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PubMed2004

Modulation of cytokine production by low and high retinoid diets in ovalbumin-sensitized mice.

Retinoids modulate many physiological processes such as the differentiation and growth of different cell types, including cells from the immune system. We have previously shown that retinoids modulate IgE production in vitro and in vivo. In the present study we investigated the effects of retinoids in non-sensitized and ovalbumin-sensitized mice that were fed for 11 weeks with three different vitamin A (VA) diets: a) VA-deficiency diet, b) base diet, and c) base diet supplemented with 0.5% all-trans-retinoic acid (ATRA). Phorbol-myristate-acetate (PMA)/ionomycin-stimulated SMC (splenic mononuclear cells) from mice fed with ATRA and the vitamin A-deficient diet group showed increased interleukin-4 (IL-4) responses in non-sensitized mice. After ovalbumin sensitization in the VA-deficient and the ATRA supplementation diet groups, no significant effects on IL-4 production were observed. By contrast, gamma interferon (IFN-gamma production from PMA/ionomycin-stimulated SMC was enhanced in the VA-deficient diet group in ovalbumin-sensitized mice, and also in non-sensitized mice compared to the base and the ATRA-supplemented diet group. The data indicate that VA and retinoid content in a diet influences the cytokine response in non-sensitized and also ovalbumin-sensitized mice. Therefore these molecules may serve as active modulators of cytokine production in vivo that are responsible for the induction and persistence of atopic diseases.

Animals↗
PubMed2004

Retinoid-related molecules require caspase 9 for the effective release of Smac and the rapid induction of apoptosis.

Certain retinoid-related molecules (RRMs) with agonist or antagonist activities have been described to induce apoptosis in a variety of cancer cell lines and show promise for the treatment of cancer. Similar to other chemotherapeutic drugs, these retinoid analogs have been suggested to induce apoptosis through the intrinsic pathway, which requires the release of cytochrome c from the mitochondria for the effective activation of caspase 9. Expression of a catalytically inactive form of caspase 9, which functions as a dominant negative mutant, inhibits the induction of DEVDase activity and nuclear fragmentation by selective RRMs. Whereas the RRMs could induce the release of cytochrome c in the absence of caspase 9 activity, the later is necessary for the effective release of Smac/Diablo from the mitochondria. Furthermore, overexpression of Bcl-2 or Bcl-X(L) also inhibits RRM-induced apoptosis. We demonstrate that activation of caspase 2 by the agonist MX2870-1 requires caspase 9 activity and is inhibited by Bcl-2 overexpression. In contrast, the antagonist MX781 induces cleavage of procaspase 2 upstream of mitochondria and independently of caspase 9. Thus, two retinoid analogs with unique characteristics activate two distinct apical caspases (2 or 9) to initiate apoptosis. In addition to caspase-mediated cell death, sustained exposure to the RRMs can also lead to loss of cell viability in cells lacking caspase 9 activity or in cells stimulated in the presence of the caspase inhibitor Z-VAD-fmk. Moreover, MX2870-1 and MX781 produce cell cycle arrest independently of caspase activity and the retinoid receptors.

Apoptosis↗
PubMed1997

Retinoids augment the bystander effect in vitro and in vivo in herpes simplex virus thymidine kinase/ganciclovir-mediated gene therapy.

Metabolic cooperation via gap junctional intercellular communication (GJIC) is an important mechanism of the bystander effect in gene therapy using the herpes simplex virus thymidine kinase/ganciclovir (HSVtk/GCV) 'prodrug' system. Since retinoids have been reported to increase GJIC by induction of connexin expression, we hypothesized that these compounds could be used to augment the HSVtk/GCV bystander effect. Addition of all-trans retinoic acid increased GJIC in tumor cell lines, augmented expression of connexin 43, and was associated with more efficient GCV-induced in vitro bystander killing in cells transduced with HSVtk via either retrovirus or adenovirus vectors. This augmentation of bystander effect could also be seen in vivo. HSVtk-transduced tumors in mice treated with the combination of GCV and retinoids were significantly smaller than those treated with GCV or retinoids alone. These results provide evidence that retinoids can augment the efficiency of cell killing with the HSVtk/GCV system by enhancing bystander effects and may thus be a promising new approach to improve responses in gene therapy utilizing the HSVtk/GCV system to treat tumors or vascular restenosis.

Animals↗
PubMed1999

Retinoids and adipose tissues: metabolism, cell differentiation and gene expression.

Vitamin A derivatives (retinoids) play a key role in mammalian development and cell differentiation. Isomers of retinoic acid, the main active metabolite of vitamin A, activate retinoid receptors that act as ligand-dependent transcription factors and affect gene expression. White and brown adipose tissues are major sites of storage of vitamin A derivatives and they play an active role in whole body metabolism of retinoids. Moreover, adipose tissues are targets for the action of retinoic acid. In most cases retinoic acid impairs adipocyte differentiation although its final effects on adipose tissue development depend on retinoic acid concentration, isomers availability and expression of retinoid receptor subtypes in the white or brown adipocyte. Retinoic acid (RA) has a specific effect on brown adipose tissue, because it activates transcription of the gene for uncoupling protein-1, responsible for brown fat thermogenesis.

Adipose Tissue↗
PubMed1999

4HPR triggers apoptosis but not differentiation in retinoid sensitive and resistant human embryonal carcinoma cells through an RARgamma independent pathway.

Retinoids signal biological effects through retinoic acid receptors (RAR) and retinoid X receptors (RXR) and their co-regulators. We previously reported that all-trans retinoic acid (RA) triggers terminal differentiation in the human embryonal carcinoma cell line NTERA-2 clone D1 (NT2/D1), through an RARgamma dependent pathway. RARgamma repression in NT2/D1-R1 cells accounts for RA resistance in this line. This report finds RARgamma repression is due to selective repression of RARgamma but not RARbeta transcription in NT2/D1-R1 cells. The repression is neither due to mutations in RARgamma nor its promoter containing the RA response element. Prior work was confirmed and extended by demonstrating that an RARgamma selective agonist preferentially signals differentiation of NT2/D1 cells, while RARalpha/beta, RARbeta, RXR agonists and an RAR pan-antagonist do not even when NT2/D1 cells are treated with these retinoids at 10 microM dosages. None of these examined retinoids induced differentiation of the RA resistant NT2/D1-R1 cells. In contrast, N-(4-hydroxyphenyl)retinamide (4HPR), a reported transcriptional activator of RARgamma was shown to potently induce growth inhibition and apoptosis in both NT2/D1 and NT2/D1-R1 cells. 4HPR-induced apoptosis was unaffected by co-treatment of both cell lines with equimolar RAR antagonist. Semi-quantitative reverse transcription-polymerase chain reaction (RT - PCR) assays of total RNA from 4HPR-treated NT2/D1 and NT2/D1-R1 cells did not reveal RARgamma induction. Since 4HPR signals in RA-resistant NT2/D1-R1 cells having an RARgamma transcriptional block, these results indicate that 4HPR triggers apoptosis but not differentiation through an RARgamma independent pathway. Taken together, these findings implicate a therapeutic role for 4HPR mediated apoptosis in germ cell tumors even when a maturation block is present.

Anticarcinogenic Agents↗
PubMed1996

All-trans-retinoic acid 4-hydroxylation in human liver microsomes: in vitro modulation by therapeutic retinoids.

All-trans retinoic acid (ATRA) induces remission in patients with acute promyelocytic leukaemia. Other retinoids, including 9-cis- and 13-cis-retinoic acid (9-cis- and 13-cis-RA), are now being evaluated for their therapeutic potential. The elimination of ATRA is partially dependent on cytochrome P450 (P450)-mediated 4-hydroxylation, but the interaction of other retinoids with P450 has not yet been assessed. In the present study 9-cis- and 13-cis-RAs, as well as all-trans-retinol and three isomeric retinals were found to inhibit ATRA 4-hydroxylation in human hepatic microsomes, but the arotinoids acitretin and etretinate were not inhibitors 9-cis- and 13-cis-RA were competitive inhibitors of ATRA 4-hydroxylation (Ki:Km ratios 3.5 +/- 0.8 and 6.3 +/- 0.5, respectively) suggesting that these retinoids are alternate, but inferior, substrates for the P450 enzyme(s) that mediate the activity. The biotransformation of therapeutic retinoids containing the beta-ionone ring system is likely to involve the microsomal ATRA 4-hydroxylase P450.

Antineoplastic Agents↗
PubMed2006

[Retinoid metabolism and cancer].

Retinoids play important roles in cell differentiation and apoptosis, notably in epithelial tissues. Their utility in cancer therapy has been demonstrated in specific cancer types. Use of retinoic acid (RA) in the treatment of acute promyelocytic leukemia was the first successful example of retinoid-based differentiation therapy. RA has since been evaluated for treatment of other cancers, revealing variable effectiveness. The observation that expression of enzymes involved in RA biosynthesis is suppressed during tumorigenesis suggests that intra-tumor depletion in RA levels may contribute to tumor development and argues for the use of retinoids in cancer treatment. However, the induction of RA-inactivating enzymes is one of the mechanisms that may limit the efficacy of retinoid therapy and contribute to acquired resistance to RA treatment, suggesting that retinoic acid metabolism blocking agents may be effective agents in differentiation therapy.

Anticarcinogenic Agents↗
PubMed2000

Is there a role for retinoids to treat minimal residual disease in neuroblastoma?

A variety of pre-clinical and clinical data point toward high drug levels of retinoids being required to achieve optimal efficacy against neuroblastoma. The results of the Kohler trial reported in this issue demonstrate that low-dose 13-cis-RA does not have clinical efficacy against neuroblastoma in a setting of minimal residual disease. A comparison of the Kohler trial with the US CCG trial provides clinical evidence that high-dose levels of retinoids are optimal for treating minimal residual disease in neuroblastoma. The comparison of high-dose and low-dose 13-cis-RA studies in neuroblastoma suggests the intriguing possibility that high dose, pulse schedules of other retinoids could be effective as therapeutic and chemopreventive agents in diseases where low-dose, chronic retinoid administration was not effective. Pre-clinical and perhaps clinical studies of the latter concept should be considered.

Humans↗
PubMed2001

Immunolocalization of retinol-binding protein, cellular retinoic acid-binding protein I and retinoid X receptor beta in the porcine reproductive tract during the oestrous cycle.

Retinoid-binding proteins and nuclear receptors are expressed in the reproductive tissues of different species and their expression is hormonally regulated. In the present study, we demonstrated immunocytochemically the temporal and spatial localization of retinol-binding protein (RBP), cellular retinoic acid-binding protein I (CRABPI) and retinoid X receptor beta (RXRbeta) in porcine ovary, oviduct and uterus during the oestrous cycle. RBP and CRABPI were localized in the cytoplasm, whereas RXRbeta occurred in the nucleus. RBP was not detected in either the ovary or the oviduct at any stage of the oestrous cycle. CRABPI was present in luteal cells of the ovary only during dioestrus and in glandular and ciliated cells of the oviduct during oestrus. In the ovary, RXRbeta was always present in granulosa cells and germinal epithelium, with highest levels observed during oestrus. In the uterus, RXRbeta was present throughout the cycle in both the endometrium and the myometrium. However, changes in RXRbeta were observed in the endometrium, with highest levels observed during dioestrus. RBP and CRABPI could be observed in the endometrium only during dioestrus. The results show that the occurrence of retinoid-binding proteins and nuclear receptors in individual tissues of the reproductive tract are strongly dependent on the stage of the oestrous cycle. In the oviduct, the expression of CRABPI seems to be dependent on oestrogen, whereas in the uterus the expression of RBP and CRABPI is influenced by progesterone. The association of expression in different sections of the reproductive tissues investigated shows that the presence of specific proteins involved in retinoid metabolism was dependent on events associated with ovulation, the migration of the oocyte through the oviduct and the possible implantation of the blastocyst into the uterus.

Animals↗
PubMed1995

Multimeric complexes of the PML-retinoic acid receptor alpha fusion protein in acute promyelocytic leukemia cells and interference with retinoid and peroxisome-proliferator signaling pathways.

The t(15;17) chromosomal translocation, specific for acute promyelocytic leukemia (APL), fuses the PML gene to the retinoic acid receptor alpha (RAR alpha) gene, resulting in expression of a PML-RAR alpha hybrid protein. In this report, we analyzed the nature of PML-RAR alpha-containing complexes in nuclear protein extracts of t(15;17)-positive cells. We show that endogenous PML-RAR alpha can bind to DNA as a homodimer, in contrast to RAR alpha that requires the retinoid X receptor (RXR) dimerization partner. In addition, these cells contain oligomeric complexes of PML-RAR alpha and endogenous RXR. Treatment with retinoic acid results in a decrease of PML-RAR alpha protein levels and, as a consequence, of DNA binding by the different complexes. Using responsive elements from various hormone signaling pathways, we show that PML-RAR alpha homodimers have altered DNA-binding characteristics when compared to RAR alpha-RXR alpha heterodimers. In transfected Drosophila SL-3 cells that are devoid of endogenous retinoid receptors PML-RAR alpha inhibits transactivation by RAR alpha-RXR alpha heterodimers in a dominant fashion. In addition, we show that both normal retinoid receptors and the PML-RAR alpha hybrid bind and activate the peroxisome proliferator-activated receptor responsive element from the Acyl-CoA oxidase gene, indicating that retinoids and peroxisome proliferator receptors may share common target genes. These properties of PML-RAR alpha may contribute to the transformed phenotype of APL cells.

Animals↗
PubMed1996

A novel class of retinoid antagonists and their mechanism of action.

Retinoids regulate a broad range of biological processes through two subfamilies of nuclear retinoid receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Recently, we reported a novel type of retinoic acid antagonist (SR11335) and showed that this compound can inhibit retinoic acid (RA)-induced activation of a human immunodeficiency virus type 1 (HIV-1) promoter construct that contains a special RA response element (RARE). We have now further characterized the antagonism mediated by SR11335 and of newly synthesized structurally related compounds. Two compounds, SR11330 and SR11334, which are poor transactivators, also showed antagonist activities, inhibiting all-trans-RA (tRA) and 9-cis-RA. The retinoids inhibited transcriptional activation of RAR/RXR heterodimers effectively, while inhibition of RXR homodimers was less efficient. Inhibition was observed on several RAREs, including the TREpal, betaRARE, apoAI-RARE, and CRBPI-RARE. In addition, the antagonists inhibited tRA-induced differentiation of HL-60 cells. The antagonist did not interfere with DNA binding of the receptors. In limited proteolytic digestion assays, SR11335 induced resistance of the receptors to proteolysis, but the pattern of the degradation was not altered from that induced by tRA, suggesting that these antagonists induce their biological effects by competing with agonists for binding to RARs, thereby preventing the induction of conformational changes of the receptors necessary for transcriptional activation.

Animals↗
PubMed1997

Lipocalin-type prostaglandin D synthase (beta-trace) is a newly recognized type of retinoid transporter.

Lipocalin-type prostaglandin D synthase is responsible for the biosynthesis of prostaglandin D2 in the central nervous system and the genital organs and is secreted into the cerebrospinal fluid and the seminal plasma as beta-trace. Here we analyzed retinoids binding of the enzyme by monitoring the fluorescence quenching of an intrinsic tryptophan residue, and appearance of circular dichroism around 330 nm, and a red shift of the UV absorption spectra of retinoids. We found that the enzyme binds all-trans- or 9-cis-retinoic acid and all-trans- or 13-cis-retinal, but not all-trans-retinol, with affinities (Kd of 70-80 nM) sufficient for function as a retinoid transporter. All-trans-retinoic acid inhibited the enzyme activity in a noncompetitive manner, suggesting that it binds to the same hydrophobic pocket as prostaglandin H2, the substrate for prostaglandin D synthase, but at a different site in this pocket. It is likely that this enzyme is a bifunctional protein that acts as both retinoid transporter and prostaglandin D2-producing enzyme.

Alanine↗
PubMed1997

Identification of a retinoid/chicken ovalbumin upstream promoter transcription factor response element in the human retinoid X receptor gamma2 gene promoter.

To investigate the mechanisms involved in the transcriptional control of retinoid X receptor (RXR) gene expression, the 5'-flanking region of the human RXRgamma2 isoform was characterized. An imperfect hexamer repeat (gamma retinoid X response element; gammaRXRE) with a single nucleotide spacer (GGTTGAaAGGTCA) was identified immediately upstream of the RXRgamma2 gene transcription start site. Cotransfection studies in CV-1 cells with expression vectors for the retinoid receptors RXRalpha and retinoic acid receptor beta (RARbeta) demonstrated that the gammaRXRE confers retinoid-mediated transcriptional activation with preferential activation by RXR in the presence of its cognate ligand, 9-cis-retinoic acid (RA). Electrophoretic mobility shift assays demonstrated that RXR homodimer binding to gammaRXRE is markedly enhanced by 9-cis-RA, whereas RAR.RXR heterodimer binding is ligand-independent. DNA binding studies and cell cotransfection experiments also demonstrated that the nuclear receptor, chicken ovalbumin upstream promoter transcription factor (COUP-TF), repressed transcription via the gammaRXRE. Cotransfection experiments revealed that COUP-TF and RXRalpha compete at the gammaRXRE to modulate transcription bidirectionally over a wide range. These results demonstrate that the human RXRgamma2 gene promoter contains a novel imperfect repeat element capable of mediating RXR-dependent transcriptional autoactivation and COUP-TF-dependent repression.

Alitretinoin↗
PubMed1998

Selective activation of an apoptotic retinoid precursor in macrophage cell lines.

Advances in the understanding of the retinoid signaling mechanism has allowed the discovery of highly selective retinoids that activate only one specific receptor class, subtype, or signaling pathway. These novel compounds lack certain of the common retinoid toxicities and therefore suggest promising new approaches for therapeutic applications. We describe here a new compound, 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid methyl ester (MX84), that is selectively activated in macrophages, leading to killing of only macrophage monocyte type cells in vitro. We provide evidence that MX84 is an inactive precursor that is converted into an active apoptosis-inducing retinoid in macrophages. The macrophage activity is also secreted, and our data suggest that the secreted activity is a phospholipase D type activity. Our observation may lead to the development of molecules that are highly macrophage-selective apoptosis inducers in vivo and that could represent important novel therapeutics against diseases caused by excessive macrophage activity.

Apoptosis↗
PubMed1998

Inhibition of ribonuclease P activity by retinoids.

The effect of two naturally occurring (retinol and all-trans retinoic acid) and two synthetic (isotretinoin and acitretin) analogs of vitamin A (retinoids) on tRNA biogenesis was investigated employing the RNase P of Dictyostelium discoideum as an in vitro experimental system. RNase P is an ubiquitous and essential enzyme that endonucleolytically cleaves all tRNA precursors to produce the mature 5' end. All retinoids tested revealed a dose-dependent inhibition of RNase P activity, indicating that these compounds may have a direct effect on tRNA biogenesis. Detailed kinetic analysis showed that all retinoids behave as classical competitive inhibitors. The Ki values determined were 1475 microM for retinol, 15 microM for all-trans retinoic acid, 20 microM for isotretinoin, and 8.0 microM for acitretin. On the basis of these values acitretin is a 184, 2.5, and 1.9 times more potent inhibitor, as compared with retinol, isotretinoin, and all-trans retinoic acid, respectively. Taking into account that retinoids share no structural similarities to precursor tRNA, it is suggested that their kinetic behavior reflects allosteric interactions of these compounds with hydrophobic site(s) of D. discoideum RNase P.

Acitretin↗
PubMed2000

Regulation of vascular endothelial growth factor expression in human keratinocytes by retinoids.

Vascular endothelial growth factor (VEGF) is overexpressed in hyperproliferative diseases, such as psoriasis and cancers, which are characterized by increased angiogenesis. Experimentally, VEGF overexpression can be induced by the treatment of cell cultures and biological tissues with phorbol esters, such as 12-O-tetradecanoylphorbol-13-acetate (TPA). Using normal human keratinocytes in conventional cultures and skin grafted onto nude mice in vivo, we show that retinoids can inhibit TPA-mediated VEGF gene induction at the transcriptional level. Because retinoids are biologically active either by interacting with the nuclear retinoic acid receptors or by interfering with the activator protein 1 (AP1) transcription factor, we studied the effect of the retinoic acid derivative CD 2409, which exhibits strong anti-AP1 activity but does not bind to the known retinoic acid receptors in vitro. The results demonstrate that the inhibition of VEGF expression by retinoids only depends on their anti-AP1 activity and does not require gene transactivation via retinoic acid response elements. Because the VEGF promoter contains four potential AP1 binding sites, we used different promoter constructs to identify the functional site responsible for TPA induction and retinoid inhibition. This site turned out to be localized at position -621 of the 5' flanking region of the VEGF gene.

Adaptor Protein Complex 1↗
PubMed2004

N-retinylidene-phosphatidylethanolamine is the preferred retinoid substrate for the photoreceptor-specific ABC transporter ABCA4 (ABCR).

ABCA4, a member of the family of ATP binding cassette (ABC) proteins found in rod and cone photoreceptors, has been implicated in the transport of retinoid compounds across the outer segment disk membrane following the photoactivation of rhodopsin. Mutations in the ABCA4 gene are responsible for Stargardt macular dystrophy and related retinal degenerative diseases that cause a loss in vision. To identify the retinoid substrate that interacts with ABCA4, we have isolated ABCA4 from rod outer segment disk membranes on an immunoaffinity matrix and analyzed retinoid compounds that bind to ABCA4 using high performance liquid chromatography and radiolabeling methods. When all-trans-retinal was added to ABCA4 in the presence of phosphatidylethanolamine, approximately 0.9 mol of N-retinylidene-phosphatidylethanolamine and 0.3 mol of all-trans-retinal were bound per mol of ABCA4 with an apparent K(d) of 2-5 microm. ATP and GTP released these retinoids from ABCA4, whereas ADP, GDP, and nonhydrolyzable derivatives, adenosine 5'-(beta,gamma-imido)triphosphate and guanosine 5'-(beta,gamma-imido)triphosphate, were ineffective. One mole of N-retinyl-phosphatidylethanolamine, the reduced form of N-retinylidene-phosphatidylethanolamine, bound per mol of ABCA4, whereas 0.3 mol of all-trans-retinal were bound in the absence of phosphatidylethanolamine. No binding of all-trans-retinol to ABCA4 was observed. Our results indicate that ABCA4 preferentially binds N-retinylidene-phosphatidylethanolamine with high affinity in the absence of ATP. Our studies further suggest that ATP binding and hydrolysis induces a protein conformational change that causes N-retinylidene-phosphatidylethanolamine to dissociate from ABCA4.

ATP-Binding Cassette Transporters↗
PubMed1997

The lacrimal gland expresses nuclear retinoid X receptors.

PURPOSE: The lacrimal gland expresses nuclear retinoic acid receptors. This suggests that retinoids are involved in control of gene expression in the lacrimal gland. Retinoid X receptors (RXRs) form heterodimers with and are required for activation of retinoic acid receptors. The purpose of this study was to identify retinoid X receptors in the lacrimal gland. METHODS: Total RNA was purified from rat, rabbit and human lacrimal glands and from cultured rat lacrimal cells. RNA was analyzed by northern blotting using cDNA probes for RXR alpha, RXR beta and RXR gamma. Nuclear protein extracts from rat and rabbit lacrimal glands were probed for RXR beta by immunoblotting, using a mouse monoclonal antibody. RESULTS: RXR alpha mRNA transcripts (5 kb) and RXR beta mRNA transcripts (3.3 kb) are present in the lacrimal glands of all species studied and in cultured rat lacrimal cells. RXR gamma mRNA (1.9 kb) was detected only in the rabbit lacrimal gland. RXR beta is expressed as a 50 kDa protein in rat and rabbit lacrimal glands. CONCLUSIONS: This study confirms the presence of RXRs in the lacrimal gland, thereby supporting a role for retinoids and their nuclear receptors in the control of gene transcription in the lacrimal gland.

Animals↗