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PubMed2005

Regulation of ultraviolet B radiation-mediated activation of AP1 signaling by retinoids in primary keratinocytes.

The main cause of skin cancer and photo-aging is chronic exposure to ultraviolet B (UVB) radiation. Such damage can be ameliorated by retinoid treatment. UVB-radiation-induced skin carcinogenesis is associated with the induction of activator protein 1 (AP1) signaling and factors, namely FOS and JUN family members. We investigated the effects of several retinoids, all-trans-retinoic acid (tRA), 9-cis-retinoic acid (cRA), and N-(4-hydroxyphenyl)-retinamide (HPR), on UVB-induced damage in primary mouse keratinocytes. In addition, the interplay between UVB radiation, retinoid receptors, and AP1 signaling was assessed using Western blot analysis and ribonuclease protection and gene reporter assays. Exposure of keratinocytes to UVB radiation caused a down-regulation of the retinoid receptor protein levels in a proteasome-mediated manner. In contrast, FOS and JUN proteins were transiently induced shortly after exposure to UVB radiation. Retinoid treatment caused a dose-dependent reduction in the levels of retinoid receptor proteins. When irradiated cells were treated with retinoids, no significant effects on AP1 protein expression were noted. Interestingly, pretreatments with tRA and cRA, but not HPR, suppressed UVB-radiation-induced AP1 activity by more than 50%, whereas post-treatment failed to produce similar effects. Our findings indicate that the inhibition of AP1 activity by retinoids explains, at least in part, the chemopreventive potential of retinoids in UV-radiation-associated epidermal damage.

Animals↗

PubMed2000

Therapeutic applications for ligands of retinoid receptors.

Synthetic retinoids, ligands for the RAR and RXR members of the steroid/thyroid superfamily of nuclear hormone receptors, are used for the treatment of psoriasis, acne, photoaging and cancer. Retinoid mechanisms of action for these conditions largely involve effects on epithelial differentiation and modulation of inflammation with some impact on the immune system. Retinoid medicinal chemistry in recent years has identified ligands highly specific for one of the three RAR subtypes (RAR-alpha) and for the RXR family of receptors, as well as antagonists for the RARs, RARalpha and the RXRs. Structure-activity relationships among the novel retinoid classes are reviewed along with potential therapeutic activities and side effects. RAR-alpha specific retinoids inhibit cancer cell growth but lack other retinoid toxicities, including skin irritation now ascribed to RAR-gama. RXR-specific retinoids lower blood glucose in animal models of type 2 diabetes albeit with a potential for mild hypothyroidism. Function-selective retinoids, especially a class of RAR antagonists called inverse agonists, have unexpected gene regulatory activity. Given the diverse properties and tissue distributions of the retinoid receptors, synthesis of additional classes of receptor-specific and function-selective ligands has the potential to produce novel therapeutic applications.

Animals↗

PubMedDate not supplied

Receptor-selective retinoid agonists and teratogenic activity.

Retinoid mechanism of action is dependent upon interaction with the retinoid nuclear RAR and RXR subfamilies of receptors. Study of ligands selective for the different receptors or which modify that interaction may provide insight into which receptors play roles in or contribute to retinoid teratogenesis. The retinoids considered here include in the RAR alpha-selective arylcarboxamidobenzoic acid CD 336 (Am580), the RAR beta/gamma-selective naphthalenecarboxylic acid CD 135 and the adamantyl-phenylcarboxamidobenzoic acid CD 394, the RAR-selective tetrahydrotetra-methylanthracenylbenzoic acid (TTAB) SRI 3961, the carboxyphenylretinamide SRI 7167-67, and the RXR-selective diarylisopropylidene SR 11217. CD 135 has a 3-fold higher affinity for RAR beta when compared with RAR gamma, whereas CD 394 has a 3-fold higher affinity for RAR gamma when compared with RAR beta. A separate investigation into potential amelioration of retinoid teratogenesis by concomitant administration of the cyclohexanetrione (Ro 31-0521) was also conducted. When pregnant hamsters were given an oral bolus of CD 336 or CD 135 during the early primitive streak stage of gestation, these retinoids proved 60-100 times more potent teratogens than all-trans-retinoic acid. Intubation of CD 394 resulted in production of terata similar to that seen after an equivalent dose of all-trans-retinoic acid. Administration of SRI 3961 found this compound 8000 times more potent than all-trans-retinoic acid, while SRI 7167-67 failed to show any evidence for developmental toxicity even after exposure to 105 mg/kg. Studies with the RXR-selective SR 11217 found it to be far less potent than all-trans-retinoic acid. These data point to the conclusion that those retinoids which have no affinity for retinoid nuclear receptors also have little potential for induction of developmental toxicity at doses which do not also provoke maternal intoxication. Comparing in vitro transcriptional activation of wild-type human RAR for the supertoxic TTNBP (Ro 13-7410) and TTAB (SRI 3961) with their relative teratogenic potency in hamster found that the more toxic congener also had the lower in vitro EC50 transactivation value (at ratios approximating their differential toxicities measured as administered dose). The RAR beta/gamma-selective CD 135 (TTNN) was not as efficient as TTNBP (Ro 13-7410) or TTAB (SRI 3961) in hRAR transactivation and CD 135 was less toxic than either Ro 13-7410 or SRI 3961. Although the RXR-selective SR 11217 failed to elicit terata after moderate doses, malformations consistent with those induced by high doses of retinoic acid could be produced following a single large bolus of SR 11217. Under the conditions here, simultaneous administration of Ro 31-0521 with all-trans-retinoic acid appeared to reduce the total percentage of abnormal fetuses seen after exposure to retinoic acid alone, but fetal body weights remained depressed and the numbers of dead embryos remained elevated, suggesting only limited influence of the cyclohexanetrione on retinoid developmental toxicity.

Animals↗

PubMed1999

Retinoid kinetics in eye tissues of VPP transgenic mice and their normal littermates.

PURPOSE: VPP mice, which possess a mutant transgene for opsin (V20G, P23H, P27L), exhibit a progressive rod degeneration that resembles one form of human autosomal dominant retinitis pigmentosa. In the present study the association of the development of VPP rod degeneration with abnormal operation of the retinoid visual cycle was examined. METHODS: Dark-adapted VPP mice and normal littermates were anesthetized and the pupils dilated. One eye of each animal was illuminated for 2 minutes; the other eye was shielded from the light and served as a control. Each animal was then dark adapted for a defined period (0-300 minutes) and killed. Retinoids contained in the retina, retinal pigment epithelium (RPE), and extracellular medium were recovered by means of formaldehyde-, isopropanol- and ethanol-based extractions and analyzed by high-performance liquid chromatography. RESULTS: Total amounts of retinoid recovered from unilluminated eyes of 2-month-old normal and VPP mice were 425 +/- 90 picomoles per eye and 115 +/- 33 picomoles per eye, respectively (mean +/- SD). Relative distributions of retinoids within normal and VPP eyes were similar. In normal and VPP animals, illumination for 2 minutes produced a similar immediate reduction in the molar percent of total retinoid represented by 11-cis retinal in the retina (average reduction of 34% and 28% in normal and VPP animals, respectively) and a similar transient increase of all-trans retinal in the retina. In both groups the decline of all-trans retinal was accompanied by an increase in total retinyl ester. In normal and VPP animals, a period of approximately 40 minutes or more preceded initiation of the recovery of 11-cis retinal in the retina, and the time course of this recovery was generally similar to that for the decline of retinyl ester. The overall dark-adaptation period required for half-completion of 11-cis retinal recovery was approximately 150 minutes. In neither group did illumination produce a substantial peak of all-trans retinol in the retina. CONCLUSIONS: The evident approximately fourfold reduction of total retinoid in the eyes of 2-month-old VPP mice is consistent with histologic and electroretinographic abnormalities determined in previous studies. Despite this marked abnormality in retinoid content, retinoid cycling in the VPP is remarkably similar to that in normal littermates. The data place constraints on the functional consequences of any abnormality in retinoid processing that may be present at this stage of the VPP rod degeneration.

Animals↗

PubMed2000

Simultaneous quantification of various retinoids by high performance liquid chromatography: its relevance to alcohol research.

BACKGROUND: We established a high performance liquid chromatography system that allowed simultaneous quantification of various retinoids. METHODS: We applied the retinoids to a high performance liquid chromatography system with a silica gel absorption column. Samples were separated by the system with a binary multistep gradient with two kinds of solvent that contained n-Hexan, 2-propanol, and glacial acetic acid in different ratios. Each retinoid was detected at a wavelength of 350 nm. RESULTS: This condition allowed separation of 13-cis-retinoic acid, 9-cis-retinoic acid, all-trans-retinoic acid, 13-cis-retinol, all-trans-retinol, all-trans-4-oxo-retinoic acid, and 13-cis-4-oxo-retinoic acid as distinct single peaks. Each retinoid was also analyzed separately and its retention time determined. To ascertain the reliability of this system for retinoid quantification, retinoids at various concentrations were applied to the system. We observed the linearities between the concentration and area under the curve of the peak for each retinoid by linear least-squares regression analysis up to 2.5 ng/ml for all retinoic acids and up to 5 ng/ml for all retinols. There was no significant scattering in tests of within-day reproducibility or day-to-day reproducibility. Using this system, we examined effects of light exposure on isomerization of retinoids. When retinoids were exposed to room light for 2 hr, the amounts of all but 13-cis-retinol changed significantly. In particular, the amounts of all-trans-retinoic acid and 9-cis-retinoic acid were reduced by 40% and 60%, respectively. CONCLUSION: The HPLC system established in this study should be useful for studying the oxidation pathway of retinol to retinoic acid. A light-shielded condition is required when particular retinoic acids are analyzed.

Alitretinoin↗

PubMed2001

Identification of effective retinoids for inhibiting growth and inducing apoptosis in bladder cancer cells.

PURPOSE: Retinoids modulate the growth and differentiation of normal and malignant epithelial cells in vitro and in vivo, and inhibit bladder carcinogenesis in animal models. Retinoid analogs have been used in several clinical chemoprevention trials of superficial bladder cancer recurrence. There is a clear need to identify new effective retinoids and develop novel approaches for the chemoprevention and treatment of superficial bladder cancer. We investigated the effects of various retinoids on growth inhibition and apoptosis induction in bladder cancer cell lines. MATERIALS AND METHODS: Ten grades 1 to 3 bladder cancer cell lines and the 4 retinoids all-trans-retinoic acid, 9-cis retinoic acid, 4-(N-hydroxyphenyl) retinamide (4HPR) and LGD1069 were used in the study. We compared the ability of these retinoids to inhibit growth, induce apoptosis, affect the expression of nuclear retinoid receptors and modulate apoptosis related genes. RESULTS: Most bladder cancer cell lines did not express retinoic acid receptor beta and were resistant to the effect of all-trans-retinoic acid and 9-cis retinoic acid on growth inhibition and apoptosis induction, even at a concentration of 10(-5) M. The 2 cell lines that expressed retinoic acid receptor beta were constitutively sensitive to the growth inhibitory effect of all-trans-retinoic acid. 4HPR inhibited cell growth by about 90% in all but 1 cell line and induced apoptosis at a concentration of 10(-5) M after a 24-hour treatment. LGD1069 had virtually no effect. All-trans-retinoic acid and 4HPR induced retinoic acid receptor beta expression in 1 bladder cancer cell line. However, the effect of 4HPR on cell growth and apoptosis were not related to the constitutive expression of retinoic acid receptor beta. 4HPR decreased bcl-2 expression in 6 of 8 bladder cancer cell lines but did not change p53 gene expression. CONCLUSIONS: The results demonstrate that 4HPR is the most potent growth inhibitor and apoptosis inducer of the retinoids tested. Lack of retinoic acid receptor beta expression may be responsible for cell resistance to all-trans-retinoic acid but not to the other retinoids.

Apoptosis↗

PubMed2001

Apoptosis induction in cancer cells by a novel analogue of 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid lacking retinoid receptor transcriptional activation activity.

The retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN) is reported to have anticancer activity in vivo. Induction of cell cycle arrest and apoptosis in cancer cell lines refractory to standard retinoids suggests a retinoid-independent mechanism of action for AHPN. Conformational studies suggested that binding of AHPN does not induce an unusual conformation in retinoic acid receptor (RAR) gamma. The 3-chloro AHPN analogue MM11453 inhibited the growth of both retinoid-resistant (HL-60R leukemia, MDA-MB-231 breast, and H292 lung) and retinoid-sensitive (MCF-7 breast, LNCaP prostate, and H460 lung) cancer cell lines by inducing apoptosis at similar concentrations. Before apoptosis, MM11453 induced transcription factor TR3 expression and loss of mitochondrial membrane potential characteristic of apoptosis. MM11453 lacked the ability to significantly activate RARs and retinoid X receptor alpha to initiate (TREpal)(2)-tk-CAT reporter transcription. These results, differential proteolysis-sensitivity assays, and glutathione S-transferase-pulldown experiments demonstrate that, unlike AHPN or the natural or standard synthetic retinoids, MM11453 does not behave as a RAR or retinoid X receptor alpha transcriptional agonist. These studies strongly suggest that AHPN exerts its cell cycle arrest and apoptotic activity by a signaling pathway independent of retinoid receptor activation.

Antineoplastic Agents↗

PubMed2002

Expression of retinoid-related genes in serum-free cultures of normal, immortalized and malignant human oral keratinocytes.

Retinoids are used in the clinical treatment of oral squamous carcinoma, including both early and late stages. Inter-individual variation in responsiveness, including a common insensitivity of advanced stages, suggest that changes in retinoid-related functions might characterize tumor development. To investigate a genetic basis for this hypothesis, an in vitro multi-step model of carcinogenesis involving normal (NOK), SV40 T antigen-immortalized (SVpgC2a) and malignant (SqCC/Y1) oral keratinocytes was analysed under identical culture conditions using micro-array technique (Affymetrix HG_U95A chip) for expression of 52 genes related to retinoid metabolism and actions. The variable detection of between 22-26 transcripts in the cell lines, involving binding/transport factors, receptors, transcriptional activators/repressors and responsive genes, indicated specificity in regards to the expression of known retinoid-related genes in oral keratinocytes. The transformed cell lines variably exhibited differences as compared to NOK, i.e., lower transcript levels for cellular retinol binding protein, the cellular retinoic acid binding protein II (CRABP II) and retinoic acid receptor gamma, whereas in contrast, the levels of CRABP I were higher. Transcripts for proteins interacting with nuclear retinoid receptors were similarly expressed among the cell types, whereas transcripts for retinoid-metabolizing enzymes were generally not detected. Finally, transcripts of retinoid-responsive genes, including RARRES3, RI58, NN8-4AG and midkine, were variably expressed. The overall results imply selective expression of retinoid-related functions in normal and transformed keratinocytes, and that cell transformation can impair the capacity for binding and storage of retinol as well as retinoic acid-mediated signalling. These multiple alterations are consistent with possible retinoid insensitivity during oral carcinogenesis.

Cell Line↗

PubMed2003

Clinically potential subclasses of retinoid synergists revealed by gene expression profiling.

Retinoids have chemopreventive and therapeutic potency in oncology and dermatology, although their application is restricted by many undesirable side effects. For the development of more effective and less toxic retinoids, gene expression analyses using DNA microarrays have the potential to supplement conventional screening methods, which are based on the changes in cell morphology and/or function. In this study, we applied the class prediction algorithm, which was used in the molecular phenotyping of tumors, for the classification of synthetic retinoids (Am80 and Tp80) and retinoid synergists (HX630, TZ335, and PA024) as all-trans retinoic acid-like, 9-cis retinoic acid-like, and control-like classes. By analyzing the effects of all-trans retinoic acid and 9-cis retinoic acid on the gene expressions in a human promyelocytic leukemia cell line, HL60, we successfully selected 50 marker genes whose expression pattern could distinguish these classes. Moreover, the classification revealed the existence of two subclasses among the retinoid synergists used with Am80. Close inspection of the DNA microarray analyses indicated that these two subclasses had different effects on the apoptosis of HL60 cells, and this was confirmed by in vivo experiments. These results indicate that the retinoidal activity of Am80, which has already been used in clinical trials, could be modulated differently by the two classes of retinoid synergists. Thus, these two subclasses of retinoid synergists have the potency to widen the usage of Am80. Our analyses demonstrated that the gene expression profiling could provide important information for developing useful retinoid synergists by compensating conventional screening methods.

Alitretinoin↗

PubMed1991

Identification of retinoids with nuclear receptor subtype-selective activities.

Retinoic acid (RA) and its synthetic analogues, retinoids, have shown promising results in the prevention of epithelial carcinogenesis and in the treatment of acute promyelocytic leukemia and various proliferative skin disorders. Retinoid action on gene regulation is mediated by three distinct nuclear retinoic acid receptor subtypes, RA receptors alpha, beta, and gamma. The existence of multiple RA receptors has raised the possibility that receptor subtype-specific retinoids with reduced side effects can be developed. To analyze the activity of retinoids at the molecular level, we used a receptor activation assay. RA and 22 retinoids were compared on the three receptor subtypes. We found the alpha receptor to be least sensitive to activation by RA and the gamma receptor to be most sensitive. Compared with RA, one of the retinoids showed increased activity for the alpha and beta receptors. Three retinoids revealed no gene activation activity and showed no antagonistic effects when assayed in the presence of RA. Surprisingly, several of the retinoids were efficient activators of the beta and gamma receptors but poor activators or nonactivators of the alpha receptor. Our data demonstrate that the three RA receptor subtypes have differential ligand activation specificities and that the design of receptor subtype-selective retinoids is possible.

Animals↗

PubMed1999

A selective retinoid with high activity against an androgen-resistant prostate cancer cell type.

Retinoic acid (RA) and its natural and synthetic analogs, the retinoids, regulate many biological processes, including development, differentiation, cell growth, morphogenesis, metabolism and homeostasis. Retinoid effects are mediated by specific nuclear receptors, the RARs and RXRs. Because of their ability to control cell growth and induce differentiation, retinoids are being examined for the prevention and treatment of several cancers. The majority of retinoids so far analyzed and available inhibit primarily cell proliferation and tumor progression but cannot eliminate cancer cells. In addition, the beneficial effects of the natural retinoids are undermined by undesirable side effects, possibly due to indiscriminate activation of all retinoid receptor subtypes and response pathways. Here, we show that a synthetic retinoid, CD-271, that activates selectively the RAR gamma subtype in a given context, shows increased anti-proliferative activity against certain carcinoma cells over all-trans-retinoic acid (tRA). CD-271 exhibits enhanced activity against DU-145 prostate adenocarcinoma cells through apoptosis-inducing activity, while tRA does not. The selective anti-cancer cell action appears to be receptor-mediated as an RAR antagonist reverses the inhibition. This profile was not seen with other selective retinoids, such as RAR alpha-selective agonists, anti-AP-1 compounds and a non-apoptosis inducing RAR gamma agonist. Our data point to a specific role for RAR gamma in controlling the growth of the prostate, consistent with previous RAR gamma gene knockout data. The identified retinoid represents a new class of compounds with potential for the treatment of prostate cancer.

Androgens↗

PubMed1993

Photoreceptor recovery in retinoid-deprived rats after vitamin A replenishment.

Dietary deficiency in the retinoid precursors of the visual pigment chromophore 11-cis retinal results in the synthesis of photoreceptor outer segments containing opsin in excess of the vitamin A available for rhodopsin regeneration. This suggests that vitamin A-free opsin may be incorporated into newly synthesized outer segment disc membranes. If this opsin is functionally intact, it should be possible convert it to rhodopsin in vivo by providing the appropriate retinoids, and the resulting rhodopsin should should be able to mediate visual transduction. Experiments were conducted to evaluate this possibility and to identify the rate-limiting steps in photoreceptor recovery from retinoid depletion. Rates were maintained on diets either containing or lacking retinoid precursors of 11-cis retinal for 23 weeks, at which time outer segment opsin content greatly exceeded the availability of visual cycle retinoids in the retina. The retinoid-deprived animals were then each given a single intramuscular injection of all-trans retinol. At various time intervals after retinol administration, electroretinograms (ERGs) were recorded on some rats, and retinal rhodopsin contents were determined in others. At similar time intervals, blood and retinal pigment epithelial (RPE) retinoid levels and photoreceptor outer segment size were also determined. No significant increase in retinal rhodopsin content was observed up to 8 hr after injection, despite the fact that by 3 hr, blood retinol levels had recovered to more than 30% of normal. By 1 day after injection, however, rhodopsin levels had recovered to 30% of normal and ERG responses showed increases in visual sensitivity commensurate with the recovery of rhodopsin. The lag in rhodopsin recovery was apparently due to delayed uptake of retinol from the blood by the RPE. Photoreceptor outer segment size was reduced by over 50% in the retinoid- deprived rats and did not begin to recover by 1 day. By 1 week, however, outer segment size had returned to an average of 65% of normal. Commensurate with this regrowth of the outer segments, both rhodopsin levels and visual sensitivity increased between 1 and 7 days after vitamin A administration. Because the rates of recovery in rhodopsin levels and visual sensitivity greatly exceeded the normal rate of new opsin synthesis at short time intervals after vitamin A repletion, it appears that the opsin incorporated into the disc membranes of retinoid-deprived rats is able to form functional rhodopsin in vivo when the chromophore is supplied. Regrowth of the outer segments back to their normal size is required for full recovery of visual sensitivity.

Animals↗

PubMed2000

Teratogenicity, tissue distribution, and metabolism of the retro-retinoids, 14-hydroxy-4,14-retro-retinol and anhydroretinol, in the C57BL/6J mouse.

The retro-retinoids 14-hydroxy-4,14-retro-retinol (14-HRR) and anhydroretinol (AR) are endogenous metabolites of retinol (Vitamin A). 14-HRR and retinol, but not retinoic acid, promote the proliferation of lymphocytes and fibroblasts when cultured in serum-free medium, whereas AR competitively inhibits these growth-supportive effects. Retinol and all-trans-retinoic acid are potent teratogens. This study shows the teratogenic potencies of 14-HRR and AR compared to retinol at a single gestational time. Also reported is the metabolism of these retinoids in nonpregnant mouse liver, the primary storage tissue of vitamin A, where many retinoids will be present at their highest concentration. Additionally, measurement of these metabolite concentrations was carried out in pregnant mouse plasma and embryos because they are the most relevant to teratology. Single intraperitoneal administration of 60 mg/kg of all-trans-retinol (retinol) to C57BL/6J mice at gestational day 7.5 produced a significant induction of eye and axial skeletal malformations. The equivalent dose of 14-HRR or AR induced a lower frequency of embryolethality and eye and axial skeletal malformations indicating that these retro-retinoids are less potent teratogens than retinol. The distribution of 14-HRR, AR, retinol, and their metabolites was determined in the liver at a single time point after retinoid administration. Two hours after 60 mg/kg of 14-HRR treatment, HRR esters are detected. Two hours after 600 mg/kg of AR treatment, 14-HRR is detected, suggesting that 14-HRR, a reported metabolite of retinol, can be biosynthesized from AR. In both cases, neither retinoic acid nor retro-retinoid acidic metabolites were detected. Two hours after 60 mg/kg of retinol treatment, 14-HRR, 13,14-dihydroxyretinol (DHR), AR, and retinoic acid were detected. A new endogenous retro-retinoid, to which the 4-hydro-5-hydroxy-anhydroretinol structure is proposed, was detected in all liver extracts. Retinoic acid, 14-HRR, and DHR were present in plasma and embryos of retinol-treated pregnant mice. Plasma and embryos of AR-treated pregnant mice contained 14-HRR and AR, but the retinoic acid concentration did not increase compared to controls. In summary, the retro-retinoids 14-HRR and AR are weaker teratogens than retinol. The low teratogenicity observed might be due to the facts that 14-HRR and AR do not contain the terminal carboxylic group involved in binding and activation of the retinoic acid nuclear receptors and they are not metabolized to acidic retinoids.

Abnormalities, Drug-Induced↗

PubMed2000

Coexpression of keratins 13 and 16 in human keratinocytes indicates association between hyperproliferation-associated and retinoid-induced differentiation.

In human skin, epidermal differentiation occurs in two ways: normal differentiation, characterized by keratin 10 expression, and alternative differentiation. Alternative differentiation can be hyperproliferation-associated differentiation (expression of keratin 16) or the reinduction of an embryonic type of differentiation (expression of keratin 13). This embryonic type of differentiation is also seen following treatment with retinoids. In the present study, the hypothesis that hyperproliferation-associated and retinoid-induced differentiation are separate processes was investigated. Two areas of normal skin were treated for 24 h with 0. 1% all-trans-retinoic acid. Subsequently, one of the areas was tape-stripped and treatment was continued for 48 h. Multiparameter flow cytometry permitted simultaneous measurement of two coexpressed differentiation markers (retinoid-induced and normal differentiation or retinoid-induced and hyperproliferation-associated differentiation) and the proliferation characteristics (cells in S/G(2)M phase). Concerning normal and retinoid-induced differentiation, the all-trans-retinoic acid-induced expression of keratin 13 was only seen in tape-stripped retinoid-treated skin and exclusively together with that of keratin 10. The assessment of hyperproliferation-associated and retinoid-induced differentiation showed slight expression of keratin 13 without expression of keratin 16 in tape-stripped skin. Coexpression of keratins 16 and 13 was exclusively seen in tape-stripped retinoid-treated skin. The finding that keratin 13 expression following treatment with all-trans-retinoic acid occurred exclusively in hyperproliferative skin suggests that retinoid-induced and hyperproliferation-associated differentiation are coupled. Coexpression of keratins 13 and 16 provides direct experimental evidence for this association.

Adhesives↗

PubMed1992

Potentiation of IL-2-induced t-cell proliferation by retinoids.

We evaluated the capacity of retinoids to potentiate proliferative responses of murine T-cells to recombinant human interleukin 2 (rIL-2). Concanavalin A (Con A) prestimulated spleen cells responded in a dose-dependent manner to added rIL-2. All-trans-retinoic acid (RA) at 10(-8) M potentiated the proliferative response by fivefold at saturating levels of IL-2. In similar experiments, two closely related retinamides, all-trans-(phenyl)retinamide (PR) and N-(4-hydroxyphenyl)retinamide (4-HPR), also potentiated murine splenocyte rIL-2 responses. Potentiation of IL-2-induced proliferation was dose-responsive to the concentration of added retinoid with peak potentiation occurring at 10(-10) - 10(-8) M in the presence of 10 U/ml rIL-2. Significant potentiation was observed at retinoid concentrations as low as 10(-14) M. Fluorescence flow cytometry of the responding cells revealed that among L3T4+, Lyt-2+ or total T-cells, at 72 h following Con A stimulation, essentially all of the cells expressed IL-2 receptors (IL-2R). This apparently represents near maximum IL-2R expression and treatment of the cells with retinoids did not increase IL-2R expression at that time point. The potentiation of IL-2 responses by retinoids was also observed with IL-2-dependent HT-2 cells, 98% of which were IL-2R positive. HT-2 proliferative responses to rIL-2 were potentiated as much as fourfold by 10(-10) M RA. HT-2 proliferative responses to rIL-2 were potentiated by all three retinoids dose dependently. Significant potentiation was observed with as little as 10(-14) M retinoid. Retinoids in the absence of IL-2 induced no proliferative responses. These data suggest that retinoids can augment the capacity of IL-2 to induce T-cell proliferation using Con A-activated murine splenic T-cell blasts and a long-term-cultured T-cell line.

Animals↗

PubMed1998

Retinoic acid receptor gamma1 expression determines retinoid sensitivity in pancreatic carcinoma cells.

BACKGROUND & AIMS: Retinoids inhibit growth and induce differentiation in a variety of pancreatic carcinoma cells. The goal of this study was to examine the molecular mechanisms responsible for retinoid sensitivity. METHODS: Anchorage-independent growth was examined in AR42J, DSL-6A/C1, and Capan-2 cells using a human tumor clonogenic assay. Retinoid receptors were characterized by a reverse-transcription polymerase chain reaction. Retinoic acid receptor gamma1 (RARgamma1) was stably transfected into AR42J cells using lipofectamin and into DSL-6A/C1 using ballistomagnetic gene transfer. Receptor expression was verified using Southern and Northern blotting as well as electrophoretic mobility shift assays. RESULTS: Retinoid treatment resulted in a dose-dependent growth inhibition of Capan-2 cells, whereas growth was not affected in AR42J and DSL-6A/C1 cells. A selective loss of RARgamma1 expression was observed in both retinoid-resistant cell lines, whereas all other retinoid receptor subtypes showed an identical expression pattern. Retinoid treatment of three independent RARgamma1-expressing cell clones of AR42J and DSL-6A/C1 cells resulted in pronounced growth inhibition compared with wild-type control cells. CONCLUSIONS: RARgamma1 expression determines sensitivity of pancreatic carcinoma cells to retinoid-mediated growth inhibition and might therefore serve as a valuable predictive marker for retinoid treatment of pancreatic cancer.

Animals↗

PubMed1982

Inhibition of chemical carcinogenesis by retinoids.

Retinoids are effective inhibitors of chemical carcinogenesis in the mammary gland, esophagus, and urinary bladder of experimental animals. Modification of the basic retinoid structure has produced retinoids with increased target organ specificity, resulting in increased anticancer activity with reduced systemic toxicity. Combining retinoid treatment with hormonal manipulation results in a synergistic inhibition of mammary carcinogenesis; this combination approach also inhibits mammary tumor recurrence following surgical removal of the first mammary tumor. Retinoids are most effective when administered shortly after the carcinogenic insult. However, even when retinoid treatment if delayed, the compounds are still effective cancer chemopreventive agents for the mammary gland and urinary bladder. The length of time that retinoid exposure can be delayed and retain an anticancer effect is directly related to tumor latency, with a longer delay permissible against tumors with long latent periods. Current research focuses on the identification of new retinoids with increased chemopreventive activity and decreased toxicity, and combination studies which will provide treatment regimens with increased anticancer activity as well as information pertaining to mechanisms of retinoid action.

Animals↗

PubMed1983

Lack of inhibition by retinoids of bis(2-oxopropyl)nitrosamine-induced carcinogenesis in Syrian hamsters.

Syrian hamsters were treated with either a low (10 mg/kg body weight) or high (40 mg/kg body weight) single dose of bis(2-oxopropyl)nitrosamine (BOP) and beginning 1 week later fed either low (0.2 mmol/kg diet) or high (0.4-1.0 mmol/kg diet) levels of one of four retinoids [13 cis retinoic acid (13-cis-RA), N-ethylretinamide (ERA), N-(2-hydroxyethyl)retinamide (OHERA) or N-(phenyl)retinamide (PRA)] for periods of 40 or 50 weeks. The high retinoid levels (0.4-1.0 mmol/kg diet) fed following the highest BOP treatment enhanced pancreatic carcinoma yields (average number/effective animal) in males fed all four retinoids, and in females fed ERA and 13-cis-RA. Enhanced adenoma yields were also seen in all groups when high retinoid levels were fed following 40 mg BOP/kg body weight. However, these retinoid levels caused an increased adenoma yield in male hamsters only and did not modify carcinoma yields when fed following 10 mg BOP/kg body weight. Similarly, tumor yields at extra-pancreatic sites were elevated in retinoid-fed hamsters of both sexes after 40 mg BOP/kg body weight and in males fed ERA and 13-cis-RA after 10 mg BOP/kg body weight when retinoids were given at the high levels (0.4-1.0 mmol/kg diet). Increased incidences of bile duct and liver tumors in particular were found in hamsters given 40 mg BOP/kg body weight. Consumption of retinoid levels of 0.4 mmol/kg diet and above was also associated with a high incidence of liver cell necrosis, ovarian cysts and ovarian hemorrhage. Retinoids (ERA, OHERA, and PRA) fed at the low level (0.2 mmol/kg diet) following the low BOP dose did not enhance carcinogenesis in the pancreas or at other sites and did not cause alterations in morphologic observations.

Animals↗