrations of several natural and synthetic retinoids. CRABP II mRNA levels were measured by quantitative Northern blotting and compared, when possible, with those obtained after topical application of the same retinoids to human skin. All eight active retinoids tested induced a concentration-dependent CRABP II mRNA response in the fibroblast assay. In contrast, one known inactive retinoid (meta-carboxy TTNPB), differing from the active form only in the position of the carboxyl substituent, failed to evoke a response. The fibroblast and human skin bioassays agreed with respect to relative potency and response amplitude for three of the three retinoids tested. Retinoic acid was approximately 10-fold more potent than retinal in both assays, suggesting that oxidation to retinoic acid underlies the activity of retinol in fibroblasts as well as in intact skin. In support of this hypothesis, treatment with liarozole, an inhibitor of P450-mediated retinoic acid oxidative catabolism, significantly increased fibroblast CRABP II mRNA levels and potentiated the effects of retinol by 1.5-fold at concentrations at which it had no effect on its own. Taken together, these results identify the fibroblast CRABP II response as a reproducible measure of retinoid bioactivity with promise as a predictor of human skin responses and further suggest that metabolism is an important determinant of retinoid bioactivity in vivo.

Biological Assay↗
PubMed2005

The retinoid X receptor-selective retinoid, LGD1069, down-regulates cyclooxygenase-2 expression in human breast cells through transcription factor crosstalk: implications for molecular-based chemoprevention.

Retinoids and their derivatives can suppress the development of cancer in animals and in humans. We and others have shown that retinoid X receptor (RXR)-selective retinoids or "rexinoids" suppress the development of breast cancer in several animal models with minimal toxicity. LGD1069 (Bexarotene) is a potent RXR-selective retinoid with reduced toxicity compared with naturally occurring retinoids. In this study, we investigated the expression of LGD1069-modulated biomarkers. We previously did cDNA array analysis of LGD1069-treated breast cells using Affymetrix microarrays. These studies identified many LGD1069-regulated genes, one of which was cyclooxygenase-2 (COX-2). Because COX-2 inhibitors have been shown to prevent cancer in other model systems, we investigated whether LGD1069 inhibits the expression of COX-2 in mammary tissue and in normal human mammary epithelial cells (HMEC). In mouse mammary tumor virus-erbB2 mice treated with LGD1069, there was a marked decrease of COX-2 expression in both normal and malignant mammary tissues. The effect of LGD1069 on COX-2 expression was also investigated in normal human breast cells. COX-2 expression was markedly reduced by treatment with LGD1069 at the RNA and protein level in normal HMECs; LGD1069 suppressed COX-2 promoter activity. We also showed that LGD1069 inhibited activator protein (AP-1)-dependent transcription in these breast cells, and that suppression of COX-2 expression was due to sequestration of CBP/p300. These results from in vivo and in vitro studies suggest that LGD1069, an RXR-selective retinoid, inhibits COX-2 expression by suppression of COX-2 transcription in part through transrepression of the AP-1 transcription factor. Thus, RXR-selective retinoids that inhibit AP-1 activity and suppress COX-2 expression may be particularly promising drugs for breast cancer prevention. Furthermore, such RXR-selective retinoids may be most useful in combination with antiestrogens for more effective prevention of breast cancer in women at high risk of this disease.

Animals↗
PubMed2002

Novel synthetic retinoids and separation of the pleiotropic retinoidal activities.

Retinoids, all-trans-retinoic acid (1a) and its analogs, act as specific modulators of cellular differentiation and proliferation, through binding to and activating specific nuclear receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Retinoids have chemotherapeutic roles in dermatology and oncology, but their usefulness is restricted by the high toxicity of retinoic acid and its hydrophobic analogs. We have developed various retinoidal benzoic acid derivatives, and named them retinobenzoic acids. Among them, aromatic amides such as Am80 (7) and Am580 (8) have superior pharmacological characteristics, including RAR subtype selectivity. Structural modification based on the ligand superfamily concept afforded several types of RAR antagonists, benzimidazole derivatives, BIPh (41) and BIBn (42), and dibenzodiazepine derivatives, LE135 (46) and LE540 (47). LE135 (46) is a unique antagonist with RARbeta-selectivity. During investigations on the structure-activity relationships of retinobenzoic acids, several retinoid synergists (RXRs agonists), such as HX600 (49), DA113 (55h) and TZ335 (57), have been found. These compounds are expected to modulate other nuclear receptors which form heterodimers with RXRs, besides retinoids. Further, we found some RXRs antagonists, HX531 (60) and HX603 (61), which inhibit the activation of both RXR homodimers and RXR RAR heterodimers. In this review, we describe our investigations on these structurally and biologically unique retinoids and retinoid-regulatory compounds.

Animals↗
PubMed1998

Initial retinoid requirement for early avian development coincides with retinoid receptor coexpression in the precardiac fields and induction of normal cardiovascular development.

Vitamin A requirement for early embryonic development is clearly evident in the gross cardiovascular and central nervous system abnormalities and an early death of the vitamin A-deficient quail embryo. This retinoid knockout model system was used to examine the biological activity of various natural retinoids in early cardiovascular development. We demonstrate that all-trans-, 9-cis-, 4-oxo-, and didehydroretinoic acids, and didehydroretinol and all-trans-retinol induce and maintain normal cardiovascular development as well as induce expression of the retinoic acid receptor beta2 in the vitamin A-deficient quail embryo. The expression of RARbeta2 is at the same level and at the same sites where it is expressed in the normal embryo. Retinoids provided to the vitamin A-deficient embryo up to the 5-somite stage of development, but not later, completely rescue embryonic development, suggesting the 5-somite stage as a critical retinoid-sensitive time point during early avian embryogenesis. Retinoid receptors RARalpha, RARgamma, and RXRalpha are expressed in both the precardiac endoderm and mesoderm in the normal and the vitamin A-deficient quail embryo, while the expression of RXRgamma is restricted to precardiac endoderm. Vitamin A deficiency downregulates the expression of RARalpha and RARbeta. Our studies provide strong evidence for a narrow retinoid-requiring developmental window during early embryogenesis, in which the presence of bioactive retinoids and their receptors is essential for a subsequent normal embryonic development.

Animals↗