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PubMed1995

Retinoid signaling and the generation of regional and cellular diversity in the embryonic mouse spinal cord.

Retinoid-dependent gene expression accompanies the emergence of distinct regions and cell classes in the mouse spinal cord around midgestation. We asked whether changes in the expression of retinoid signaling molecules and retinoid-responsive genes reflect the establishment of this regional and cellular diversity. At E10.5, retinoic acid (RA) receptors (RAR)alpha, RAR beta, the retinoid X receptor (RXR) gamma, cellular RA binding protein (CRABP)I, CRAPBII, and cellular retinol binding protein (CRBP)I mRNAs are found throughout the entire anterior-posterior (AP) axis of the cord, as is RA (Colbert et al. [1993] Proc. Natl. Acad. Sci. U.S.A. 90:6572-6576) and RA-sensitive transgene expression (Balkan et al. [1992] Proc. Natl. Acad. Sci. U.S.A. 89:3347-3351). At E12.5, RA, transgene expression, and RAR beta become restricted to the cervical and lumbar cord. RAR alpha, CRABPI, and RXR gamma, however, are found throughout the AP extent. CRABPII and CRBPI, although expanded within the cervical and lumbar regions, are also found throughout the AP axis. Thus, several retinoid signaling molecules continue to be expressed beyond distinct regions of the spinal cord where RA is available and some RA-responsive genes are either restricted or enhanced. Exogenous RA can activate a more widespread response resulting in ectopic transgene and RAR beta expression in the thoracic and sacral cord. Not all RA-sensitive genes, however, respond; CRABPII and CRBPI expression patterns are unchanged. Finally, not every cell within the normal or exogenously induced domains of RA-dependent gene expression responds to RA, nor does every cell express RA receptors or binding proteins. Thus, regional and cellular differences in the distribution of the known retinoid receptors and binding proteins do not predict absolutely where or whether retinoid sensitive genes will be expressed or where retinoids will be available in the developing spinal cord. Instead, retinoid-mediated gene expression in the cervical and lumbar cord seems to reflect retinoid responses that rely both on the local availability of retinoids, the identity of the responding gene, and an indeterminate array of retinoid signaling molecules.

Animals↗

PubMed2000

Recent developments in receptor-selective retinoids.

Natural (all trans-retinoic acid, RA) and synthetic retinoids exhibit potent anti-proliferative, normalization of differentiation and anti-inflammatory activities which appear to account for their therapeutic effects in acne, psoriasis, photoaging, precancerous lesions and established cancers. Although RA has shown considerable promise in dermatologic indications, certain side effects have restricted its use as a choice of agent for chronic administration. Systematic synthesis of receptor-selective retinoids has resulted in two topical drugs, Tazorac/Zorac (tazarotene) and Differin (adapalene). Tazorac is indicated for psoriasis and acne and Differin gel for the treatment of acne. These drugs bind to the retinoic acid receptor (RAR) family members. Various RAR subtype-specific and function-selective retinoids have been synthesized. These retinoids, which are in various stages of pre-clinical development for the treatment of cancers, psoriasis and as an antidote to Accutane-mediated mucocutaneous toxicity, will also be discussed in this review. Discovery of another retinoid receptor, retinoid X receptor (RXR), revealed that RXR-specific retinoids already existed in retinoid chemical libraries. Structure activity relationship studies based upon binding and transactivation assays led to the synthesis of RXR-specific ligands with high affinities for RXR subtypes. These compounds were found to be effective in the treatment of hyperglycemia in animal models of type II diabetes. The discovery of novel retinoids along with an increased understanding of the biological functions and mechanisms of action of retinoid receptors are likely to result in improved treatments for existing responsive indications and identification of new retinoid therapeutic targets.

Adapalene↗

PubMed1999

Effects of novel RAR- and RXR-selective retinoids on myeloid leukemic proliferation and differentiation in vitro.

Retinoids such as all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid (9-cis-RA) have an important role in many aspects of proliferation and differentiation of hematopoietic cells. They exert their effects by binding to retinoic acid receptors (RARs) and/or retinoid X receptors (RXRs). We studied the effects of novel retinoids on proliferation and differentiation of HL-60 and NB4 myeloid leukemic cells, as well as acute promyelocytic leukemia (APL) cells from patients. RXR-selective SR11345 (Retinoid C) had little ability to inhibit the clonal growth and to induce the differentiation of either HL-60 or NB4 cells. However, SR11276 (Retinoid E), which activated both the RAR and RXR classes, and SR11278 (Retinoid D), which activated the RAR subtypes alpha, beta, and gamma, could inhibit clonal growth of both cell types, as well as leukemic cells from APL patients. The combination of ATRA and either SR11276 or SR11278 additively inhibited APL cell proliferation. SR11302 (Retinoid A), with reported anti-AP-1 activity and no activation of RARs and RXR and SR11363 (Retinoid B), which selectively activated RARbeta and gamma, were inactive. The clonal proliferation of both HL-60 and NB4 cells that were pulse-exposed to 10(-9) mol/L ATRA, SR11276, SR11278, or SR11345 for 3 days, washed, and plated in methylcellulose culture were inhibited by 0%, 51%, 21%, and 1% for HL-60 cells and 43%, 41%, 35%, and 1% for NB4, respectively, compared with nontreated control cells. When the HL-60 cells were pulse-exposed to 10(-9) mol/L of either SR11278 or SR11276, plus 10(-9) mol/L ATRA for 3 days, colony numbers were reduced by 46% and 64%, respectively. Induction of leukemic cell differentiation as determined by the nitroblue tetrazolium (NBT) assay showed that the combination of 10(-7) mol/L of either SR11278 or SR11276 with 10(-7) mol/L ATRA had additive effects on HL-60 cells, NB4 cells, and fresh APL cells. Induction of CD11b expression on both HL-60 and NB4 cells occurs during their differentiation. Expression of this antigen was synergistically augmented by the combination of either 10(-7) to 10(-8) mol/L SR11278 or 10(-7) to 10(-9) mol/L SR11276 with 10(-9) mol/L ATRA compared with either analog alone in HL-60 cells. Expression of the novel myeloid specific transcription factor C/EBPepsilon was increased by SR11278 and SR11276 in both the HL-60 and NB4 cell lines. We conclude that retinoids or combination of retinoids with specificities for both RAR and RXR may markedly enhance the ability of ATRA to inhibit clonal growth and induce differentiation of HL-60 and NB4 leukemic cells. This occurs in the absence of continuous contact with retinoids.

CCAAT-Enhancer-Binding Proteins↗

PubMed2005

Retinoid processing proteins in the ocular ciliary epithelium.

PURPOSE: To identify retinoids and retinoid processing proteins in the ocular ciliary epithelium (CE), and to compare in cultured ciliary epithelial cell lines promoter activities of the cellular retinaldehyde binding protein (CRALBP) and interphotoreceptor retinoid binding protein (IRBP). METHODS: Retinoid processing proteins were detected by RT-PCR, western analysis and immunocytochemistry. PCR products were verified by DNA sequence analysis. Retinoids were measured by normal phase HPLC and UV visible spectroscopy. Reporter product from CRALBP and IRBP promoter fragments was measured following transient transfection in bovine pigmented and nonpigmented CE cells. RESULTS: CRALBP, IRBP, cellular retinol binding protein (CRBP), 11-cis-retinol dehydrogenase (11-cis-RDH), lecithin:retinol acyltransferase (LRAT), and ATP binding cassette receptor (ABCR) were detected in human CE tissue by RT-PCR. Retinal pigment epithelium specific protein 65 kDa (RPE65) mRNA and protein were also detected. CRALBP and IRBP were detected by western analysis in tissue extracts from bovine CE and were localized to the PE and NPE cell layers, respectively, by immunocytochemistry. IRBP immunoreactivity was also detected in aqueous humor. Retinoids identified in the bovine CE include retinyl esters (7.4+/-3.5 pMol/mg of protein) and all-trans-retinol (14.9+/-1.1 pMol/mg of protein). Betacarotene was also tentatively identified. 11-cis-Retinoids were not detected. In CE cell cultures, the CRALBP p2.1-kb promoter construct exhibited reporter activity 15-30 fold above basal level, with 2 fold more activity in pigmented than nonpigmented CE cells. IRBP promoter constructs exhibited low level reporter activities in vitro in both CE cell layers. CONCLUSIONS: The ocular CE expresses genes encoding components of the rod visual cycle. The differential localization of CRALBP and IRBP along the bilayer of the CE suggests a potential role in retinoid transport and/or retinoid metabolism. However, the absence of 11-cis-retinoids suggests that the function of retinoid processing proteins in the CE differs from that of the retina.

ATP-Binding Cassette Transporters↗

PubMed1999

Complexity, retinoid-responsive gene networks, and bladder carcinogenesis.

Carcinogenesis involves inactivation or subversion of the normal controls of proliferation, differentiation, and apoptosis. However, these controls are robust, redundant, and interlinked at the gene expression levels, regulation of mRNA lifetimes, transcription, and recycling of proteins. One of the central systems of control of proliferation, differentiation and apoptosis is retinoid signaling. The hRAR alpha nuclear receptor occupies a central position with respect to induction of gene transcription in that when bound to appropriate retinoid ligands, its homodimers and heterodimers with hRXR alpha regulate the transcription of a number of retinoid-responsive genes. These include genes in other signaling pathways, so that the whole forms a complex network. In this study we showed that simple, cause-effect interpretations in terms of hRAR alpha gene transcription being the central regulatory event would not describe the retinoid-responsive gene network. A set of cultured bladder-derived cells representing different stages of bladder tumorigenesis formed a model system. It consisted of 2 immortalized bladder cell lines (HUC-BC and HUC-PC), one squamous cell carcinoma cell line (SCaBER), one papilloma line (RT4), and 4 transitional cell carcinomas (TCC-Sup, 5637, T24, J82) of varying stages and grades. This set of cells were used to model the range of behaviors of bladder cancers. Relative gene expression before (constitutive) and after treatment with 10 microM all-trans-retinoic acid (aTRA) was measured for androgen and estrogen receptor; a set of genes involved with retinoid metabolism and action, hRAR alpha nd beta, hRXR alpha and beta CRBP, CRABP I and II; and for signaling genes that are known to be sensitive to retinoic acid, EGFR, cytokine MK, ICAM I and transglutaminase. The phenotype for inhibition of proliferation and for apoptotic response to both aTRA and the synthetic retinoid 4-HPR was determined. Transfection with a CAT-containing plasmid containing an aTRA-sensitive promoter was used to determine if the common retinoic acid responsive element (RARE)-dependent pathway for retinoid regulation of gene expression was active. Each of the genes selected is known from previous studies to react to aTRA in a certain way, either by up- or down-regulation of the message and protein. A complex data set not readily interpretable by simple cause and effect was observed. While all cell lines expressed high levels of the mRNAs for hRXR alpha and beta that were not altered by treatment with exogenous aTRA, constitutive and stimulated responses of the other genes varied widely among the cell lines. For example, CRABP I was not expressed by J82, T24, 5637 and RT4, but was expressed at low levels that did not change in SCaBER and at moderate levels that decreased, increased, or decreased sharply in HUC-BC, TCC-Sup and HUC-PC, respectively. The expression of hRAR alpha, which governs the expression of many retinoid-sensitive genes, was expressed at moderate to high levels in all cell lines, but in some it was sharply upregulated (TCC-Sup, HUC-PC and J82), remained constant (5637 and HUC-BC), or was down-regulated (SCaBER, T24 and RT4). The phenotypes for inhibition of proliferation showed no obvious relationship to the expression of any single gene, but cell lines that were inhibited by aTRA (HUC-BC and TCC-Sup) were not sensitive to 4-HPR, and vice versa. One line (RT4) was insensitive to either retinoid. Transfection showed very little retinoid-stimulated transfection of the CAT reporter gene with RT4 or HUC-PC. About 2-fold enhancement transactivation was observed with SCaBER, HUC-BC, J82 and T24 cells and 3-8 fold with 5637, TCC-Sup cells. In HUC-BC, a G to T point mutation was found at position 606 of the hRAR alpha gene. This mutation would substitute tyrosine for asparagine in a highly conserved domain. These data indicate that retinoid signaling is probably a frequent target of inactivation in bladder carcinogenesis. (ABSTRAC

Animals↗

PubMed1990

Retinoids inhibit phospholipase A2 in human synovial fluid and arachidonic acid release from rat peritoneal macrophages.

Retinoids have demonstrated antiinflammatory activity in certain animal models and human disease states. The mechanism by which retinoids elicit this activity is unknown. Some retinoids are known to inhibit arachidonic acid (AA) release and metabolism in intact cells in vitro. Retinoids may exert their antiinflammatory effects by inhibiting phospholipase A2 (PLA2) and the resultant production of inflammatory AA metabolites. Retinoids were evaluated in vitro as inhibitors of the PLA2 activity in human synovial fluid (HSF-PLA2). Of the naturally occurring, nonaromatic retinoids tested, all-trans-retinal, all-trans-retinoic acid (all-trans-RA) and 13-cis-RA were the most potent inhibitors (IC50 S 6-15 microM), whereas all-trans-retinol was much less potent. Of the synthetic aromatic retinoids and arotinoids examined, the free carboxylic, sulfonic, and sulfinic acid forms were more than 15-fold more potent inhibitors of HSF-PLA2 than their corresponding ethyl esters. These retinoids also were evaluated as inhibitors of calcium ionophore A23187-induced AA release from rat peritoneal macrophages. All-trans-RA and 13-cis-RA were potent inhibitors of AA release from these cells (IC50 S 4 microM), while the other natural retinoids were inactive. Of the aromatic retinoids and arotinoids tested, the free acid forms (IC50 S 2-6 microM) were 5- to 21-fold more potent inhibitors of AA release from the macrophages than their corresponding ethyl esters. The potencies of the arotinoids as inhibitors of HSF-PLA2 appeared to correlate with their potencies as inhibitors of AA release from A23187-stimulated rat peritoneal macrophages. These data support the hypothesis that one possible mechanism for the known antiinflammatory activity of some retinoids may be by inhibition of phospholipase A2.

Animals↗

PubMed2005

Retinoids interfere with the AP1 signalling pathway in human breast cancer cells.

Retinoic acid and its synthetic analogs exert major effects on many biological processes including cell proliferation and differentiation and are now considered as promising pharmacological agents for prevention and treatment of various cancers. The capacity of retinoids to inhibit AP1-responsive genes seems to be the basis for the chemopreventive and chemotherapeutic effects of these agents against hyperproliferative diseases. However, the molecular basis of retinoid antiproliferative properties remains to this day largely unknown. Here, we showed that retinoids inhibit phorbol ester-induced MMP-1 and MMP-3 expression in human breast cancer cells. Transcriptional interference was observed for both retinoid agonist and antagonist treatments, revealing separated transactivation and transrepression functions of retinoids. In addition, we examined MAP kinases as potential targets of retinoid signalling in human breast cancer cells and demonstrated that retinoids repress AP1-responsive gene expression by inhibiting MKK6/p38 and mainly MEK/ERK signalling pathways. On the contrary, the JNK-dependent pathway was not identified as a molecular relay for AP1 activity and was insensitive to retinoid treatments. Finally, we established that overexpressed c-fos and c-jun partially abolished the ability of retinoids to inhibit AP1 activity, suggesting that c-jun and/or c-fos containing dimers may constitute one target of retinoids for transrepression of AP1. All together, our data help to improve our understanding of how retinoids antagonize AP1 activity and may regulate tumoral cell proliferation.

Breast Neoplasms↗

PubMed1988

Structure-activity relationships of retinoids in developmental toxicology. III. Contribution of the vitamin A beta-cyclogeranylidene ring.

The teratogenic potency of congeners of all-trans-retinoic acid (all-trans-RA) containing modifications or substitution of the naturally occurring beta-cyclogeranylidene ring was determined in Golden hamsters and compared to that of all-trans-RA. The following ring-modified retinoids were screened: phenyl (Ro 8-8717), furyl (Ro 8-9750), 4-methoxy-2,3,6-trimethylphenyl (Ro 21-6667), which also has a thiomethylene group in place of the trans-8,9 double bond of the etretin side chain, 4-hydroxy-2,3,6-trimethylphenyl (Ro 11-4768), 2-chloro-3,6-dimethyl-4-methoxyphenyl (Ro 12-0995), 2-(1-methoxyethyl)-5,5-dimethyl-1-cyclopentenyl (Ro 10-1770), 2-acetyl-5,5-dimethyl-1-cyclopentenyl (Ro 8-7699), and 10,11-epoxy-11,11-dimethyl (juvenile hormone III), which also has the bonds corresponding to the 7,8- and 11,12-double bond of the retinoid skeleton saturated. The retinoids Ro 12-4824, Ro 12-4825, and SRI2712-24 had C4-keto, C18-hydroxyl, and C18-methyl substituents, respectively. Motretinid (Ro 11-1430) had both 4-methoxy-2,3,6-trimethylphenyl ring and ethyl amide polar group modifications. Single oral retinoid doses administered to pregnant dams at 10:00 AM on Day 8 neither induced signs of hypervitaminosis A nor induced weight loss in any of the treated groups. Teratogenically active retinoids induced a malformation syndrome identical to that induced by all-trans-RA. At retinoid doses that were associated with malformations in all of the fetuses, embryolethality remained near that of vehicle-treated controls. The phenyl retinoid Ro 8-8717 was embryolethal but was not teratogenic. The ethyl amide derivative of the human and animal teratogen etretinate, motretinid, was teratogenic only at the highest dose administered, 350 mg/kg. The retinoids Ro 12-4824, Ro 12-4825, Ro 8-7699, and SRI 2712-24 were as potent as all-trans-RA. The chlorine substituted retinoid, Ro 12-0995, was sixfold more teratogenic than all-trans-RA, and the cyclopentene retinoid, Ro 10-1770, was 19 times more potent than all-trans-RA. The retinoids with furyl or epoxy group substitution for the cyclohexenyl ring were devoid of teratogenic activity up to equimolar doses of 75 mg/kg of all-trans-RA, and Ro 21-6667 was teratogenically inactive at a dose equivalent to 150 mg/kg of all-trans-RA. Major modifications of the beta-cyclogeranylidene ring can be made without altering teratogenic activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2006

Structure elucidation of retinoids in biological samples using postsource decay laser desorption/ionization mass spectrometry after high-performance liquid chromatography separation.

Retinoids [retinol (vitamin A) and its metabolites] function in the visual cycle, embryonic development, cellular differentiation, and tissue homeostasis. Notwithstanding pivotal roles of retinoids in mammals, the limited number of commercially available retinoid standards is a major roadblock to identifying and studying retinoids in biological samples. Therefore, a need exists for improved methods to identify retinoid metabolites. We analyzed polar and nonpolar retinoids, including retinoic acid, retinol, retinyl acetate, and other retinyl esters, using postsource decay laser desorption/ionization mass spectrometry (PSD-LDI MS). PSD analysis was employed to examine the PSD fragmentation patterns of retinoids, as these patterns can be used for the characterization of retinoids from biological samples without the need for matching retention time with a commercially available or synthetic retinoid. Mechanisms for the formation of these PSD fragment ions are proposed. The feasibility of employing PSD after HPLC separation was demonstrated by characterizing the endogenous retinoids in canine kidney epithelial cell extracts and in mouse lung. We show that the PSD-LDI MS approach described here can facilitate the identification and characterization of retinoids from mammalian cells and tissues.

Animals↗

PubMed1999

Role of retinoid receptors in the prevention and treatment of breast cancer.

Retinoids are vitamin A-related compounds that have been found to prevent cancer in animals and humans. In this review, we discuss the role of retinoids and their receptors in the treatment and prevention of breast cancer. The retinoid receptors are expressed in normal and malignant breast cells, and are critical for normal development. In breast cells, when bound by retinoid hormones, these proteins regulate proliferation, apoptosis, and differentiation. The mechanism by which retinoids inhibit breast cell growth has not been completely elucidated, however, retinoids have been shown to affect multiple signal transduction pathways, including IGF-, TGFbeta-, and AP-1-dependent pathways. Retinoids have also been shown to suppress the growth and prevent the development of breast cancer in animals. These agents suppress tumorigenesis in carcinogen-treated rats and in transgenic mice, and inhibit the growth of transplanted breast tumors. These promising preclinical results have provided the rationale to test retinoids in clinical trials for the treatment and prevention of breast cancer. Several retinoids, including all trans retinoic acid and 9-cis retinoic acid, have been shown to have modest activity in the treatment of breast cancer, and these agents are now in clinical trials in combination with cytotoxic agents and anti-estrogens. Another retinoid, 4-HPR, is currently being tested in a human cancer prevention trial. Preliminary results suggest that 4-HPR may suppress breast cancer development in premenopausal women. Future clinical trials will focus on testing new synthetic retinoids that have reduced toxicity and enhanced therapeutic and preventive efficacy.

Animals↗

PubMed1999

Novel retinoids with receptor selectivity and functional selectivity.

Retinoids mediate a number of physiological pathways through their effects on cellular growth and differentiation. Upon binding to retinoic acid receptors (RARs) and retinoid X receptors (RXRs), retinoids regulate cellular processes by directly modulating the expression of responsive genes. The wide-ranging effects of retinoid action are attributable to two main factors-the ubiquitous distribution of several subtypes and isoforms of RARs and RXRs, and the ability of these receptors to regulate numerous genes upon ligand activation. The broad range of effects mediated by retinoids means not only that they have many potential therapeutic applications but also that non-selective retinoids are associated with a high incidence of adverse effects. The design of retinoids that are receptor-selective and function-selective is a strategy that is proving successful in developing novel retinoids that offer not only good efficacy but also good tolerability. Tazarotene, a receptor-selective retinoid indicated for the topical treatment of psoriasis, is at the forefront of this new generation of retinoids. In the near future, other receptor-selective retinoids may prove useful for the treatment of other dermatological diseases, cancer, and diabetes.

Antineoplastic Agents↗

PubMed2003

Oral retinoid use reduces cutaneous squamous cell carcinoma risk in patients with psoriasis treated with psoralen-UVA: a nested cohort study.

BACKGROUND: Small open studies of patients at high risk for squamous cell carcinoma (SCC) of the skin suggest that oral retinoid use reduces the risk of these tumors. Among patients at lower risk, randomized trials of low doses of retinoids did not demonstrate significant chemopreventive effects. Patients with psoriasis treated with oral psoralen-UVA have a high risk of SCC development. Oral retinoids are used to treat psoriasis. We performed a nested cohort study to assess whether oral retinoids reduce skin cancer risk among patients with psoriasis exposed to psoralen-UVA. METHODS: From 1985 to 2000, 135 patients (11.3% of surviving patients in our cohort) used retinoids for at least 26 weeks in 1 year or more. For these 135 patients, we compared each person's SCC and basal cell carcinoma incidence during years of substantial oral retinoid use and other years. We used Poisson regression models to adjust for potential confounders. RESULTS: In a paired analysis, which compared each patient's own tumor experience while using and not using retinoids, retinoid use was associated with a 30% reduction in SCC incidence (196 SCCs/1000 and 302 SCCs/1000 years of use and no use, respectively; P =.002). After adjusting for other factors associated with SCC risk, the incidence of SCC was significantly decreased during years of substantial retinoid use (incidence rate ratio = 0.79; 95% confidence interval = 0.65, 0.95). Oral retinoid use and basal cell carcinoma incidence were not significantly associated. CONCLUSION: In patients with psoriasis treated with psoralen-UVA, systemic retinoid use reduced SCC risk but did not significantly alter basal cell carcinoma incidence.

Adult↗

PubMed1992

Retinoids in cancer prevention and therapy.

Retinoids are a class of compounds structurally related to vitamin A. In preclinical studies, all-trans retinoic acid (tretinoin), 13-cis retinoic acid (isotretinoin) and the aromatic retinoids etretinate and acitretin have preventive and therapeutic effects on carcinogen-induced premalignant and malignant lesions. Clinically, chemoprevention with isotretinoin and etretinate has been tested with some degree of success in such indications as basal cell carcinomas, squamous cell carcinomas, superficial bladder tumors and second primary tumors in patients with squamous cell carcinoma of the head and neck. Limited therapeutic success has also been achieved with retinoid treatment of precancerous and cancerous conditions of the skin, oral cavity, larynx, lung, bladder and vulva. Dramatic therapeutic effects have been observed in the treatment of acute promyelocytic leukemia with tretinoin, which leads to very high rate of complete remission. Excellent results were recently reported in the treatment of squamous cell carcinomas of the skin and cervix with a combination of isotretinoin and recombinant interferon alfa-2a (rIFN alfa-2a, Roferon-A). The mechanism of action of retinoids is through modulation of cell proliferation and differentiation. Retinoids vary in their capacity to induce differentiation and to inhibit proliferation in a series of human transformed hematopoietic and epithelial cell lines. Some cytokines potentiate the retinoid-induced cell differentiation and act synergistically with retinoids to inhibit cell proliferation. The pattern of synergism is dependent upon the combination and tumor cell line tested. The discovery of nuclear retinoid receptors has contributed substantially to the understanding of the mechanism of action of retinoids at the molecular level. Further understanding of the molecular biology of retinoids is expected to contribute to a rational design of new retinoids in the future, which in turn may result in improvements in the prevention and therapy of cancer.

Animals↗

PubMed1991

Retinoids and interferon: a new promising combination?

The retinoids: all-transretinoic acid (tretinoin), 13-cis retinoic acid (isotretinoin) and the aromatic retinoids etretinate and acitretin have a preventive and therapeutic effect on chemically-induced tumours. Clinically, retinoids have shown variable effectiveness in therapy and/or prevention of oncological diseases of skin, head and neck, lung, bladder, vulva and bone marrow. With a few exceptions, monotherapy with retinoids has not been satisfactory. Similarly, monotherapy with interferon alpha has been used successfully only for some specific indications. Retinoids have a marked differentiation-inducing effect which may contribute to their therapeutic effect. Experiments were carried out in transformed cell lines to test the combination of retinoids with interferon alpha and other cytokines on differentiation. In HL-60 cells, an acute promyelocytic leukaemia cell line, induction of differentiation was determined by induction of an oxidative burst potential. Retinoids showed the following order of activity: tretinoin greater than isotretinoin greater than acitretin. Cytokines had no differentiation-inducing effect by themselves. However, the addition of the following cytokines to retinoids potentiated the retinoid-induced differentiation: IFN alpha, IFN beta, IFN gamma, TNF alpha, G-CSF, IL-1 alpha and IL-4. In experiments with HL-60 or other cell lines, the pattern of differentiation-induction was always dependent on the particular retinoid/cytokine combination. IFN alpha provoked a marked potentiation of retinoid-induced differentiation. The combination of the antiproliferative and differentiation-inducing effect of the retinoids together with the antiproliferative, immunostimulatory and differentiation-potentiating effects of IFN alpha suggests that this combination might be a particularly promising treatment for neoplastic diseases.

Cell Differentiation↗

PubMed2001

Cyclin proteolysis as a retinoid cancer prevention mechanism.

The retinoids, natural and synthetic derivatives of vitamin A, are active in cancer therapy and prevention. Their biological effects are mediated through ligand-dependent interactions with retinoid receptors that associate with specific co-regulators. A better understanding of retinoid chemopreventive mechanisms is needed. Our prior work revealed that all-trans-retinoic acid (RA) prevented tobacco-specific carcinogenic transformation of cultured human bronchial epithelial cells. RA signaled G1 arrest that permitted repair of genomic DNA damage caused by these carcinogens. RA triggered G1 arrest at least partly through proteasome-dependent degradation of cyclin D1. Proteasomal inhibitors blocked RA-mediated cyclin D1 degradation. To confirm that a specific proteolysis pathway was induced by RA-treatment, a degradation assay was established using in vitro translated cyclin D1 and cellular extracts from RA-treated or untreated human bronchial epithelial cells. Incubation of RA-treated but not the control cellular extracts with in vitro translated cyclin D1 led to cyclin degradation. This degradation depended on the PEST domain of cyclin D1, implicating ubiquitination in this retinoid degradation. Retinoid receptor selective agonists demonstrated that retinoic acid receptor (RAR)beta and retinoid X receptor (RXR) but not RARalpha- or RARgamma-dependent pathways signaled this cyclin degradation. Findings were extended to the NT2/D1 human embryonal carcinoma differentiation model where a similar pathway was activated by RA-treatment. To determine whether G1 cyclins were involved directly in bronchial preneoplasia, immunohistochemical expression profiles for cyclins D1 and E were examined. Aberrant expression of these cyclins was frequent in bronchial preneoplasia. Taken together, these findings indicate that ubiquitin-dependent proteolysis of G1 cyclins is a retinoid chemoprevention mechanism. Whether the retinoids represent the optimal agents to activate this pathway is the subject of ongoing work. These findings provide a rationale for combining the retinoids in chemoprevention trials with other agents that do not activate this proteolysis pathway. What is now known about the retinoids as cancer prevention agents will be reviewed. Emphasis is placed on retinoid effects on cell cycle progression at G1.

Animals↗

PubMed2002

Retinoid receptor-specific agonists alleviate experimental glomerulonephritis.

Retinoids are potent antiproliferative and anti-inflammatory compounds. We previously demonstrated that the natural pan-agonists all-trans retinoic acid (RA) and 13-cis RA efficiently preserve renal structure and function in rat mesangioproliferative glomerulonephritis. We examine effects of synthetic retinoid receptor-specific agonists 1) to identify common and receptor subtype-specific pathways in this model and 2) to characterize effects of retinoids on the renal endothelin (ET) system. Vehicle-injected control rats were compared with rats treated with daily subcutaneous injections of agonists specific for retinoid A (Ro-137410) and retinoid X (Ro-257386) receptors and the complex anti-activator protein-1 active retinoid BMS-453 7 days after induction of anti-Thy1.1 nephritis (n = 7-9/group). The different retinoids lowered glomerular ET-1 and ET type A and B receptor gene expression in control and nephritic rats with comparable efficacy. Reduction of glomerular c-Fos and GATA-2 mRNA expression levels suggests downregulation of transcription factors required for ET expression. The different retinoids were similar in their action on the glomerular capillary occlusion score, number of total glomerular cells, and glomerular infiltrating macrophage count. They differed in their ability to normalize blood pressure (Ro-257386 > BMS-453 > arotinoid), albuminuria (BMS-453 > Ro-257386 > arotinoid), and creatinine clearance (arotinoid > BMS-453 > Ro-257386). No signs of toxicity were observed. We conclude that all retinoid agonists with different subtype specificity are highly efficient in reducing renal damage and proliferation of mesangial cells. Retinoid X and A receptor-specific pathways are apparently involved in the antiproliferative, anti-inflammatory, and anti-ET action. Further studies are indicated to define the potential use of retinoid agonists in inflammatory renal disease.

Albuminuria↗

PubMed1993

Pharmacological effects of retinoids on skin cells.

Retinoids exert profound pleiotropic effects in skin, affecting many aspects of cell differentiation and proliferation. For this reason, retinoids have prominent pharmacological effects on major skin cells (keratinocytes, dermal fibroblasts, melanocytes, sebocytes) and have shown great potential as therapeutic agents in dermatology. In keratinocytes, retinoids induce proliferation, resulting in epidermal hyperplasia. Retinoids also modulate epidermal differentiation, however, many of the suppressive effects of retinoids observed in vitro do not occur in vivo. Dermal fibroblasts are important target cells of retinoids and are stimulated to produce extracellular matrix proteins, particularly when skin is damaged by wounding, ultraviolet radiation or glucocorticoids. Retinoids regulate pigmentation and can lighten hyperpigmented skin in animals and humans. Studies with cultured melanocytic cells show that tyrosinase activity is reduced by retinoids. The powerful sebosuppressive effect of some retinoids, such as 13-cis-retinoic acid, demonstrates that sebocyte differentiation is altered by retinoids. Retinoids inhibit proliferation and lipid synthesis in cultured human sebocytes and alter their keratin expression.

Animals↗

PubMed2006

Retinoids induce growth inhibition and apoptosis in mast cell tumor cell lines.

Retinoids are well recognized as promising antitumor agents in humans. However, there have only been a few reports about the effect of retinoids in canine cancers. To investigate the antitumor effect of retinoids on mast cell tumors (MCT), inhibitory effect on cell growth and induction of apoptosis were examined in vitro. Although sensitivity of these cells differed among the cells, the growth of three MCT cell lines (CoMS, CM-MC and VI-MC) were inhibited dose dependently when they were treated with retinoids. FACS analysis of PI-stained nuclei revealed an apoptotic fraction in CM-MC cells about 30% when treated with retinoids, while those of control cells were less than 5%. Caspase-3 activation was observed after retinoid treatment in CM-MC cells. This was confirmed by inhibiting the retinoid-induced apoptosis using the pan-caspase inhibitor, ZVAD-FMK. Both retinoid receptors, RARs and RXRs, were detected by immunoprecipitation followed by western blot analysis in all the three MCT cells. These data suggests that retinoids inhibit the growth of MCTs partly through apoptosis, and this growth inhibition by retinoids may be mediated by RARs and RXRs. We conclude that retinoid may be a potential adjunctive chemotherapeutic agent for the treatment of canine MCT.

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