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PubMed2000

Retinoid signalling acts during the gastrula stages to promote primary neurogenesis.

Retinoid signalling has been manipulated at different developmental stages to identify a critical period in the gastrula embryo for retinoid-dependent primary neurone formation. The expression of retinoid receptor RARalpha2 in the posterior neuroectoderm of the gastrula embryo is therefore consistent with a role in primary neurogenesis. In addition we show that the expression of neurogenin-1 and XDelta-1, two genes that contribute to the determination of primary neurone cell-fate in the gastrula embryo, respond to retinoid signalling. These results indicate that retinoid signalling is required for an early step in the process of primary neurogenesis. When retinoid signalling is increased, the number of primary neurones increases, but the phenotype is not the same as the neurogenic phenotype that follows the overexpression of a dominant negative form of XDelta-1. Whereas increased retinoid signalling expands the width of primary neurone stripes, dominant negative XDelta-1 increases the density of primary neurones within the stripes. When retinoid signalling is increased and the primary neurone stripes expand, the expression domain of a floorplate marker contracts. Conversely, when retinoid signalling is inhibited, the expression patterns of floorplate markers widen. These results indicate that retinoid signalling acts at an early stage in primary neural development when the fates of different regions of the neuroectoderm are being determined.

Basic Helix-Loop-Helix Proteins↗

PubMed1999

Modulation of endothelial cell proliferation by retinoid x receptor agonists.

One feature that contraindicates the wide therapeutic use of natural retinoids is their adverse effects during systemic use and the lack of receptor selectivity. In contrast, synthetic retinoids are distinguishable from each other on the basis of their partial or exclusive preference in binding and activation of selective retinoid receptors. We examined the inhibitory activities of natural and synthetic retinoids for their ability to reverse basic fibroblast growth factor-induced endothelial cell proliferation. Both the naturally occurring retinoids at nanomolar concentrations reversed basic fibroblast growth factor-induced endothelial cell proliferation. Among the synthetic retinoids tested, retinoic acid receptor/retinoid x receptor pan-agonist AGN 191659 [(E)-5-[2-(5,6,7, 8-tetrahydro-3, 5,5,8,8-pentamethyl-2-naphtyl) propen-1-yl]-2-thiophenecarboxylic acid] and retinoid x receptor pan-agonist AGN 191701 [(E)-2-[2-(5,6,7,8-tetrahydro-3, 5,5,8, 8-pentamethyl-2-naphthyl) propen-1-yl]-4-thiophenecarboxylic acid] at nanomolar concentrations reversed the basic fibroblast growth factor-induced endothelial cell proliferation. Since none of the retinoic acid receptor agonists tested had any effect, the inhibitory effect of AGN 191659 could be attributed to its retinoid x receptor receptor activity. These results suggest that retinoid x receptor agonists may be more selective anti-angiogenic agents due to their ability to inhibit endothelial cell proliferation.

Animals↗

PubMed2000

The control of Xenopus embryonic primary neurogenesis is mediated by retinoid signalling in the neurectoderm.

In Xenopus, the primary neurons form in three domains either side of the midline in the posterior neurectoderm. At the late neurula stage there are approximately 120 primary sensory neurons on each side of the embryo. Co-injecting synthetic mRNA encoding retinoic acid receptor alpha (NR1B1) and retinoid X receptor beta (NR2B2) results in an increase in the number of primary neurons and this is further enhanced by the addition of retinoic acid indicating that elevated retinoid signalling promotes an increase in the number of cells undergoing primary neurogenesis. However, primary neurogenesis remains confined to the three domains that normally give rise to primary neurons indicating that not all regions of the neurectoderm respond equivalently to elevated retinoid signalling. The inhibition of retinoid signalling with a dominant negative retinoid receptor or treatment with citral, an inhibitor of retinoid metabolism, inhibits the formation of primary neurons. However, the lateral extent of the neurectoderm does not differ following these experimental manipulations suggesting that changes in primary neuron cell number, in response to changes in retinoid signalling, cannot be accounted for by significant gains or losses of neurectoderm. In addition, two lines of evidence are presented to suggest that retinoid signalling affects primary neurogenesis by acting directly on the neurectoderm. First, animal caps neuralized by noggin undergo primary neurogenesis in response to retinoid signalling and second primary neurogenesis is elevated in neural conjugates in which the ectodermal, but not the mesodermal, component has been co-injected with RAR/RXR mRNA.

Acyclic Monoterpenes↗

PubMed1996

[Retinoid antagonists].

Retinoids, retinoic acid and its bioisosters, regulate many biological functions such as cell differentiation, proliferation and embryonic development in vertebrates, through binding to and activating their specific nuclear receptors. There are two classes of nuclear receptors for retinoids, retinoic acid receptors (RAR alpha, beta, gamma) and retinoid X receptors (RXR alpha, beta, gamma). Several retinoid antagonists, which bind to but not activate RARs, have been reported. Among them, 4-(5H-7,8,9,10-tetrahydro-5,7,7,10,10-pentamethylbenzo[e]naphtho [2,3-b][1,4]diazepin-13-yl)benzoic acid (LE135, 20) is a RAR beta-selective retinoid antagonist. Structure-activity relationships of LE135 (20) showed that the naphthalenyl analogs [LE540 (21) and LE550 (22)] are more potent retinoid antagonists in HL-60 assay. Contrary to the antagonistic activity of LE135 (20), an isomer of LE135 (20), 4-[5H-2,3-(2,5-dimethyl-2,5-hexano)-5-methyldibenzo- [b,e][1,4]diazepin-11-yl)benzoic acid (HX600, 39) enhanced the activities of retinoids. Although the synergistic activity of HX600 (39) can be explained by the binding to RXRs and the further activation of RAR/RXR heterodimer activated by retinoid (RAR ligand), the significantly different biological character of HX600 (39) from the typical RXR-selective ligand suggested the possibility of the participation of other nuclear receptors or cofactors in the retinoid synergism.

Animals↗

PubMed1997

Retinoic acid receptor alpha expression correlates with retinoid-induced growth inhibition of human breast cancer cells regardless of estrogen receptor status.

Retinoic acid receptor (RAR) alpha has been shown to play a role in retinoid-induced growth inhibition of human breast cancer cell lines that express the estrogen receptor (ER). The dogma in the field has been that ER-positive breast cancer cell lines respond to retinoid treatment because they express RAR alpha, whereas ER-negative breast cancer cell lines are refractory to retinoid treatment and have been thought to express little or no RAR alpha. We set out to test several ER-negative breast cancer cell lines for expression of RAR alpha protein and responsiveness to retinoids in growth inhibition assays. Of six ER-negative breast cancer cell lines that were tested, one (SK-BR-3) had high levels of RAR alpha protein as measured by ligand-binding immunoprecipitation (approximately 55 fmol/mg protein) and also displayed sensitivity to growth inhibition by retinoids (9-cis-retinoic acid; EC50, approximately 3 nM). These cells were more sensitive than an ER-positive cell line, T-47D, which expressed approximately 35 fmol RAR alpha/mg total protein (9-cis retinoic acid; EC50, approximately 50-100 nM). Another ER-negative cell line, Hs578T, also expressed RAR alpha (approximately 23 fmol/mg) and was sensitive to retinoid-induced growth inhibition, albeit to a lesser extent than SK-BR-3 or T-47D cells. In contrast, the other ER-negative cell lines tested expressed low (<10 fmol/mg) or no detectable levels of RAR alpha protein and also did not respond to retinoids in growth inhibition assays. A RAR alpha agonist displayed 100 times greater potency than a RARgamma agonist in growth inhibition of both T-47D and SK-BR-3 cells, suggesting RAR alpha involvement in the process. Furthermore, a RAR alpha antagonist completely abolished the growth inhibition induced by RAR agonists, implying that the activity of the agonists is exerted solely through RAR alpha, not RARgamma, which is also expressed in both cell lines. Additionally, although retinoid X receptor (RXR) compounds are weakly active in growth inhibition of the RAR alpha-positive cell lines, they markedly increased the growth-inhibitory activity of RAR ligands. RXR compounds also potentiated the action of the antiestrogen 4-hydroxytamoxifen to inhibit the growth of T-47D cells. These findings have clinical ramifications in that patients with ER-negative tumors that are RAR alpha positive may be candidates for retinoid therapy. Additionally, combinations of RXR ligands with RAR ligands (especially RAR alpha agonists) and/or antiestrogens may have utility in the treatment of breast cancer.

Alitretinoin↗

PubMedDate not supplied

Induction of apoptosis in MCF-7 breast carcinoma cell line by RAR and RXR selective retinoids.

Induction of apoptosis in MCF-7 breast carcinoma cell line by various retinoids was measured by cytofluorimetry and DNA fragmentation assay. Retinoids with marked or high selectivity for RAR alpha, RAR beta, RAR gamma or RXR alpha were tested. All these retinoids were capable of inducing apoptosis, in a dose- and time-dependent way. MCF-7 cell line expressed RAR alpha, RAR gamma and RXRs, but not RAR beta. Compared to untreated MCF-7 cells, after 2 days of incubation with each of the selective retinoids, a substantial increase in apoptotic cells was observed, even at the lowest concentration of 10(-8) M. Among the various analysed selective retinoids only slight differences were observed. All-trans retinoic acid and 13-cis retinoic acid induced apoptosis only after 6 days and 9-cis-retinoic acid after 4 days of incubation. Since all receptor selective retinoids substantially inducedapoptosis, it may be concluded that RAR alpha, RAR gamma and RXR alpha are able to mediate programmed cell death in the tested tumor cell line. Highly selective retinoid receptor agonists and antagonists may be useful for clarifying the function of retinoid receptors and for further progress in the field of cancer prevention and therapy by retinoids.

Apoptosis↗

PubMed1997

Activity of retinoic acid receptor-gamma selectively binding retinoids alone and in combination with interferon-gamma in breast cancer cell lines.

Retinoids modulate several cell functions and especially inhibit the growth of a wide variety of cells including breast cancer. Retinoic acid receptor-gamma (RAR-gamma) has been shown to mediate the antiproliferative activity of retinoids. To further test this hypothesis we examined the effects of different RAR-gamma selectively binding retinoids (CD2325, CD2247, CD666 and CD437) on breast cancer cell lines. With exception of CD2247, all retinoids inhibited proliferation of MCF-7, SKBR-3, T47D and ZR-75-1 breast cancer cell lines, similar to the natural compound all-trans retinoic acid (ATRA). In addition, all 4 compounds were able to act synergistically with interferon-gamma (IFN-gamma) in all breast cancer cell lines including the retinoid-resistant BT-20 and 734-B lines. In functional transactivation assays we demonstrated that only in the MCF-7 cell line, TPA-mediated AP-1 activity was suppressed only by ATRA and CD2325, whereas in SKBR-3, another RA-sensitive breast cancer cell line, it was not. The synergistic antiproliferative activity involving retinoids and IFN-gamma could not be explained by an enhanced anti-AP-1 activity. No correlation was found between expression of RARs and cellular retinoic acid binding proteins (CRABPs) and antiproliferative effects of the retinoids. RAR-gamma selectively binding retinoids are potent inhibitors of breast cancer cell proliferation, alone and in combination with IFN-gamma. For this reason and because of a possible low toxicity, as compared with retinoic acid, we speculate that these RAR-gamma selective binding retinoids might be of clinical importance.

Binding, Competitive↗

PubMed2000

Retinoids and ovarian cancer.

Each year, an estimated 26,000 women in the United States are diagnosed with ovarian cancer. During any given year, approximately 14,500 women die from this disease. Ovarian cancer is the seventh most common cancer in women worldwide, after breast, cervix, colon/rectum, stomach, corpus uteri, and lung cancers. In the U.S., ovarian cancer is the second most common gynecologic cancer, and is the fourth leading cause of solid tumor cancer deaths among women. Currently, postoperative chemotherapy of ovarian cancer is still suboptimal. Drug resistance is a common problem resulting in only 20 approximately 30% overall 5-year survival rates. Clearly, continued development of alternative therapeutic strategies is essential for the management of this fatal disease. A number of recent studies have suggested that retinoids may play a potential role as an ovarian cancer chemotherapeutic agent. Retinoids, the natural and synthetic derivatives of vitamin A, have been shown to inhibit the growth of human ovarian cancer cells both in vivo and in culture. This review will initially summarize what is known about the pathological and molecular characteristics of ovarian carcinoma. It will then describe retinoid metabolism and the role of the cellular and nuclear retinoid binding proteins in mediating retinoid action. Following this general review of retinoids and their function, data supporting the role of retinoic acid as a suppresser of ovarian carcinoma cell growth will be presented. Particular attention will be paid to studies suggesting that members of the RB family of proteins and RB2/p130, in particular, are the molecular targets responsible for retinoid mediated inhibition of ovarian carcinoma cell growth. This review will then conclude with a brief discussion of two synthetic retinoids, 4 HPR R(fenretinide) and AHPN/CD437, which have been shown to induce apoptosis in ovarian tumor cells. It will be clear from the studies summarized in this review that retinoids represent a potentially powerful alternative to present chemotherapeutic approaches to the treatment of late stage ovarian cancer.

Antineoplastic Agents↗

PubMed1985

The effect of retinoids on haemopoiesis--clinical and laboratory studies.

Retinoids affect the growth and differentiation of haemopoietic cells. Individuals deficient in retinoids become anaemic; replacement therapy with retinoids corrects the anaemia. Retinoids enhance the clonal proliferation of erythroid and myeloid precursors in soft-gel culture; all-trans-retinoic acid and 13-cis-retinoic acid are the most potent. Retinoids also induce the differentiation of HL-60 promyelocytes to functional granulocytes and can induce cells from other relatively mature, myeloid cell lines to undergo partial differentiation. Cells from less mature myeloid leukaemic lines are often resistant to induction of differentiation by retinoids. Like cells from established lines, relatively mature leukaemic cells (promyelocytes, myelomonoblasts) harvested from patients can undergo differentiation in vitro in the presence of retinoids. A few reports suggests that a minority of patients with myeloid leukaemia or preleukaemia who receive 13-cis-retinoic acid will have improvement in their haemopoiesis. Further studies are required to understand the mechanism of action of retinoids on the growth and differentiation of haemopoietic cells and to explore more fully the therapeutic potential of retinoids.

Animals↗

PubMedDate not supplied

Uptake and processing of [3H]retinoids in rat liver studied by electron microscopic autoradiography.

The role of rat liver cell organelles in retinoid uptake and processing was studied by electron microscopic autoradiography. [3H]Retinoids were administered either orally, to make an inventory of the cell organelles involved, or intravenously as chylomicron remnant constituents to study retinoid processing by the liver with time. No qualitative differences were observed between the two routes of administration. Time-related changes in the distribution of grains were studied using chylomicron remnant [3H]retinoids. The percentages of grains observed over cells and the space of Disse at 5 and 30 min after administration were, respectively: parenchymal cells, 72.6 and 70.4%; fat-storing cells, 5.0 and 18.1%, and the space of Disse, 14.4 and 8.9%. Low numbers of grains were observed over endothelial and Kupffer cells. The percentages of grains observed over parenchymal cell organelles were, respectively: sinusoidal area, 59.6 and 34.4%; smooth endoplasmic reticulum associated with glycogen, 13.8 and 13.4%; mitochondria, 5.4 and 13.6%; rough endoplasmic reticulum, 4.2 and 7.3%, and rough endoplasmic reticulum associated with mitochondria, 3.7 and 6.5%. It is concluded that chylomicron remnant [3H]retinoids in combination with electron microscopic autoradiography provide a good system to study the liver processing of retinoids in vivo. These results, obtained in the intact liver under physiological conditions, further substantiate that retinoids are processed through parenchymal cells before storage occurs in fat-storing cell lipid droplets, that retinoid uptake is not mediated through lysosomes and that the endoplasmic reticulum is a major organelle in retinoid processing.

Administration, Oral↗

PubMed2003

Induction of senescence-associated growth inhibitors in the tumor-suppressive function of retinoids.

Retinoids, physiological regulators of cell growth and differentiation, are used in the treatment or chemoprevention of several malignant diseases. This class of compounds can induce growth arrest or apoptosis in tumor cells. Permanent growth arrest of retinoid-treated cells is often assumed to result from retinoid-induced differentiation. Recent studies in breast carcinoma and neuroblastoma cells demonstrated that retinoids can stop tumor cell growth through the program of senescence rather than differentiation. Retinoid-induced tumor suppression is associated with the induction of multiple intracellular and secreted growth-inhibitory proteins. Most of these proteins were also found to be upregulated in senescent cells. The induction of senescence-associated growth inhibitors appears to be an indirect effect of retinoids. Elucidation of the mechanisms responsible for the induction of growth-inhibitory genes in retinoid-treated cells should help in developing agents that would mimic the antiproliferative effect of retinoids in retinoid-insensitive cancers.

Animals↗

PubMed1999

Maintenance of retinoid metabolism in human retinal pigment epithelium cell culture.

If transplantation of cultured retinal pigment epithelium (RPE) or iris pigment epithelium (IPE) is to be successful in the treatment of ocular disease, it is imperative to demonstrate that these cells can perform all of their necessary metabolic functions. Unfortunately, a critical function of the RPE, retinoid metabolism, is often lost rapidly in culture. We have examined whether or not nonspecific proteolytic enzymes commonly used in cell isolation and serial passaging may be responsible for this loss of function, and we have investigated novel isolation and passaging techniques which can alleviate this loss of retinoid metabolism.RPE cells were obtained from human donor eyes by enzymatic and nonenzymatic methods. Cells were cultured either on control tissue culture inserts or on inserts coated with a layer of thermally responsive poly(N -isopropylacrylamide-co-cinnamoylcarbamidemethylstyrene). Upon confluence, cells were detached either by trypsinization or by lowering dish temperature. Retinoid metabolism of cells was assessed after isolation and culture by incubating membrane fractions with3H-all- trans -retinol. Retinoid metabolism was also measured in freshly isolated IPE, corneal endothelium (CE), an RPE cell line (D407), and two hepatocyte cell lines (Hepa 6 and HepG2). Membrane fractions from cells isolated nonenzymatically or using collagenase/hyaluronidase formed 11- cis -retinol, retinal isomers and retinyl esters. Retinoid metabolism of RPE cells freshly isolated by trypsinization showed no 11- cis -retinal and little 11- cis -retinol formation. Nondamaged cells cultured on thermally responsive surfaces detached in sheets upon temperature change. They showed metabolism similar to that of cells freshly isolated by nonenzymatic means. After trypsinization, confluent cultures dissociated into individual cells, but these cells showed poor retinoid metabolism, including no detectable retinyl esters or 11- cis -retinoid isomers. IPE, CE and Hepa 6 did not show any retinoid metabolism. D407 and HepG2 produced retinals, but not the 11- cis isomer.RPE cells isolated using trypsin lose the ability to form critical intermediates in the visual cycle. Collagenase/hyaluronidase or nonenzymatic cell isolation techniques enable these functions to be maintained. After cell culture, thermally responsive surfaces allow nonenzymatic cell detachment and excellent maintenance of retinoid metabolism.

Adolescent↗

PubMed1995

Effects of various synthetic retinoids on proliferation and immunophenotype of human melanoma cells in vitro.

Since response rates in human melanoma are low with currently available therapeutic modalities, we have reevaluated the potential usefulness of retinoids as new alternatives for therapy of metastatic melanoma. Nine synthetic retinoids with high affinity and/or selectivity for the retinoic acid receptors (RAR) alpha, beta, and gamma were studied in comparison to all-trans retinoic acid (RA) for their in vitro effects on melanoma cell proliferation and for their immunomodulating capacities using four human melanoma cell lines. Eight out of ten retinoids tested had no effect on melanoma cell growth, whereas the remaining two compounds with high RAR-gamma selectivity (CD437 and CD2325) showed a dose-dependent antiproliferative effect on all melanoma cell lines with IC50 (concentration inhibiting response by 50%) values between 10(-6) and 10(-7)M. Further analyses showed that paracrine-mediated tumor cell growth inhibition such as induction of transforming growth factor (TGF)-beta described as one mechanism of retinoid action and enzyme systems such as tyrosinase and monoamine oxidase were not involved in mediating the antiproliferative effects exerted by the two retinoids. Four of nine retinoids modulated HLA-DR expression on human melanoma cells, and expression levels of intercellular adhesion molecule 1 (ICAM-1) was increased by another subset of compounds. These effects were, however, not correlated to the receptor selectivity of the retinoids. The potent growth inhibitory effect of the RAR-gamma-selective retinoids and the immunomodulating capacities of the retinoids open an interesting alternative for new antiproliferative and immunomodulatory strategies in the treatment of metastatic melanoma.

Antigens, CD↗

PubMed1985

Effects of retinoid deficiency on the development of the heart and vascular system of the quail embryo.

The regulatory role of retinoids in growth and differentiation has been examined in vitro and in vivo by light and scanning electron microscopy using retinoid-deficient and control quail embryos between the 5-15 somite stage, as well as 2- and 2.5-day-old embryos. Fertile, retinoid-deficient eggs were obtained from flocks of quail maintained on a retinoid- and carotenoid-deficient diet, supplemented only with small amounts of retinoic acid methyl ester as described by Thompson et al. 1969. As described previously, retinoid deprivation during embryonal development causes abnormalities in organs of epithelial and mesenchymal origin, most dramatically preventing the formation of the extraembryonal circulatory system in the avian embryo. Our in vivo studies show that the basis for the latter defect is the failure of the primitive heart tubes to open at their posterior end, thus preventing the formation of omphalomesenteric veins normally connecting the embryonal with the extraembryonal circulatory system. Early manifestation of the retinoid-deficient defect may result also in formation of a cardia bifida, late manifestation in development of a single dilated ventricle. In contrast, the extraembryonal vascular system of blood islands is well developed. Heart function as shown by the rate of heart beat is reduced in deficient embryos. Our in vitro studies demonstrate similar defects in the development of the circulatory system by culture of normal 24-h embryos on retinoid-deficient agar medium; conversely, normal development is observed upon culture of retinoid-deficient embryos on retinoid-containing agar medium.

Animals↗

PubMed1990

Structure-activity relationships of retinoids in developmental toxicology. IV. Planar Cisoid conformational restriction.

To evaluate the influence of the three-dimensional configuration of retinoids on teratogenic activity, 14 retinoids were studied in hamsters. Retinoids with a conformational restriction of the retinoic acid polyene chain adjacent to the beta-cyclogeranylidene ring showed increased teratogenic potency and retinoids with aromatic conformational restriction adjacent to the polar terminus showed potency equivalent to retinoic acid. Conformational restriction of the polyene chain that permits rotation of the bond adjacent to the beta-cyclogeranylidene ring abolished teratogenic activity. Incorporation of dimethyl substituents at positions corresponding to C1 and C4 positions of retinoic acid enhanced teratogenic potency. Elimination of the twist chair conformation of gem-dimethyl substituents via incorporation of a benzothiopyran or substituted planar aromatic ring decreased teratogenic potency. Planar cisoid conformational restriction alone was insufficient to confer teratogenic activity in that elimination of the polar terminus abolished teratogenic activity. That an acidic polar terminus, as contrasted to a carboxyl residue per se, was required for teratogenic activity was illustrated by administration of a retinoidal phenyl sulfone which was metabolized to the corresponding teratogenic sulfonic acid. Retinoid teratogenicity in hamsters depends upon the assumption of a 10,11 cisoid and/or 12,13 cisoid rotameric form by a conjugated spacer greater than five carbon atoms in length located between a hydrophobic ring system and an acidic terminus, ionized at physiologic pH. Comparison of the relative teratogenic potencies of this series of conformationally restricted retinoids with their activities in assays for chemoprevention activity showed that those analogs with high intrinsic control of epithelial or mesenchymal cell differentiation were also the more potent teratogens. The results suggest that those biochemical mechanisms responsible for retinoid control of normal adult or neoplastic cell differentiation also mediate retinoid-induced teratogenesis.

Abnormalities, Drug-Induced↗

PubMed1989

Effects of retinoids on human thymus-dependent and thymus-independent mitogenesis.

The effects of all-trans-retinoic acid (RA), 13-cis-retinoic acid, and N-(4-hydroxyphenyl)retinamide on the mitogenic responses of various populations of human lymphocytes have been evaluated. Superoptimal concentrations of mitogens allowed the greatest RA-induced potentiation of lymphocyte proliferation. All three retinoids at concentrations as low as 5 x 10(-14)M significantly potentiated the proliferation of adenoidal and tonsillar lymphocytes stimulated by pokeweed mitogen (PWM). However, the responses of adenoidal and tonsillar lymphocytes to Staphylococcus aureus Cowan strain A were not potentiated by retinoids. Retinoids also caused significant potentiation of proliferation of PWM-stimulated peripheral blood lymphocytes (PBL). However, endpoint concentrations of retinoids required to significantly potentiate PBL proliferative responses to PWM were much higher than required for potentiation of adenoidal or tonsillar lymphocytes. PBL responses to concanavalin A (Con A) were significantly potentiated by retinoid concentrations as low as 10(-8) to 10(-10) M. Retinoid-potentiated responses were also observed wi Con A-stimulated thymocytes, but the endpoint concentrations required for significant potentiation were 10-fold higher than required to potentiate PBL responses to Con A. These data indicate that the sensitivity of lymphocytes to the retinoid-mediated potentiation of mitogenesis depends on the lymphoid compartment from which the cells are obtained. Tonsillar and adenoidal lymphocytes were the most responsive of the lymphocytes tested to the retinoid-induced potentiation of PWM responses. In addition, retinoids appear to selectively potentiate T cell-dependent proliferative activity.

Adenoids↗

PubMed1993

Correlation of the ability of retinoids to inhibit promoter-induced anchorage-independent growth of JB6 mouse epidermal cells with their activation of retinoic acid receptor gamma.

Retinoids inhibit the biological effects induced in mouse epidermal cells by the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Specific nuclear retinoic acid receptors (RARs) have been identified in the epidermis, but the specific receptor that mediates the inhibitory response by retinoids is not established. Retinoic acid and six conformationally restricted retinoids were evaluated in an in vitro bioassay using the JB6 mouse epidermal cell line. These activities were then compared with the ability of these retinoids to activate the RARs in transient transfection assays for transcriptional activation to identify the retinoid receptor involved in inhibiting TPA-induced anchorage-independent growth. The retinoids inhibited TPA-induced colony formation of JB6 cells in semisolid medium at concentrations that were not toxic based on colony formation of attached cells. These concentrations ranged from less than 10(-9)-10(-6) M. 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylanthracen-2-yl)benzoic acid (TTAB) was the most potent retinoid, with an EC50 of 0.8 nM. Both RAR alpha and RAR gamma were expressed in JB6 cells. Expression of RAR beta was not detected in these cells using a polymerase chain reaction assay, consistent with its extremely low level in mouse skin. Inhibition of the TPA response by these retinoids in JB6 cells correlated only with their transcriptional activation of RAR alpha, but not with that of RAR alpha. These results suggest that RAR gamma is most probably the receptor that mediates the chemopreventive effects of retinoids in mouse epidermis.

Animals↗

PubMed2005

Retinoid-induced bone thinning is caused by subperiosteal osteoclast activity in adult rodents.

Excess of Vitamin A (retinol) and related compounds (retinoids) induces bone fragility and is associated with increased hip fracture incidence in humans. Yet, their impact on the adult skeleton has been studied in relatively little detail. It is assumed that they induce generalized bone loss and decrease long-bone thickness due to reduction of radial bone growth. Here we characterized early skeletal responses of adult rodents to retinoid treatment, revealing novel aspects of retinoid action on the mature skeleton. The retinoid Ro 13-6298, given subcutaneously for 4 days, induced bone loss in the hind limbs of 12- and 56-week-old rats and of 15-week-old mice. In vivo monitoring of bone mass and geometry changes by peripheral quantitative computed tomography demonstrated that bone mass decline was due to subperiosteal cortical bone loss, which induced a shrinkage of bone diameter, whilst cancellous bone mass was preserved. We observed that the native retinoic acid isomer all-trans RA induced an identical pattern of bone loss. Histomorphometric evaluation revealed that increased subperiosteal osteoclastic bone resorption caused the cortical bone destruction. Interestingly, bone resorption was suppressed in cancellous bone, which was in agreement with reduced in vitro formation of osteoclasts from bone marrow cells that were derived from the proximity of cancellous bone. The retinoid-induced increase in subperiosteal bone resorption could be blocked by bisphosphonate as direct potent inhibitor of osteoclast action, but not by estradiol. Retinoid treatment induced a reduction of bone-forming surfaces at the subperiosteal site, but not in cancellous bone. In vitro osteoblast performance was also reduced or unchanged, depending on the cellular system used and assay type/duration. In conclusion, our studies revealed that the impact of retinoids on bone is highly bone-compartment-specific at early treatment phases. Furthermore, we showed that bone diameter shrinks in the adult skeleton after retinoid treatment due to subperiosteal osteoclastic bone resorption. Thus, retinoid-induced bone thinning is not only due to reduced radial bone growth as previously assumed. Our findings might explain why high intake of retinol is associated with increased hip fracture risk in the elderly and suggest a therapy to prevent such potential negative effects.

Animals↗