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PubMedDate not supplied

In vivo regulation of rat epididymal proteins by retinoids: analysis by two-dimensional electrophoresis.

The role of retinoids in the regulation of epididymal fluid protein expression was investigated. We compared the patterns of two-dimensional electrophoretic gels of proteins from luminal fluids, cytosols and spermatozoa (from control rats only) of control, retinoid-depleted, retinoid-depleted retinoic acid-complemented and retinoid-depleted testosterone-supplemented rats. This study compared the luminal fluid patterns from the 4 diets and observed 13 proteins whose expression was dependent on nutritional status. Eight were either absent or very weakly expressed in retinoid-depleted animals only, while their presence was obvious in control rats and in the retinoid-deficient retinoic acid- and testosterone-complemented groups. The expression of 8 proteins was greatly enhanced in retinoid-depleted testosterone-supplemented fluids as compared to control fluids. Five of the regulated proteins seemed to be captured by spermatozoa as they were observed in sperm protein patterns of control rats. These results clearly show that the synthesis of several epididymal proteins is influenced by retinoids. Since testosterone-supplemented animals on retinoid-free diet elicited the same response as retinol and retinoic acid ones, testosterone is likely to be the mediator of retinoid action on epididymal protein synthesis. Nevertheless, the observation of one protein whose expression is stimulated by retinoic acid only and is totally independent of testosterone also favors the direct influence of this retinoid.

Animals↗

PubMed1997

Retinoids in head and neck chemoprevention.

Over the last few years, we have witnessed tremendous progress in both basic and clinical research on retinoids. Preclinical studies have indicated the potential of retinoids in cancer prevention and therapy, but the actual successful application of retinoids in clinical chemoprevention trials has been the recent and exciting development in the field of retinoid research. Our understanding of the role of retinoids in normal developmental processes and the differentiation of normal and malignant cells, and the fundamental discovery of the nuclear retinoid receptors that act as transcription modulating factors regulating specific gene expression have been major advances in the field of basic retinoid research. Chemoprevention is the newest research approach in our efforts to control upper-aerodigestive tract cancers, which have one of the lowest cure rates among epithelial malignancies, and in which the occurrence of second primary tumors further burdens the dismal prognosis of patients. The efficacy of retinoids in the reversal of oral premalignant lesions and the prevention of second primary tumors has generated tremendous enthusiasm among retinoid researchers, particularly those in the field of chemoprevention. Current explorations of combinations of retinoids with biologic response modifiers such as alpha-interferon, as well as new receptor-selective retinoids, hold promise for the future.

Anticarcinogenic Agents↗

PubMed1999

Differential responses of normal, premalignant, and malignant human bronchial epithelial cells to receptor-selective retinoids.

Using an in vitro lung carcinogenesis model consisting of normal, premalignant, and malignant human bronchial epithelial (HBE) cells, we analyzed the growth inhibitory effects of 26 novel synthetic retinoic acid receptor (RAR)- and retinoid X receptor (RXR)-selective retinoids. RAR-selective retinoids such as CD271, CD437, CD2325, and SR11364 showed potent activity in inhibiting the growth of either normal or premalignant and malignant HBE cells (IC50s mostly <1 microM) and were much more potent than RXR-selective retinoids. Nonetheless, the combination of RAR- and RXR-selective retinoids exhibited additive effects in HBE cells. As the HBE cells became progressively more malignant, they exhibited decreased or lost sensitivity to many retinoids. The activity of the RAR-selective retinoids, with the exception of the most potent retinoid, CD437, could be suppressed by an RAR panantagonist. These results suggest that: (a) RAR/RXR heterodimers play an important role in mediating the growth inhibitory effects of most retinoids in HBE cells; (b) CD437 may act through an RAR-independent pathway; (c) some of the RAR-selective retinoids may have the potential to be used in the clinic as chemopreventive and chemotherapeutic agents for lung cancer; and (d) early stages of lung carcinogenesis may be responsive targets for chemoprevention by retinoids, as opposed to later stages.

Antineoplastic Agents↗

PubMed2000

Activation of retinoic acid receptor alpha is sufficient for full induction of retinoid responses in SK-BR-3 and T47D human breast cancer cells.

Retinoid signaling via retinoic acid (RA) and retinoid X receptors (RARs and RXRs) regulates mammary epithelial cell growth and differentiation. Loss of RAR-beta might represent an early event during breast carcinogenesis. Higher differentiated, estrogen-dependent, estrogen receptor (ER)-positive (ER+) mammary carcinoma cells have been found to contain relatively high levels of RAR-alpha and to be responsive to retinoids, whereas most undifferentiated, estrogen-independent, ER-negative (ER-) cells are characterized by low RAR-alpha expression and by retinoid resistance. In contrast, RAR-gamma is detectable at equal levels in both ER+ and ER- cells. In the present investigation, we directly examined the relative contribution of the distinct retinoid receptors to the retinoid response of breast cancer cells by comparing the effects of low concentrations of specific retinoids, which selectively activate individual receptor subtypes, on growth, cell cycle distribution, apoptosis, and on the autoregulation of RAR-alpha and RAR-gamma in ER- SK-BR-3 and ER+ T47D breast cancer cells. In vitro growth activity was determined by using a colorimetric cell viability assay and analysis of cell cycle distribution, and apoptosis was performed by flow cytometry of propidium iodide-stained or fluorescent Annexin V-labeled cells, respectively, whereas expression of RAR-alpha and RAR-gamma was determined by Northern blotting. Both cell lines are retinoid sensitive and express high amounts of RAR-alpha, RAR-gamma, and RXR-alpha. RAR-alpha-selective compounds (AM80 and AM580) inhibit cell growth, induce G1 arrest, stimulate apoptosis, and up-regulate RAR-alpha and RAR-gamma mRNA as efficiently as RAR/RXR-pan-reactive (9-cis RA) and RAR-pan-reactive retinoids (all-trans RA, TTNPB). Remarkably, an RAR-alpha antagonist (Ro 41-5253) not only blocks the RAR-alpha-selective agonists but also the pan-reactive compounds. In contrast, RAR-13-selective (CD417), RAR-gamma-selective (CD437/AHPN), and RXR-alpha-selective (Ro 25-7386) retinoids exert no effects on the examined parameters. Thus, our results support the idea that RAR-alpha is the crucial receptor mediating the biological effects during retinoid signaling in both ER- SK-BR-3 and ER+ T47D human breast cancer cells.

Antineoplastic Agents↗

PubMed1997

[In vitro study on the effects of the novel retinoids on the proliferation and differentiation of normal and leukemic cells].

OBJECTIVE: To evaluate the prospect for clinical use of four novel retinoid compounds (retinoid 1, retinoid 2, retinoid 3 and retinoid 4), which were different structurally from all-trans retinoic acid. METHODS: The effects of the four retinoids on the differentiation and clonal proliferation of NB4 cells and fresh acute promyelocytic leukemia (APL) cells and on the proliferation of normal hematopoietic cells were studied. Cell morphological examination,nitro tetrazolium blue reduction test, cell cycle dynamics, and colony formation assay were used in the study. RESULTS: Novel retinoids induced differentiation of NB4 and fresh APL cells, and markedly inhibited CFU-L growth of NB4 and fresh APL cells. The activity related to their chemical structures and retinoid 2 was more active. The novel retinoids enhanced the growth of CFU-GM, CFU-E and CFU--Meg of normal bone marrow cells. CONCLUSION: These novel retinoids, especially retinoid 2, may regulate the proliferation and differentiation of normal hematopoiesis, induce APL cell differentiation and maturation, and are worthy of further study for clinical use.

Cell Differentiation↗

PubMed1994

Retinoids in bladder, testis and prostate cancer: epidemiologic, pre-clinical and clinical observations.

Genitourinary cancers--bladders, testis and prostate--account for almost 50,000 deaths per year. Epidemiologic data suggest that individuals with low serum retinoid levels or low dietary intake of retinoid-containing foodstuffs have an increased risk of bladder and prostate cancer. Preclinical investigations show that a variety of retinoids suppress the proliferation of prostate and bladder cancer cells and induce differentiation in teratocarcinoma cells. Retinoids prevent the emergence of murine bladder and prostate cancers in carcinogen-treated animals. Clinical data are disappointing or inconclusive. A single well-conducted phase 2 trial of 13-cis retinoic acid in patients with germ cell tumors was negative. Several historically controlled as well as prospectively randomized, placebo-controlled trials of retinoids in superficial bladder cancer have failed to provide evidence of the efficacy of retinoids. Two studies of all-trans-retinoic acid in advanced prostate cancer have been negative. Despite compelling preclinical rationale, retinoids have failed to yield positive results in the clinical management of prostate, bladder or testis cancers. Further work is needed to define subsets of patients in whom retinoids might be active, and whether new retinoids or new approaches to retinoid delivery will improve the clinical usefulness of retinoids in these tumors.

Antineoplastic Agents↗

PubMedDate not supplied

Retinoid-induced growth arrest of breast carcinoma cells involves co-activation of multiple growth-inhibitory genes.

Retinoids are used in leukemia therapy and chemoprevention of cancers. Treatment of MCF-7 breast carcinoma cells with low doses of retinoids induces gradual proliferation arrest with phenotypic markers of senescence. cDNA microarray hybridization and reverse transcription-polymerase chain reaction analysis showed that retinoid-induced growth arrest in MCF-7 cells in associated with strong induction of 13 genes. Four of these genes (IGF-binding protein 3, EPLIN, beta IG-H3 and FAT10) have antiproliferative activity; EPLIN and beta IG-H3 are also known to be selectively inhibited in transformed relative to normal cells. The functions of the induced genes may also account for other cellular effects of retinoids, including the proteasome-mediated protein degradation, increased cell adhesion, and retinoic acid synthesis. Only one of 13 strongly induced genes (ring finger protein TRIM31) contains a putative retinoid response element in its promoter; TRIM31 also shows the most rapid kinetics of induction by retinoids. In contrast, the antiproliferative genes contain no identifiable retinoid response elements in their promoters and show more gradual induction kinetics, suggesting that these genes are indirectly induced by retinoids. Elucidation of the mechanisms that mediate co-induction of growth-inhibitory genes in retinoid-treated cells may suggest an approach to reproducing the growth-inhibitory effect of retinoids in retinoid-insensitive human cancers.

Adenocarcinoma↗

PubMed1982

Inhibition of pancreatic carcinogenesis by retinoids in azaserine-treated rats.

Chemoprevention by retinoids of the progression of carcinomas induced in rats by azaserine was evaluated. Wistar/Lewis rats were given 15 weekly injections of azaserine, 10 mg/kg, while fed a chow diet; after the completion of carcinogen treatment, they were fed a chow diet supplemented with four different retinoids at the level of 0.5 to 2 mmol/kg diet for 1 year. The incidence of neoplasms was determined by autopsy and histological study. The incidence of pancreatic carcinoma among a male positive control group (azaserine treated, but not retinoid treated) was 42%. The incidence of pancreatic carcinoma among male rats treated with retinoids was: N-2-hydroxyethylretinamide, 6%; N-4-propionyloxyphenylretinamide, 17%; and retinylidene dimedone, 12%. The incidence in rats fed these three retinoids was significantly (p less than 0.05) below the control group incidence. Thus, these three retinoids appeared to be effective in inhibiting the progression of pancreatic carcinomas in the azaserine-induced model. A similar trend was demonstrated in females, but statistical significance was shown only in rats fed N-2-hydroxyethylretinamide. A fourth retinoid, N-4-carboxyphenylretinamide, was more toxic and less effective in chemoprevention. Since retinoids were fed after exposure to carcinogen, the effect was exerted during the postinitiation phase of carcinogenesis. The ratio of invasive pancreatic carcinomas to localized carcinomas (carcinoma in situ) was clearly higher among non-retinoid-treated rats than among those treated with retinoids. This is consistent with retarded progression in the retinoid-treated groups.

Animals↗

PubMed1997

Regulation of hepatic lecithin:retinol acyltransferase activity by retinoic acid receptor-selective retinoids.

The microsomal enzyme LRAT esterifies retinol and has been implicated in the hepatic storage of vitamin A. Previously, we showed that hepatic LRAT activity is negligible during vitamin A deficiency and that all-trans-retinoic acid (all-trans-RA) rapidly induces the activity of liver LRAT in retinoid-deficient rats. In the present studies, we have examined the ability of natural and synthetic retinoids to induce liver LRAT activity in retinoid-deficient rats. The natural retinoids retinol, all-trans-RA (100 microg), 9-cis-RA, or equal molar amounts of other retinoids were injected ip and LRAT specific activity was measured in liver homogenates 17-18 h later. In retinoid-deficient rats, liver LRAT activity was extremely low [0.13 +/- 0.03 pmol retinyl ester (RE)/min/mg liver protein, mean +/- SE]. The natural retinoids retinol and all-trans-RA strongly induced LRAT activity (12.71 +/- 1.09 and 13.10 +/- 1.55 pmol RE/min/mg, respectively), whereas 9-cis-RA induced a lower level of LRAT activity (3.96 +/- 1.88 pmol RE/min/mg, P < 0.001 vs all-trans-RA). The retinoic acid receptor (RAR)-selective analog (RAR pan-agonist) all-trans-UAB8 and the RAR-alpha-selective retinoid Am580 also strongly induced LRAT activity. In contrast, neither RXR-selective agonists nor retinoids having a retro structure were active. For retinoids with significant RAR-alpha binding activity there was a strong direct correlation between receptor binding in vitro and the ability to induce hepatic LRAT activity in vivo (r2 = 0.920). These data implicate the RARs in the induction of hepatic LRAT and suggest a predominant role for RAR-alpha-active ligands.

Acyltransferases↗

PubMed1998

Keratinocyte-specific retinoid regulation of human cellular retinoic acid binding protein-II (hCRABPII) gene promoter requires an evolutionarily conserved DR1 retinoic acid-responsive element.

Transcription of the hCRABPII gene is retinoid inducible in human skin keratinocytes (KC) but, surprisingly, not in cultured cells. The promoter for the gene harbors three putative nuclear receptor binding sites: DR5, upstream of the transcription start site; DR1 (DR1d), distal to the site; and DR1 (DR1p), a proximal variant. DR1d, but not DR1p, is conserved between human and mouse. Although DR5 has been found to be a retinoid receptor target in COS-1 cells, the function of DR1 remains unknown. We examined the functions of these DR in retinoid regulation of the hCRABPII promoter in human KC. In reporter gene assays, no significant retinoid response was observed in the promoter in cultured KC; however, overexpression of retinoid receptor heterodimers RARgamma x RXRalpha restored the response. Gel supershift assays showed that endogenous RARgamma x RXRalpha levels are much lower in cultured KC than in skin in vivo. Ligand-binding assays showed that cultured KC contain only one-third of the level of retinoic acid receptor (RAR) and one-eighth of the level of retinoid X receptor found in KC in skin. Deletion of the DR1d or DR5 sites reduced retinoid-induced promoter activity by 63% and 27%, respectively. Isolated DR1d and DR5 sites, but not DR1p, efficiently bound RARgamma-RXRalpha and conferred RAR-selective retinoid responsiveness on a heterologous promoter. These data indicate that: (i) the previously reported lack of retinoid regulation of endogenous hCRABPII gene transcription in cultured KC is likely due to insufficient levels of RARgamma x RXRalpha, but not their cofactors; (ii) the conserved DR1d site is the major functional target in RARgamma x RXRalpha regulation of hCRABPII in KC; (iii) the DR1p site is nonfunctional due to its lack of affinity for RARgamma x RXRalpha, although its half-sites share high sequence homology with the consensus retinoid receptor-binding half-site.

Base Sequence↗

PubMed2004

Suppression of human pancreatic cancer cell proliferation by AGN194204, an RXR-selective retinoid.

Retinoids may be useful agents for the treatment of pancreatic cancer. However, retinoic acid receptor (RAR)-selective retinoids produce unwanted side effects. In contrast, retinoid X receptor (RXR)-selective retinoids produce fewer side effects; however, it was not known whether RXR-selective retinoids could reduce pancreatic tumor cell proliferation. In the present study, the novel RXR-selective retinoid, AGN194204, was compared with that of other retinoids for the ability to suppress pancreatic cancer cell proliferation. We treated various pancreatic cancer cell lines with receptor-selective ligands and cytotoxic agents and monitored the effects on cell proliferation, markers of apoptosis and cell cycle. Our results indicate that AGN194204, at concentrations >10 nM, inhibits proliferation of MIA PaCa-2 and BxPC-3 cells but not the proliferation of AsPC-1 cells. Moreover, in BxPC-3 and MIA PaCa-2 cells, AGN194204 was 10-100 times more effective than RAR-selective retinoids. AGN194204-dependent suppression of MIA PaCa-2 cell proliferation is associated with reduced cyclin E and cyclin-dependent kinase 6 (cdk6) level, but cyclin D1, cdk2 and cdk4 content is not altered. In addition, p27 level increases 2-fold. The RXR-selective antagonist, AGN195393, reverses the AGN194204-dependent growth inhibition and the decline in cyclin E and cdk6 levels. In contrast, these changes are not reversed by treatment with the RAR antagonist, AGN193109. AGN194204 did not appear to alter cell apoptosis as measured by change in cleavage of procaspase-3, -8 or -9. We also examined the effects AGN194204 co-treatment with cytotoxic agents. Treatment of MIA PaCa-2 cells with AGN194204 + cisplatin, gemcitabine, 5-fluorouracil, interferon (IFN)alpha or IFNgamma resulted in an additive but not synergistic reduction in MIA PaCa-2 cell number. These results indicate that AGN194204, an RXR-selective retinoid, is a more effective inhibitor of pancreatic cell proliferation than the RAR-selective retinoids, and further indicate that AGN194204 produces an additive reduction in cell number when given with other agents. Our results suggest that RXR-selective ligands, which are less toxic than RAR-selective ligands, may be suitable agents for the treatment of pancreatic cancer.

Antimetabolites, Antineoplastic↗

PubMed1997

Expression of retinoid-responsive genes occurs in colorectal carcinoma-derived cells irrespective of the presence of resistance to all-trans retinoic acid.

BACKGROUND AND OBJECTIVES: Retinoids are metabolized in human intestinal epithelial cells to all-trans retinoic acid; however, it is unknown whether these cells express retinoid receptors, and whether sensitivity or resistance to the hormone is associated with a particular pattern of expression of retinoid-responsive genes. METHODS: Northern blot analysis and reverse transcriptase polymerase chain reaction (RT-PCR) were used to identify mRNAs for retinoid receptors. Both Relative RT-PCR and transfection of retinoid-inducible plasmid were applied to test functionality of the pathway in a model system for colorectal carcinoma progression (primary SW480, all-trans retinoic acid-sensitive cells vs. metastatic SW620, -insensitive cells). RESULTS: Three colorectal carcinoma-derived cell lines were inhibited by the hormone. Retinoic acid receptor type alpha (hRAR alpha) and retinoid X receptor type alpha (hRXR alpha) mRNAs were detected in normal enterocytes, colonocytes, and in all colorectal carcinoma-derived cells studied. Primary carcinomas and metastatic lesions expressed high amounts of hRAR alpha receptor protein, showing no simple correlation between the amounts of mRNA and receptor protein. No pattern of expression of the retinoid-responsive genes was associated with sensitivity or resistance to the retinoid. Expression of the genes occurred irrespective of resistance to the hormone or inactivity of the pathway. CONCLUSIONS: Colonocytes possess a molecular system for transduction of the retinoid signal. All-trans retinoic acid modifies gene expression and inhibits proliferation of these cells. Therefore, retinoids are likely to be effective in chemoprevention of colorectal carcinoma.

Antineoplastic Agents↗

PubMed1985

Inhibition of epidermal terminal differentiation and tumour promotion by retinoids.

Retinoids are physiological regulators of growth and differentiation for a number of epithelial tissues. In several of these, retinoids also act as pharmacological anticarcinogens. Retinoids are most effective as anticarcinogens in the post-initiation portion of carcinogenesis. In mouse skin, retinoids are inhibitors of phorbol ester-mediated tumour promotion and can cause regression of pre-existing benign tumours. Studies in vivo and in vitro have indicated that phorbol ester-mediated skin tumour promotion results from selective clonal expansion of initiated cells. We have proposed that the biological basis for selection resides in the induction of terminal differentiation in subpopulations of keratinocytes while other keratinocytes, including initiated cells, are stimulated to proliferate. Terminal differentiation is accelerated by phorbol esters through the induction of epidermal transglutaminase and consequent cornification. Retinoids inhibit terminal differentiation of keratinocytes. Retinoids also induce transglutaminase in epidermis, but they inhibit cornification. Recent results suggest a biochemical basis for this paradox. The phorbol ester-induced transglutaminase is primarily particulate but the retinoid-induced enzyme is cytosolic. The induced enzymes differ in kinetic parameters, thermal stability and in elution from ion-exchange columns. Induction of the retinoid enzyme is associated with suppression of the induction of transglutaminase by phorbol esters. The retinoid-induced epidermal transglutaminase could interfere with normal or promoter-induced differentiation by inappropriately cross-linking precursor proteins before their assembly at the cell periphery. This could explain one aspect of the inhibitory action of retinoids on tumour promotion.

Acyltransferases↗

PubMed1996

Biochemical pathways of retinoid transport, metabolism, and signal transduction.

Retinoids control the processes of differentiation, proliferation, and apoptosis from the conception of vertebrates through their deaths. It may seem improbable that a few small, simple lipids could contain and communicate such extensive and disparate information as the retinoids, but the permutations possible make this notion plausible. Retinoid actions result from coordinated interplay among more than one hormone and multiple binding proteins, biosynthetic and catabolic enzymes, receptors (acting alone or in combination not only with retinoid but also with other lipophilic hormone receptors), and receptor-response elements. This symphony is conducted in all vertebrates in deliberate spatially and temporally specific patterns. This article reviews the absorption and formation of retinol, the parent and major circulating naturally occurring retinoid; the role of retinol as substrate for biosynthesis of two hormones, i.e., all-trans-retinoic acid (atRA) and 9-cis-retinoic acid (9cRA); the integrated operations of retinoid metabolism and the intracellular retinoid-binding proteins, cellular retinol-binding protein (CRBP), and cellular RA-binding protein (CRABP), which protect (retinoids), serve (as substrate), and control (metabolic reactions); and the mechanism of RA and 9cRA action as activators of the transcription factors RA-receptor (RAR) and the retinoid X receptor (RXR). The discussion offers a mechanistic rationale for the pleiotropic actions of retinoids.

Animals↗

PubMed1995

Regulation of differentiated phenotype of rat hepatic lipocytes by retinoids in primary culture.

Activation of hepatic lipocytes to myofibroblastlike cells observed in cell culture and during liver fibrogenesis is characterized by an increase in collagen formation and cell proliferation. These changes appear to be associated with the loss of intracellular retinoid in lipocytes, the principal storage site for vitamin A in the body. To evaluate whether retinoids have the capability to suppress lipocyte activation, we exposed cultured lipocytes in both native and myofibroblastlike states to retinoids and determined their effects on collagen production, intracellular retinoid level, and cell proliferation. Retinol (1 microM) and retinoic acid (1 microM) supplementation of primary rat lipocyte cultures inhibited the spontaneous increase in collagen synthesis associated with lipocyte activation; lower concentrations of retinol (10 or 100 nM) were also effective. Simultaneously, retinol addition prevented a precipitous decline in intracellular retinoid content in the absence of added retinoid. These retinoid effects were reversed by a change to unsupplemented control medium. When cells in the myofibroblastlike state were exposed to retinol (> or = 1 microM), a significant increase in intracellular retinoid levels and reduction in collagen synthesis occurred. Lipocytes in both native and myofibroblastlike states secreted four to five times higher amounts of type I collagen than type III collagen, but retinol and retinoic acid particularly inhibited production of type I collagen. Cell proliferation measured by [3H]thymidine incorporation was also inhibited by retinol. These results demonstrate that extracellular retinoids suppress lipocyte-activated collagen synthesis and cell proliferation and support the interpretation that retinoids themselves are regulatory factors in maintenance of the lipocyte in its native, differentiated state.

Adipocytes↗

PubMed1995

Retinoids: effects on growth, differentiation, and nuclear receptor expression in human pancreatic carcinoma cell lines.

BACKGROUND & AIMS: Advanced pancreatic carcinoma has a dismal prognosis despite extensive chemotherapeutic trials. The aim of this study was to evaluate the role of retinoids as an experimental therapeutic approach for pancreatic cancer. METHODS: Four ductal and one acinar pancreatic tumor cell lines were investigated. Growth was determined by cell number and a human tumor clonogenic assay. In vivo growth was assessed by xenografts transplanted into nude mice. Differentiation was characterized by immunofluorescence microscopy and carbonic anhydrase II gene expression. Retinoid receptors were characterized by Northern blotting and reverse-transcriptase polymerase chain reaction. RESULTS: Retinoid treatment results in a time- and dose-dependent growth inhibition in vitro and in vivo of ductal but not acinar pancreatic tumor cells. Retinoid treatment induces a more differentiated phenotype in ductal tumor cells as shown by morphological criteria and increased expression of carbonic anhydrase II. All pancreatic tumor cell lines expressed a broad panel of cellular retinoid binding proteins and nuclear retinoid receptors. Retinoic acid receptor gamma and cellular retinoic acid binding protein II were found in all retinoid-sensitive ductal tumor cell lines but not in the retinoid-resistant acinar cell lines. CONCLUSIONS: Detailed knowledge of nuclear retinoid receptor expression may provide rational strategies for retinoid treatment of pancreatic cancer.

Animals↗

PubMed2001

Mechanisms of action of retinoids in gastrointestinal mucosal protection in animals, human healthy subjects and patients.

UNLABELLED: Retinoids prevent chemically induced gastric mucosal damage without inhibiting gastric acid secretion ("nutritional gastric cytoprotection"). The gastroprotective effects of retinoids do not depend on 1) vitamin A activity; 2) number of unsaturated double bonds; 3) the presence of a characteristic chemical structure of their terminal components; however, they depend on 1) intact vagal nerve and 2) adrenals in experimental animals. The gastric cytoprotective effect of retinoids produces a dose-dependent inhibition of ATP-transformation into ADP. It also increases the transformation of ATP into cAMP. Other features of these gastric cytoprotective effects of retinoids include: 1) The retinoid-induced gastric mucosal protection differs from that of PGs; 2) The cAMP is an intracellular signal in the development of gastric mucosal damage produced by chemicals (e.g., ethanol, HCl, indomethacin) and in the protection of gastric mucosa induced by retinoids (but not by PGs); 3) The gastric mucosal protection induced by retinoids and gastric mucosal permeability can be separated in time. The existence of gastric mucosal protection can be demonstrated in healthy persons (against indomethacin treatment), in patients with gastric ulcer (GU) and duodenal ulcer (DU) without any inhibition of gastric acid secretion. The serum levels of vitamin A and zeaxanthin were significantly decreased in patients with chronic gastrointestinal (GI) inflammatory diseases (e.g., terminal ileitis, ulcerative colitis), colorectal polyposis, and different (e.g., esophageal, gastric, pancreatic, hepatocellular and colorectal) malignant diseases. The serum levels of vitamin A provitamins were unchanged and their GI mucosal protective effects do not depend on vitamin A activity. CONCLUSIONS: 1) Abundant experimental and human observations clearly proved the defensive role of retinoids in the GI tract; 2) There is a correlation between the a) scavenger properties of retinoids vs. intact vagal nerve; b) scavenging properties vs. intact adrenals. 3) The GI mucosal protective effect of retinoids is correlated with biochemical changes in the GI mucosa.

Adenosine Diphosphate↗

PubMed2002

Anticancer activity and mechanism of action of retinoids in oral and pharyngeal cancer.

Retinoids are the natural and synthetic derivatives of vitamin A. Epidemiological studies indicate that a low intake of vitamin A is associated with an increased risk of squamous cancer. In vitro studies on cancer cells show that exposure to retinoids results in the inhibition of growth, by blocking the cell cycle or by inducing apoptosis. With respect to the clinical efficacy of retinoids some positive effects have been observed in early stage oral and oropharyngeal cancer. Administration of retinoids has been shown to elicit responses in leukoplakia, a premalignant lesion of the oral mucosa that frequently develops into invasive cancer. Furthermore, it has been possible with a retinoid, 13-cis-retinoic acid, to delay or inhibit the development of second primary tumors in patients who have been curatively treated for a first primary tumor in the oral cavity or oropharynx. Recent trials, however, failed to show protective effects on the development of second primary tumors. Because of the short duration of the response, the intrinsic resistance to retinoids and the toxic side effects, the treatment with this class of compounds has not become a standard therapy. Recent studies have shed light on how preneoplastic and neoplastic cells defend themselves against the growth inhibiting action of retinoids. An increased retinoid breakdown and an inactivation of nuclear retinoid receptor appear to be the cause of acquired or intrinsic resistance. This knowledge can be used to develop novel tumor-selective strategies. This review gives an update on the role of retinoids in oral and oropharyngeal cancer and their precursor lesions. The focus will be on the anticancer activity, the mechanism of action and future directions.

Anticarcinogenic Agents↗