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PubMed1980

Sister-chromatid exchange induction by metabolically activated retinoids in human diploid fibroblast cultures.

13-cis-Retinoic acid, retinyl-mthyl-ether, retinyl-phenyl-ether, retinyl-thio-ether and axerophthene each induced dose-dependent sister-chromatid exchanges (SCE) in human diploid fibroblasts. The functional relationship between retinoid concentration and SCE rate was similar in each of the 5 retinoids tested. The relationship reached a plateau at concentrations exceeding 8 micrograms/ml. alpha-Naphthoflavone (ANF), an inhibitor of P448-dependent mono-oxygenase, prevented the retinoid-induced increase of the SCE rate, but had no inhibitory effect in the presence of 4-nitroquinoline-1-oxide, an ultimate carcinogen. ANF did not reduce the spontaneously increased SCE rate in fibroblasts of patients with Bloom's syndrome. Retinoids failed to induce SCE in V79 Chinese hamster cells, which lack mono-oxygenase. Thus, we conclude that the retinoid-induced SCE rate increases independently of structural changes in the molecular side-chain ad that a metabolic activation of retinoids is required for SCE induction by cytochrome P448-dependent mono-oxygenase.

Abnormalities, Multiple↗
PubMed1985

Dose-dependent suppression by the synthetic retinoid, 4-hydroxyphenyl retinamide, of streptococcal cell wall-induced arthritis in rats.

We studied the effects of oral administration of the retinoid, 4-hydroxyphenyl retinamide (4-HPR), on group A streptococcal cell wall-induced polyarthritis in the rat, a model characterized initially by exudative inflammation of peripheral joints followed by chronic proliferative/erosive synovitis. Experimental arthritis was induced in female LEW/N rats by i.p. injection of streptococcal cell walls in saline (15 micrograms/g body weight). Depending upon the experiment, continuous daily oral administration of the retinoid was begun either 14 days prior to induction of the disease, at the time of cell wall administration and/or 11 days and 31 days after cell wall injection. Dosage was either 1 or 2 mmol 4-HPR/kg of chow. During the course of the disease, severity of clinical illness was assessed by determination of clinical severity index, by histological or radiologic examination, and by measurement of production in vitro of collagenase and prostaglandin E2 by excised synovial tissue. In rats fed the retinoid prior to cell wall injection, both the acute and the chronic responses were suppressed. In rats given the retinoid at the time of cell wall injection, the acute inflammatory response was only partially suppressed on the diet containing 2 mmol 4-HPR/kg chow, but the chronic disease was impressively inhibited in a dose dependent manner. Similarly, in animals with established disease, the drug was also effective; however, the more advanced the illness, the less effective the drug. Clinical observations were paralleled by the histological, radiographical and biochemical analyses. Treated animals showed far less synovial proliferation and joint destruction, and synovial tissues taken from these rats produced lesser amounts of collagenase and prostaglandin E2. No significant toxicity of the retinoid was noted. We conclude that oral administration of 4-HPR suppresses, in a dose and time dependent manner, both the acute and chronic stages of streptococcal cell wall-induced arthritis in rats without apparent significant toxicity. Our data suggest that studies of the effects of this retinoid on patients with chronic inflammatory synovitis are warranted.

Animals↗
PubMed2004

Identification of 14-hydroxy-retro-retinol and 4-hydroxy-retinol as endogenous retinoids in rats throughout neonatal development.

14-Hydroxy-retro-retinol was previously described as an in vivo and in vitro metabolite of retinol. Furthermore, the retinoid 4-hydroxy-retinol was identified as an endogenous occurring retinoid in the amphibian organism and an in vitro metabolite of retinol. We describe in the present study that 14-hydroxy-retro-retinol and 4-hydroxy-retinol are present in normal neonatal rat serum as endogenous occurring retinoids in normal non-vitamin A supplemented mammals (rats). Both retinoids were detected in serum and liver of neonatal rats at days 3 and 11 after birth. The respective concentrations at day 11 after birth were 41.8 +/- 2.8 ng/ml (serum)/ 104 +/- 6 ng/g (liver) for 4-hydroxy-retinol and 23 +/- 4.6 ng/ml (serum)/ 285 +/- 5 ng/g (liver) for 14-hydroxy-retro-retinol. Both retinoids could not be detected in adult rat serum and liver. From our experiments important physiological functions of these retinoids during postnatal development could be postulated.

Animals↗
PubMed2006

Regulation of retinoic acid receptors alpha, beta and retinoid X receptor alpha after sciatic nerve injury.

Cell culture experiments indicated that activation of the retinoic acid signaling system is involved in axonal regeneration. This hypothesis was tested with sciatic nerve injury in the rat. Since the effect of retinoic acid is mediated via retinoic acid receptors and retinoid X receptors, we investigated mRNA and protein expression of these receptors during injury-induced degeneration and regeneration. Seven days after crush injury, transcript concentrations of all retinoic acid receptors and of retinoid X receptor alpha were significantly higher than in non-lesioned nerves. Protein levels of retinoic acid receptor alpha, retinoic acid receptor beta and retinoid X receptor alpha were upregulated 4, 7 and 14 days after injury. In degenerating nerves a significant increase of retinoic acid receptor alpha was detected 7 and 14 days, and of retinoic acid receptor beta 14 and 21 days after complete transection. Immunohistochemical staining of retinoid receptors revealed their expression in Schwann cells and macrophages. In addition, we observed that retinoic acid receptor alpha and retinoid X receptor alpha appeared in the cell nuclei of macrophages during the lesion-induced inflammatory reaction, and that retinoid X receptor alpha-staining co-localized with some regenerating axons. Experiments with Schwann cell primary cultures revealed an effect of retinoic acid on the expression of the neuregulin receptor ErbB3, suggesting that one function of retinoic acid consists in the regulation of neuroglial interactions after peripheral nerve injury.

Animals↗
PubMed2000

Effects of retinoids on cell toxicity and apoptosis in leukemic blast cells from patients with non-M3 AML.

All-trans retinoic acid (ATRA) induces complete remission in acute promyelocytic leukemia (APL or M3). In this study we measured the effect of retinoids alone and in combination with daunorubicin (DNR) on cell growth and apoptosis in blast cells from patients with non-M3 AML. Cells from 21 patients were incubated in 0.2 microM daunorubicin for 1 h or in 1 microM ATRA or 9-cis-RA continuously and in the combinations of DNR with both retinoids. Cell toxicity and apoptosis were analyzed after 96 h. Both ATRA and 9-cis-RA reduced the viability significantly to 86 and 84%, respectively (P = 0.003 for ATRA and 0.02 for 9-cis-RA). The expression of CD34 correlated to a higher sensitivity to ATRA (P = 0.003). When retinoids were added to DNR the mean decrease in viability was 11 percentage points with ATRA (P = 0.003) and nine percentage points with 9-cis-RA (P = 0.02). Apoptosis was induced by both retinoids and the percentage of apoptotic cells was increased from 16% in the controls to 24% with ATRA (P = 0.03) and to 26% with 9-cis-RA (P = 0.04). When the retinoids were added to DNR the apoptotic rate increased from 41% with DNR alone to 51% with ATRA (P = 0.01) and to 49% with 9-cis-RA (P = 0.03). We conclude that ATRA and RA exert a slight but clear cytotoxic and apoptotic effect on AML blast cells after 96 h incubation and that retinoids can have an additive or synergistic effects on cell toxicity when added to daunorubicin.

Acute Disease↗
PubMed1980

Retinoids specifically enhance the number of epidermal growth factor receptors.

Retinoids elicit many biological and biochemical responses from cells in vitro. One widely used criterion for the responsiveness of cells to retinoids is inhibition of growth; retinoids reduce the saturation density and/or growth rate of many normal and tumorigenic cell lines. Propagation of eukaryotic cells has been demonstrated to be dependent on the presence of macromolecular growth factors such as epidermal growth factor (EGF), which can stimulate proliferation of epithelial and fibroblastic cell lines. We now describe the effect of retinoids on the binding of EGF to its receptor. Retinoic acid enhances binding of 125I-labelled EGF to various fibroblastic and epidermal cell lines. It has no marked effect on the affinity of this growth factor for its receptor, but increases the number of EGF receptor sites. Retinoic acid has little effect on the binding of concanavalin A (Con A) and insulin, indicating the specific nature of the action of retinoids on cell-surface glycoproteins. Treatment of cells with the phorbol ester 12-o-tetradecanoyl phorbol-13-acetate (TPA) and retinoic acid shows poor antagonism between these compounds on EGF binding. It has been previously shown that retinoids induce or stimulate differentiation of embryonal carcinoma cells. EGF binding can be used as a marker to monitor differentiation of these cells.

Animals↗
PubMed1998

Retinoid-induced apoptosis in normal and neoplastic tissues.

Vitamin A and its derivatives (collectively referred to as retinoids) are required for many fundamental life processes, including vision, reproduction, metabolism, cellular differentiation, hematopoesis, bone development, and pattern formation during embryogenesis. There is also considerable evidence to suggest that natural and synthetic retinoids have therapeutical effects due to their antiproliferative and apoptosis-inducing effects in human diseases such as cancer. Therefore it is not surprising that a significant amount of research was dedicated to probe the molecular and cellular mechanisms of retinoid action during the past decade. One of the cellular mechanisms retinoids have been implicated in is the initiation and modulation of apoptosis in normal development and disease. This review provides a brief overview of the molecular basis of retinoid signaling, and focuses on the retinoid-regulation of apoptotic cell death and gene expression during normal development and in pathological conditions in vivo and in various tumor cell lines in vitro.

Apoptosis↗
PubMed2003

Active repression by unliganded retinoid receptors in development: less is sometimes more.

The retinoid receptors have major roles throughout development, even in the absence of ligand. Here, we summarize an emerging theme whereby gene repression, mediated by unliganded retinoid receptors, can dictate cell fate. In addition to activating transcription, retinoid receptors actively repress gene transcription by recruiting cofactors that promote chromatin compaction. Two developmental processes for which gene silencing by the retinoid receptors is essential are head formation in Xenopus and skeletal development in the mouse. Inappropriate repression, by oncogenic retinoic acid (RA)**Abbreviations used in this paper: APL, acute promyelocytic leukemia; dnRARalpha, dominant-negative version of the RARalpha; E, embryonic age; HDAC, histone deacetylase; LCoR, ligand-dependent corepressor; NCoR, nuclear receptor corepressor; RA, retinoic acid; RAR, RA receptor; RARE, RXR homodimer bound to bipartite response element; RXR, retinoid X receptor; TSA, trichostatin A; CYP26, cytochrome p450, 26; TR, thyroid hormone receptor. receptor (RAR) fusion proteins, blocks myeloid differentiation leading to a rare form of leukemia. Our current understanding of the developmental role of retinoid repression and future perspectives in this field are discussed.

Animals↗
PubMed1995

N-(4-hydroxyphenyl)retinamide: interactions with retinoid-binding proteins/receptors.

The cellular transport, metabolism and biological activity of retinoids are mediated by their specific binding proteins and nuclear receptors. For an understanding of the mode of action of retinoids with potential cancer chemopreventive or other biological activity, it is important to study their interactions with these binding proteins and receptors. In our attempts to understand the action of N-(4-hydroxyphenyl)retinamide (4HPR) and other retinamides in the prevention of cancer, we observed that 4HPR binds to a serum protein with a molecular size of approximately 20,000. The retinoid, however, did not show any binding affinity for cellular retinol-binding protein (CRABP) or for cellular retinoic acid-binding protein (CRABP). However, it showed binding affinity for the nuclear receptors of retinoic acid (RARs) equivalent to 15% of that of retinoic acid. The physicochemical properties of the 4HPR binding protein in the serum were identical to those of serum retinol binding protein (RBP). Antibodies against RBP quantitatively immunoprecipitated the protein-4HPR complex, confirming that the retinoid specifically binds to RBP. Although retinol and 4HPR cross-competed for RBP binding, N-phenylretinamide, in which the 4-hydroxyl group is absent, and N-(4-methoxyphenyl)retinamide, a major cellular metabolite of 4HPR, in which the hydroxyl group is blocked, did not show affinity for the binding protein. The results indicate that the hydroxyl group of 4HPR is essential for binding of this type of retinoid to RBP. Thus, our studies suggest that serum transport of 4HPR may be facilitated by RBP. To bind more efficiently to CRBP, CRABP, or RARs/RXRs, the retinoid may require further metabolic change.

Animals↗
PubMed2001

Apoptosis induction by acyclic retinoid: a molecular basis of 'clonal deletion' therapy for hepatocellular carcinoma.

We have shown previously that administration of acyclic retinoid to cirrhotic patients who had undergone curative treatment of preceding hepatocellular carcinoma (HCC) induced the disappearance of serum lectin-reactive alpha-fetoprotein (AFP-L3) and subsequently reduced the incidence of second liver cancers. AFP-L3 is a tumor marker that indicates the presence of occult tumors below the detection limit by diagnostic images. Therefore, we have proposed a new concept of 'clonal deletion' therapy with acyclic retinoid for the cancer chemoprevention against HCC. Such eradication of AFP-L3-producing latent malignant (or premalignant) cells from the liver suggested a new strategy to prevent HCC, which may be involved in the same category as cancer chemotherapy. In the present series of studies, we explored the molecular mechanism of 'clonal deletion' and found a novel mechanism of apoptosis induction by the retinoid. We have demonstrated a modification of a retinoid receptor, RXRalpha, by mitogen-activated protein (MAP) kinase-dependent phosphorylation, resulting in the loss of transactivating activity. This may lead HCC cells to be resistant to natural retinoic acid. However, acyclic retinoid restored the function of phosphorylated RXRalpha and induced its downstream pro-apoptotic genes including tissue transglutaminase, an enzyme that is implicated in apoptosis. Tissue transglutaminase-dependent apoptosis in HCC cells was independent of the activation of caspases. This novel mechanism of retinoid-induced apoptosis may give a clue to understand the molecular mechanism of clonal deletion.

Antineoplastic Agents↗
PubMed1983

Membrane glycoconjugate visualization and biosynthesis in normal and retinoid-treated epidermis.

Cell-membrane glycoconjugates can be visualized for ultrastructural and fluorescence studies with certain surface markers, such as lectins and antisaccharide antibodies. When frozen sections of mammalian epidermis are treated with a battery of rhodamine-conjugated lectins, the cell membranes display a pattern of increased sugar complexity during keratinocyte maturation. Although this vectorial sequence is disrupted following retinoid treatment, these changes occur only at high doses and late in the course of treatment, suggesting that retinoid-induced alterations may be secondary. Seemingly as a result of specific glycosidase activity within the cytosol of both granular and cornified cells, lectin staining suddenly disappears from stratum corneum cell membranes. Although lectins stain membrane glycoconjugates of cultured human keratinocytes, quantitative techniques are required to recognize differences in proliferating versus postmitotic cells and in cultures supplemented with various growth factors. Whereas retinoids consistently depress glycoprotein synthesis in cultured keratinocytes, in organ culture they stimulate epidermal glycoprotein, and particularly glycolipid, biosynthesis. These studies suggest (1) that visualization of membrane glycoconjugates with lectins can reveal important variations in normal and pathologic epidermal differentiation, (2) that lectins may reveal subtle quantitative alterations in differentiation in vitro, (3) that retinoid stimulation of glycoconjugate biosynthesis either displays important species differences or requires a higher level of organization than occurs in cell culture, and (4) that the retinoid effect on glycoconjugate biosynthesis in organ culture may provide another useful bioassay for retinoid potency.

Animals↗
PubMed2004

The specificity of alcohol dehydrogenase with cis-retinoids. Activity with 11-cis-retinol and localization in retina.

Studies in knockout mice support the involvement of alcohol dehydrogenases ADH1 and ADH4 in retinoid metabolism, although kinetics with retinoids are not known for the mouse enzymes. Moreover, a role of alcohol dehydrogenase (ADH) in the eye retinoid interconversions cannot be ascertained due to the lack of information on the kinetics with 11-cis-retinoids. We report here the kinetics of human ADH1B1, ADH1B2, ADH4, and mouse ADH1 and ADH4 with all-trans-, 7-cis-, 9-cis-, 11-cis- and 13-cis-isomers of retinol and retinal. These retinoids are substrates for all enzymes tested, except the 13-cis isomers which are not used by ADH1. In general, human and mouse ADH4 exhibit similar activity, higher than that of ADH1, while mouse ADH1 is more efficient than the homologous human enzymes. All tested ADHs use 11-cis-retinoids efficiently. ADH4 shows much higher k(cat)/K(m) values for 11-cis-retinol oxidation than for 11-cis-retinal reduction, a unique property among mammalian ADHs for any alcohol/aldehyde substrate pair. Docking simulations and the kinetic properties of the human ADH4 M141L mutant demonstrated that residue 141, in the middle region of the active site, is essential for such ADH4 specificity. The distinct kinetics of ADH4 with 11-cis-retinol, its wide specificity with retinol isomers and its immunolocalization in several retinal cell layers, including pigment epithelium, support a role of this enzyme in the various retinol oxidations that occur in the retina. Cytosolic ADH4 activity may complement the isomer-specific microsomal enzymes involved in photopigment regeneration and retinoic acid synthesis.

Alcohol Dehydrogenase↗
PubMed1980

Binding of retinoids to human breast cancer cell lines and their effects on cell growth.

Vitamin A and its analogues (retinoids) regulate the differentiation of epithelial tissues. Retinoids inhibit the induction of rat mammary cancers by carcinogens in vivo, and cellular binding proteins for retinoids have been demonstrated in some human breast cancer samples. In this study, we examined the model system of human breast cancer cell lines in long-term tissue culture for effects of retinoids on growth and for the presence of cellular retinoid binding proteins. Retinoic acid and retinol inhibit the growth of of MCF-7, Hs578T, and ZR-75-B cell lines. Retinoic acid is more potent than retinol in this regard: 50% growth inhibition is achieved by 6 nM retinoic acid in ZR-75-B and by 700 nM in MCF-7 and Hs578T, whereas 5-8 muM retinol is required in all three cell lines. The time to onset of growth inhibition varies markedly between cell lines and is not related to cell density or doubling time. Retinoic acid increases the doubling time of MCF-7 and ZR-75-B by two- to threefold, but causes cell death in Hs578T. The growth inhibition is reversible in every cell line by removal of retinoic acid. Specific and distinct binding of [(3)H]retinoic acid and [(3)H]retinol is present in cytosols of MCF-7 and Hs578T cells as assessed by sucrose density gradient centrifugation. In ZR-75-B, [(3)H]retinoic acid binding was present, but no binding of [(3)H]retinol was detectable. This study reveals that retinoids may play an important role in the regulation and treatment of human breast cancer and that human breast cancer cell lines represent a useful model to study this role.

Breast Neoplasms↗
PubMed2003

Etiology of congenital diaphragmatic hernia: the retinoid hypothesis.

Congenital diaphragmatic hernia (CDH) is a major life-threatening cause of respiratory failure in the newborn. Although significant efforts have been undertaken to unravel the pathophysiology of CDH, our current understanding of the etiology remains spare. Here we outline recent evidence suggesting that abnormalities linked with the retinoid signaling pathway early in gestation may contribute to the etiology of CDH. These studies include 1) the effect of altering the retinoid system in vitamin A deficient and transgenic animals; 2) disruption of the retinoid system in teratogen-induced CDH in rodents, 3) the effect of co-administration of retinoids in nitrofen-induced CDH on lung and diaphragm development, and 4) clinical evidence suggesting decreased markers of vitamin A status in human CDH. Given the substantial mortality and morbidity associated with this serious developmental anomaly, advancements in this area will be critical. We feel that there is now sufficient circumstantial and direct experimental evidence to warrant further testing of the retinoid-CDH etiology hypothesis, including examination of retinoid-regulated target genes that could be candidates for involvement in CDH.

Animals↗
PubMed2003

Transcription suppression of thromboxane receptor gene expression by retinoids in vascular smooth muscle cells.

Thromboxane (TX) A2 induces contraction and proliferation of vascular smooth muscle cells (VSMCs) via its specific membrane TX receptor (TXR), possibly leading to the progression of atherosclerosis. Retinoids, derivatives of vitamin A, have recently been shown to be anti-atherosclerotic in VSMCs. We therefore examined the effects of retinoids on TX-induced cell growth and TXR expression in VSMCs. TX-induced VSMC proliferation assessed by 3H-thymidine incorporation was completely abrogated by all-trans retinoic acid (ATRA) treatment. The expression of TXR mRNA was significantly decreased by treatment either with ATRA or its stereoisomer 9-cis retinoic acid (RA). Transcription activity of the TXR gene promoter was suppressed by treatment with these retinoids, and a study using retinoid receptor-selective agonists demonstrated that retinoic acid receptors (RARs), rather than retinoid X receptors (RXRs), were mainly involved in the transcription suppression. Deletion analyses demonstrated that the suppression was mediated via the -22/-7 GC-box related sequence. Electrophoretic mobility shift assays showed that Sp1, but not RAR and/or RXR, could bind to the element. The formation of the Sp1-DNA complex was inhibited by co-incubation with RAR, but not by RXR. Taken together, these findings suggest that TXR gene transcription suppression may be mediated by the inhibition of Sp1 binding to the -22/-7 GC-box related sequence by activated RAR, which may result in the inhibition of TX-induced VSMC proliferation. Our study indicates a novel anti-atherosclerotic action of retinoids in VSMCs.

Alitretinoin↗
PubMed2004

Human thyroid carcinoma cell lines show different retinoic acid receptor repertoires and retinoid responses.

OBJECTIVE: Disturbed expression of retinoic acid (RA) receptors (RAR/RXR) contributes to the pathogenesis and tumor progression of epithelial carcinomas. DESIGN: To examine whether altered responses to retinoids may correlate with differences in RA receptor equipment, retinoid effects were examined in human thyroid carcinoma cell lines of various differentiation stages in culture and after xenotransplantation onto rodent models. METHODS: Cell growth was assessed by the MTT test, mRNA expression was examined by Northern blot and quantitative competitive RT-PCR, and type I 5'-deiodinase (5'DI) activity was measured by in vitro deiodination assay. Nude rats and mice were used for xenotransplantation experiments. RESULTS: All-trans-RA and RAR-selective synthetic retinoids stimulated activity and mRNA expression of the thyroid differentiation marker 5'DI in the follicular thyroid carcinoma cell line FTC-133. In the less differentiated FTC-238 cells, stimulation of 5'DI activity was less pronounced than in FTC-133 cells, and a reduced level of RAR beta mRNA was detected. In the anaplastic thyroid carcinoma cell lines HTh 74 and C 643, the activity of 5'DI was not increased by retinoids, and expression of RAR alpha mRNA was reduced. Proliferation of FTC-133 and FTC-238 cells was decreased by all-trans-RA. Pretreatment of FTC-133 with RA resulted in a reduced tumor growth in xenotransplantation experiments as compared with untreated control cells. This reduction was less pronounced in the case of FTC-238 cells. Thus, retinoid therapy might be applied to treat follicular thyroid carcinomas. However, tumor-specific RAR repertoires need to be analyzed as a prerequisite for successful intervention with appropriate, probably receptor-selective retinoids.

Adenocarcinoma, Follicular↗
PubMed2000

An immortalized rat liver stellate cell line (HSC-T6): a new cell model for the study of retinoid metabolism in vitro.

Hepatocytes and hepatic stellate cells play important roles in retinoid storage and metabolism. Hepatocytes process postprandial retinyl esters and are responsible for secretion of retinol bound to retinol-binding protein (RBP) to maintain plasma retinol levels. Stellate cells are the body's major cellular storage sites for retinoid. We have characterized and utilized an immortalized rat stellate cell line, HSC-T6 cells, to facilitate study of the cellular aspects of hepatic retinoid processing. For comparison, we also carried out parallel studies in Hepa-1 hepatocytes. Like activated primary stellate cells, HSC-T6 express myogenic and neural crest cytoskeletal filaments. HSC-T6 cells take up and esterify retinol in a time- and concentration-dependent manner. Supplementation of HSC-T6 culture medium with free fatty acids (up to 300 micrometer) does not affect retinol uptake but does enhance retinol esterification up to 10-fold. RT-PCR analysis indicates that HSC-T6 cells express all 6 retinoid nuclear receptors (RARalpha, -beta, -gamma, and RXRalpha, -beta, -gamma) and like primary stellate cells, HSC-T6 stellate cells express cellular retinol-binding protein, type I (CRBP) but fail to express either retinol-binding protein (RBP) or transthyretin (TTR). Addition of retinol (10(-8)-10(-5) m) or all-trans-retinoic acid (10(-10)-10(-6) m) rapidly up-regulates CRBP expression. Using RAR-specific agonists and antagonists and an RXR-specific agonist, we show that members of the RAR-receptor family modulate HSC-T6 CRBP expression.Thus, HSC-T6 cells display the same retinoid-related phenotype as primary stellate cells in culture and will be a useful tool for study of hepatic retinoid storage and metabolism.

Animals↗
PubMed2002

Preventive efficacy of receptor class selective retinoids on HER-2/neu oncogene expressing preneoplastic human mammary epithelial cells.

Aberrant proliferation is an early-occurring event in vitro prior to tumorigenesis in vivo in the multistep process of carcinogenesis. Inhibition of aberrant proliferation therefore may represent a useful biomarker to evaluate the efficacy of chemopreventive agents. Retinoids have exhibited preventive efficacy in vitro and in vivo predominantly through the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Clinically relevant biochemical and cellular mechanistic endpoints for chemopreventive effects of retinoids should provide novel biomarkers. The present study was designed to examine the preventive efficacy of natural retinoids, all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid (9cisRA), and to identify the possible mechanisms for their effects using the HER-2/neu oncogene expressing preneoplastic human mammary epithelial 184-B5/HER cells. Seven-day treatment with ATRA and 9cisRA exhibited a dose-dependent growth inhibition. Long-term (21 days) treatment with IC20 doses of 50 nM ATRA and 100 nM 9cisRA inhibited anchorage-dependent colony forming efficiency by about 75.4% (p<0.01) and 84.9% (p<0.01), respectively. Cell cycle analysis revealed that a 24-h treatment with IC90 doses of 2 microM ATRA and 3 microM 9cisRA accumulates cells in the G0/G1 phase and inhibit S and/or G2/M phase of the cell cycle. ATRA and 9cisRA induced an 11-fold (p=0.03) and a 9-fold (p=0.04) increase in subG0/G1 (apoptotic) population relative to the solvent control, respectively. ATRA and 9cisRA induced 77% (p=0.01) and 51% (p=0.02) decrease in tyrosine kinase immunoreactivity, respectively. Similarly, the two retinoids caused almost a 50% (p=0.01) down-regulation of Bcl-2 immunoreactivity. Western blot analysis revealed that ATRA induced an increase in RARbeta expression and a decrease in RARgamma expression, while 9cisRA down-regulated RXRalpha expression. These data demonstrate that ATRA and 9cisRA may inhibit HER-2/neu induced aberrant proliferation in part by retarding cell cycle progression, down-regulating HER-2/neu-mediated signal transduction and inducing Bcl-2-dependent apoptosis through a retinoid receptor-mediated mechanism.

Alitretinoin↗