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PubMedDate not supplied

Dietary retinoids and carotenoids in rodent models of mammary tumorigenesis.

In this review of the scientific literature the relationship between retinoids, carotenoids, and mammary carcinogenesis is examined. Several retinoids have shown promise as chemopreventive agents against chemically induced mammary carcinogenesis in mice and especially in rats. The most promising retinoids are retinyl acetate (RA) and N-(4-hydroxyphenyl)retinamide (4-HPR, fenretinide). In rats, dietary administration of these retinoids reduced tumor incidence and multiplicity, and increased the latency of DMBA or MNU-induced mammary cancers. In mice, 4-HPR reduced the number of hyperplastic alveolar nodules and the number of tumors in MTV- and MTV+ mice, respectively. Among retinoids, 4-HPR is at present the most promising analogue, due to its ability to concentrate in the mammary gland. The combination of 4-HPR with tamoxifen not only is more effective in suppressing breast cancer than either agent alone, but also inhibits the appearance of subsequent cancers following the surgical removal of the first tumor. These studies suggest that retinoids, like tamoxifen, may be applicable to the prevention of contralateral breast cancer in women who underwent breast cancer surgery. It is also becoming evident that differentiation therapy and chemoprevention can become attractive alternative approaches to intensive cytotoxic chemotherapy. The role of carotenoids in the prevention of mammary carcinogenesis, however, is ambiguous. Poor absorption and low levels of carotenoids that reach the target tissues complicate interpretation of data in rodent models of mammary carcinogenesis. Very few animal studies are presently available in which purified carotenoids were found effective against mammary carcinogenesis. These results do not justify undertaking clinical evaluation of individual carotenoids against breast cancer at this time.

Animals↗
PubMed1997

Inhibition of plasma membrane NADH oxidase activity and growth of HeLa cells by natural and synthetic retinoids.

Several retinoids, both natural and synthetic, were evaluated for their ability to modulate NADH oxidase activity of plasma membranes of cultured HeLa cells and the growth of HeLa cells in culture. Both NADH oxidase activity and the growth of cells were inhibited by the naturally-occurring retinoids all trans-retinoic acid (tretinoin) and retinol as well as by the synthetic retinoids, trans-acitretin, 13-cis-acitretin, etretinate and arotonoid ethylester (Ro 13-6298). For all retinoids tested, inhibition of NADH oxidase activity and inhibition of growth were correlated closely. With tretinoin, etretinate and arotonoid ethylester, NADH oxidase activity and cell growth were inhibited in parallel in proportion to the logarithm of retinoid concentration over the range of concentrations 10(-8) to 10(-5) M. Approximately 70% inhibition of both NADH oxidase activity and growth was reached at 10 microM. With retinol, trans-acitretin and 13-cis-acitretin, inhibition of NADH oxidase activity and growth also were correlated but maximum inhibition of both was about 40% at 10 microM. The possibility is suggested that inhibition of the plasma membrane NADH oxidase activity by retinoids may be related to their mechanism of inhibition of growth of HeLa cells in culture.

Animals↗
PubMed2000

Retinoid-mediated inhibition of interleukin-12 production in mouse macrophages suppresses Th1 cytokine profile in CD4(+) T cells.

Interleukin-12 (IL-12) plays a central role in the immune system by driving the immune response towards T helper 1 (Th1) type responses characterized by high IFN-gamma and low IL-4 production. In this study we investigated whether retinoid-mediated inhibition of interleukin-12 production in mouse macrophages could regulate cytokine profile of antigen (Ag)-primed CD4(+) Th cells. Pretreatment with retinoids (9-cis-RA, all-trans-RA, TTNPB) significantly inhibited IL-12 production by mouse macrophages stimulated with lipopolysaccharide (LPS) or heated-killed Listeria monocytogenes (HKL). Retinoid-pretreated macrophages reduced their ability to induce IFN-gamma and increased the ability to induce IL-4 in Ag-primed CD4(+) T cells. Addition of recombinant IL-12 to cultures of retinoid-pretreated macrophages and CD4(+) T cells restored IFN-gamma production in CD4(+) T cells. The in vivo administration of 9-cis-RA resulted in the inhibition of IL-12 production by macrophages stimulated in vitro with either LPS or HKL, leading to the inhibition of Th1 cytokine profile (decreased IFN-gamma and increased IL-4 production) in CD4(+) T cells. These findings may explain some known effects of retinoids including the inhibition of encephalitogenicity, and point to a possible therapeutic use of retinoids in the Th1-mediated immune diseases such as autoimmune diseases.

Animals↗
PubMed2000

Modulation of retinoic acid receptor function alters the growth inhibitory response of oral SCC cells to retinoids.

Retinoids have been shown to inhibit the growth of many human tumor cells including breast, ovarian and squamous cell carcinoma (SCC). While the exact mechanism of retinoid mediated growth suppression is not known, a role for the retinoic acid receptors (RARs) and retinoid X receptors (RXRs) has been established in both the breast and ovarian tumor cell models. We set out to determine if modulation of RAR/RXR function would alter the retinoid sensitivity of oral SCC cells. We found that the growth of SCC cells was significantly inhibited by treatment with either all-trans-retinoic acid (trans-RA) or the synthetic, conformationally restricted RARgamma selective retinoids MM11254 and MM11389. In order to demonstrate a role for RAR/RXR function in this process, stable oral SCC cell clones constitutively overexpressing the dominant negative mutant RARbeta2 (R269Q) were prepared and shown to exhibit reduced RAR/RXR transcriptional transactivation activity. We found that oral SCC cells exhibiting reduced RAR/RXR function became resistant to growth inhibition by all-trans-RA, MM11254 and MM11389. Likewise, treatment of oral SCC cells with the RARgamma antagonist MM11253 was found to block the ability of MM11254 and MM11389 to inhibit SCC cell growth. Thus, modulation of RAR function through the use of RAR-gamma selective agonists, an RAR-gamma selective antagonist or a pan-RAR dominant negative mutant significantly alters the growth inhibitory response of oral SCC cells to retinoids.

Arginine↗
PubMed2001

The integral role of topical and oral retinoids in the early treatment of acne.

This article will review the rationale for early use of topical retinoids alone or in combination with topical antimicrobials in light of the pathogenesis of microcomedones and later lesions. Knowledge of the pathogenic processes in acne vulgaris has risen dramatically over the last three decades. It is now widely accepted that acne is the result of four distinct processes: increased proliferation, cornification, and shedding of follicular epithelium; increased sebum production; colonization of the follicle with Propionibacterium acnes; and induction of inflammatory responses by bacterial antigens and cell signals. Clinical focus of disease management has shifted toward earlier treatment targeting these fundamental processes. Elimination of microcomedones, the precursor to all subsequent lesions, would optimize acne therapy by preventing the later inflammatory stages of disease. With the exception of oral isotretinoin, no single first-line agent addresses all pathogenic mechanisms. Topical retinoids have comedolytic and in some cases anti-inflammatory effects, but have no direct impact on P. acnes. Thus treatment with a combination of topical retinoid and topical antimicrobial is warranted. The former can also enhance penetration of the latter by increasing microcomedonal extrusion. In selecting a combination, one must consider efficacy, cost, and likelihood of compliance. Once thought to be effective primarily for treating comedones, topical retinoids have also been demonstrated to be effective in reducing inflammatory lesions. The activity of a topical retinoid combined with an antimicrobial agent has been shown to clear more lesions and to clear them more rapidly than antimicrobial therapy alone. Topical retinoids are also used effectively to maintain remissions.

Acne Vulgaris↗
PubMed1999

Retinoid signaling by all-trans retinoic acid and all-trans retinoyl-beta-D-glucuronide is attenuated by simultaneous exposure of human keratinocytes to retinol.

Retinol and retinyl esters are converted with time to slowly increasing amounts of all-trans retinoic acid (RA) in cultured human keratinocytes. Exogenous RA has been shown to limit retinol oxidation and to increase retinol esterification. Because significant amounts of retinol are present in biologic systems, we examined whether RA and all-trans-retinoyl-beta-D-glucuronide (RAG) interact with retinol in exhibiting their activities on HaCaT keratinocytes maintained in a retinoid-free culture system. RA was more potent than RAG and retinol in inducing ultrastructural changes attributed to retinoids, inhibiting cell proliferation as well as enhancing keratin 19 expression. In addition, retinoids were able to induce cellular retinoic acid-binding protein II mRNA levels in the cultures, whereas early RA and late RAG activity was detected. The described biologic effects of RA and RAG were diminished by simultaneous cell exposure to retinol. HaCaT cells quickly metabolized retinol to retinyl esters and consequently to low amounts of RA. RA treatment led to an early high peak of cellular RA followed by reduction to trace amounts. Treatment with RAG resulted in constantly high cellular RAG and low RA levels. Under the combined RA and retinol treatment retinyl esters were increased and RA was reduced in HaCaT cells, whereas extracellular RA levels were similar to those obtained by RA alone. On the other hand, the combination of RAG and retinol resulted in higher extracellular RAG, similar cellular RAG, and lower cellular RA levels than those obtained by RAG alone without any change in retinyl esters. This study demonstrates that retinoid signaling by RA and RAG is attenuated by simultaneous exposure of HaCaT keratinocytes in vitro to retinol. The presence of retinol in the medium alters the rate of RA or RAG metabolism and thus cellular RA concentrations. The intensity of retinoid signal is probably dependent on cellular RA levels. The resulting "antagonism" among retinoids is consistent with the presence of an auto-regulatory mechanism in human keratinocytes offering protection against excessive accumulation of cellular RA.

Blotting, Northern↗
PubMedDate not supplied

Activity of ALRT 1550, a new retinoid, with interferon-gamma on ovarian cancer cell lines.

Retinoids have been shown to be effective regulators of cell proliferation and differentiation in many human cancers. The major biologic activity of the retinoids is mediated by two families of nuclear receptors: retinoic acid receptors (RARs) and retinoid X receptors (RXRs). ALRT 1550 is one of the most potent RAR selective retinoids discovered to date, with 10-100 times more activity than ATRA in competitive binding and cotransfection assays and 300 times more inhibiting activity against proliferation of cervical carcinoma cell. To evaluate the role of ALRT 1550 in ovarian cancer, the growth inhibitory activity of ALRT 1550 was determined in the ATRA-resistant ovarian cancer cell line SKOV-3 and ovarian cancer cell line 2774 after exposure to concentrations of 0.1, 1, 2.5, 5, and 10 microM for 7 days. SKOV-3 showed 51%, 53%, and 68% cell growth inhibition after treatment with ALRT 1550 at concentrations of 2.5, 5, and 10 microM, respectively, and the 2774 cell line showed 46% inhibition after treatment at 10 microM. Because interferon (IFN)-gamma was found to synergistically amplify the growth inhibition of retinoids in cultured breast cancer cells, we investigated the combination of ALRT 1550 with IFN-gamma in two ovarian cancer cell lines. ALRT 1550 (5 microM) in combination with IFN-gamma at a concentration of 500 U/ml inhibited cell growth of SKOV-3 by as much as 81% (CI = 1.88). This is a 28% greater effect than with ALRT alone. Cell line 2774 showed a 69% cell growth inhibitory effect with ALRT 1550 (5 microM) in combination with IFN-gamma at a concentration of 1000 U/ml (CI = 1.03). ALRT 1550 and IFN-gamma may act synergistically in the SKOV-3 ovarian cancer cell line and additively in the 2774 cell line. In conclusion, ALRT 1550 may be a promising drug with a high biologic modulating activity against ovarian cancer. In combination with IFN-gamma, additive and perhaps synergistic effects may be seen in some ovarian cancer cell lines. Combining these two biologic modifiers for the treatment of ovarian cancer may lower the effective dose of the retinoids, thus decreasing their side effects.

Antineoplastic Agents↗
PubMed1997

Retinoids inhibit adhesion to laminin in human pancreatic carcinoma cells via the alpha 6 beta 1-integrin receptor.

BACKGROUND & AIMS: The initial step in tumor invasion and metastasis is determined by adhesion of tumor cells to basement membranes. To evaluate their potential therapeutic use in controlling local growth and metastasis, the effects of retinoids on the adhesive properties in the human pancreatic carcinoma cell line DAN-G were examined. METHODS: The effects of retinoids on cellular adhesion were assessed by adhesion assays in vitro. The expression of laminin-binding proteins was characterized by Northern blotting, radioimmunoprecipitation, and flow-cytometric analysis. RESULTS: Treatment with retinoids results in a time- and dose-dependent inhibition of DAN-G cell adhesion to fibronection and laminin but not to collagens I, IV, and VI. The adhesion of DAN-G cells to laminin could be blocked completely by anti-alpha 6 and anti-beta 1 antibodies but not by the synthetic peptide YIGSR. Flow-cytometric analysis of DAN-G cells showed no quantitative difference for alpha 6-integrin expression in retinoid-treated and -untreated DAN-G cells. Furthermore, radioimmunoprecipitation showed no difference in the appearance of alpha 6 beta 1-integrin expression after retinoid incubation. CONCLUSIONS: Retinoids decrease pancreatic carcinoma cell adhesion to laminin via an as yet unidentified mechanism involving alteration of the alpha 6 beta 1-integrin receptor function and thereby open interesting perspectives for the modulation of infiltrative growth and metastasis in pancreatic cancer.

Animals↗
PubMed2003

Oral retinoid therapy for dermatologic conditions in children and adolescents.

The efficacy of systemic retinoid therapy in a number of dermatologic diseases is well established; however, concerns about potential side effects limit their use, especially in children. We review the efficacy and toxicity of oral retinoids in the pediatric population. The acute mucocutaneous toxicities commonly observed are typically well tolerated, readily treatable, and reversible. Systemic toxicities include teratogenicity and effects on the musculoskeletal, neurologic, and gastrointestinal systems. Children, like adults, generally tolerate short-term retinoid therapy without major complications. Concerns regarding serious systemic side effects are greater for those on high doses of oral synthetic retinoids for longer periods of time. Close patient monitoring and patient education can minimize the occurrence of complications. (J Am Acad Dermatol 2003;49:171-82.)Learning objective At the conclusion of this learning activity, participants should be familiar with use of oral retinoids for childhood dermatologic conditions such as psoriasis, acne, and ichthyoses as well as safety and risks associated with oral retinoid use in children and adolescents.

Acne Vulgaris↗
PubMed1993

Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids.

The binding of endogenous retinoids and stereoisomers of retinoic acid (RA) to the retinoid nuclear receptors, RA receptor (RARs) and retinoid X receptors (RXRs), was characterized using nucleosol preparations from transiently transfected COS-1 cells. Among several stereoisomers of RA tested, including 7-cis-, 9-cis-, 11-cis-, 13-cis-, and all-trans-RA, only 9-cis-RA effectively competes with 9-cis-[3H]RA binding to the RXRs. Additionally, the endogenous retinoid trans-didehydro-RA (t-ddRA) does not interact with RXRs, whereas the 9-cis form of ddRA competes effectively. RXRs (alpha, beta, and gamma) bind 9-cis-RA with dissociation constants (Kd) of 15.7, 18.3, and 14.1 nM, respectively. In contrast to the selectivity of RXRs for 9-cis-RA, RARs bind both t-RA and 9-cis-RA with high affinity, exhibiting Kd values in the 0.2-0.7 nM range for both ligands. Unlike RARs, the cellular RA binding proteins CRABPI or CRABPII bind t-RA but do not bind 9-cis-RA. Consistent with the binding data, 9-cis-RA and 9-cis-ddRA transcriptionally activate both GAL4-RXR and GAL4-RAR chimeric receptors with EC50 values of 3-20 nM for 9-cis-RA and 9-cis-ddRA, whereas t-RA and t-ddRA efficiently activate only GAL4-RAR chimeric receptors. Thus, 9-cis forms of endogenous retinoids can contribute to the pleiotropic effects of retinoids by interacting with both the RARs and RXRs.

Animals↗
PubMed1994

A synthetic retinoid antagonist inhibits the human immunodeficiency virus type 1 promoter.

Retinoids regulate a broad range of biological processes and affect cell growth and differentiation of many cell types, including the immune system. Recently, it was reported that human immunodeficiency virus type 1 (HIV-1) expression in macrophages is enhanced by retinoic acid (RA). Retinoid signals are mediated by the RA receptors (RARs) and retinoid X receptors (RXRs) that bind to specific RA responsive elements (RAREs) in the promoter region of susceptible genes. Here, we report on a RARE in the long terminal repeat (LTR) region that allows activation of the HIV-1 LTR. The RARE is composed of two consensus RARE half-sites (A/GGGTCA) arranged as a palindrome separated by 9 nucleotides and is activated by both RAR/RXR heterodimers and RXR homodimers. We show that the COUP (chicken ovalbumin upstream promoter) orphan receptors also bind to the HIV-1 RARE and repress the retinoid response of the HIV-1 RARE or the HIV-1 LTR. Furthermore, a newly discovered synthetic retinoid is shown to be a potent inhibitor of retinoid-induced activation of the HIV-1 RARE. These observations suggest additional approaches for the inhibition of HIV replication.

Animals↗
PubMed1996

4-Hydroxyphenyl retinamide is a highly selective activator of retinoid receptors.

Retinoids have shown promise as anti-cancer and cancer preventative agents. All-trans-N-(4-hydroxyphenyl)retinamide (4HPR) belongs to a new group of retinoids that not only inhibit the proliferation of cancer cells but also can induce apoptosis in certain cancer cells. Because of its increased efficacy against cancer cells and its low toxicity it has been entered into a number of clinical trials. However, its mechanism of action is not known, and it had been assumed that it is not a true retinoid. Here we analyze its ability to function as an activator of nuclear retinoid receptors (RARs and RXRs). We observe that, in transactivation assays, 4HPR is a potent transactivator with RARgamma and a moderate activator with RARbeta but is not an activator with RARalpha and RXRalpha. Furthermore, RARgamma-selective transactivation by 4HPR is enhanced on some response elements and reduced on others when compared to natural retinoids. In contrast to transactivation, 4HPR in transrepression assays functions mostly with RARalpha, RARbeta, and RXRalpha. Optimal receptor activation is seen at 4HPR concentrations at which it is a potent growth inhibitor and inducer of apoptosis. We conclude that 4HPR is a highly selective activator of retinoid receptors. We propose that this selective activation of the nuclear receptors is likely to be the basis for its specific biological activities and its favorable pharmaceutical properties.

Anticarcinogenic Agents↗
PubMedDate not supplied

Phenotypic/genotypic correlations in patients with epidermolytic hyperkeratosis and the effects of retinoid therapy on keratin expression.

Dominant-negative mutations in the KRT1 and KRT10 genes cause epidermolytic hyperkeratosis, a rare form of ichthyosis sometimes associated with palmoplantar keratoderma. Although there is no permanent cure, some patients improve on retinoid therapy. More knowledge is needed, however, about the mechanism of action of retinoids and the genotypic/phenotypic correlations in this disease. Thirteen patients from 10 families with generalized disease and 2 sporadic patients with nevoid lesions were studied, probably representing most of the patients in Sweden and Norway. All patients, except one nevoid case, were known to have KRT1 or KRT10 mutations. Those with mutated keratin 1 (K1) invariably had associated keratoderma (n=6). In contrast, only 1 of 7 patients with K10 mutations had this problem (p = 0.0047). Five out of 6 patients with KRT10 mutations benefited from treatment with oral acitretin (5-25mg/day) or topical tretinoin/tazarotene, but none of the patients with KRT1 mutations derived any benefit. Quantitative analysis of K1 and K10 mRNA in skin biopsies obtained before and after retinoid therapy (n=8) showed no consistent down-regulation of mutated keratin that would explain the therapeutic outcome. Instead, the mRNA expression of K2e (a normal constituent of the upper epidermis) diminished especially in nonresponders. In contrast, K4 mRNA and protein (marker of retinoid bioactivity in normal epidermis) increased in almost all retinoid-treated patients. In conclusion, our study confirms a strong association between KRT1 mutations and palmoplantar keratoderma. Retinoid therapy is particularly effective in patients with KRT10 mutations possibly because they are less vulnerable to a down-regulation of K2e, potentially functioning as a substitute for the mutated protein in patients with KRT1 mutations.

Adolescent↗
PubMed1996

Retro-retinoids in regulated cell growth and death.

Vitamin A serves as a prohormone from which three classes of active metabolites are derived: the aldehydes, the carboxylic acids, and the retro-retinoids. Although these three classes are united under the rubric of signal transduction, they act by different molecular mechanisms: the 11-cis-retinaldehydes combine with opsin to form the universal visual pigments and the retinoic acids form ligands for transcription factors, whereas the retro-retinoids, as shown here, intersect with signal transduction at a cytoplasmic or membrane site. The retro-retinoid, anhydroretinol (AR), has long been known to act as a growth inhibitor in lymphocytes, whereas 14-hydroxy-4,14-retro-retinol (14-HRR) is required for normal lymphocyte proliferation. A mutually reversible relationship exists between these two retro-retinoids as one can reverse the effects of the other when given in pharmacological doses. The common explanation for reversible inhibition is competition for a shared receptor. We now provide evidence that when AR is given to T cells unmitigated by 14-HRR, rapid cell death can occur. The circumstances are closely related to nonclassical forms of apoptosis: within 2 h of AR administration the T cells undergo widespread morphological changes, notably surface blebbing and ballooning and, inevitably, bursting. In contrast, nuclear changes are comparatively mild, as indicated by absence of chromatin condensation and overt DNA cleavage to discrete nucleosomal fragments, although DNA nicks are readily discernible by terminal deoxynucleotidyl transferase assay. What further distinguishes the AR-induced form of apoptosis from classical ones is a lack of requirements of messenger RNA and protein synthesis, suggesting that the events leading to cell death are primarily initiated and play themselves out in the cytoplasm. This view is further reinforced by the finding that herbimycin A can prevent the onset of programmed cell death. The importance of our findings is that they strongly suggest a second messenger role for vitamin A metabolites in the cytoplasmic realm that has not been seen previously. These findings are entirely compatible with a general notion that in a cell requiring multiple coordinated signals for survival, the provision of an unbalanced signal can initiate programmed cell death. Collectively, our data also challenge the paradigm that retinoids (outside vision) solely mediate their function via the steroid/ retinoic acid receptor family of nuclear transcription factors. Instead, a mode of action in the cytoplasmic realm akin to one attributed to other small lipophilic second messenger molecules, such as diacyl glycerol or ceramide, may apply to retro-retinoids.

Animals↗
PubMed2005

Defining the retinoid binding site in the rod cyclic nucleotide-gated channel.

Rod vision is initiated when 11-cis-retinal, bound within rhodopsin, absorbs a photon and isomerizes to all-trans-retinal (ATR). This triggers an enzyme cascade that lowers cGMP, thereby closing cyclic nucleotide-gated (CNG) channels. ATR then dissociates from rhodopsin, with bright light releasing millimolar levels of ATR. We have recently shown that ATR is a potent closed-state inhibitor of the rod CNG channel, and that it requires access to the cytosolic face of the channel (McCabe, S.L., D.M. Pelosi, M. Tetreault, A. Miri, W. Nguitragool, P. Kovithvathanaphong, R. Mahajan, and A.L. Zimmerman. 2004. J. Gen. Physiol. 123:521-531). However, the details of the interaction between the channel and ATR have not been resolved. Here, we explore the nature of this interaction by taking advantage of specific retinoids and retinoid analogues, namely, beta-ionone, all-trans-C15 aldehyde, all-trans-C17 aldehyde, all-trans-C22 aldehyde, all-trans-retinol, all-trans-retinoic acid, and all-trans-retinylidene-n-butylamine. These retinoids differ in polyene chain length, chemical functionality, and charge. Results obtained from patch clamp and NMR studies have allowed us to better define the characteristics of the site of retinoid-channel interaction. We propose that the cytoplasmic face of the channel contains a retinoid binding site. This binding site likely contains a hydrophobic region that allows the ionone ring and polyene tail to sit in an optimal position to promote interaction of the terminal functional group with residues approximately 15 A away from the ionone ring. Based on our functional data with retinoids possessing either a positive or a negative charge, we speculate that these amino acid residues may be polar and/or aromatic.

Animals↗
PubMed1989

Comparative aspects of carotenoids and retinoids as chemopreventive agents for cancer.

Retinoids are well established chemopreventive agents for experimental carcinogenesis of many target organs including mammary gland, urinary bladder, lung, skin, liver, pancreas, colon and esophagus. Modification of the basic retinoid structure has produced analogs with enhanced target organ specificity, increased inhibitory activity and reduced toxicity. N-(4-hydroxyphenyl) retinamide (4-HPR) currently appears to be the most efficaceous retinoid against carcinogen-induced breast, urinary bladder, and lung cancer in rodents. Retinoids are most effective when administered shortly after the carcinogen treatment; however, the treatment can be delayed significantly while maintaining its chemopreventive effect. Under various experimental conditions, combining retinoid treatment with other modifiers of growth enhances its chemopreventive activity; for example, retinoid plus hormonal modulation can provide better protection against mammary cancer than either treatment alone. The role of carotenoids in cancer chemoprevention is less well defined. Studies have been complicated by the poor absorption and low tissue levels of carotenoids in the rodent models used for such studies. Aside from experimental skin carcinogenesis, little information is available relative to the effect of carotenoids on the chemoprevention of cancer at other organ sites.

Animals↗
PubMed1999

Expression of retinoid receptor genes and proteins in non-small-cell lung cancer.

BACKGROUND: Retinoids can suppress carcinogenesis in high-risk non-neoplastic bronchial lesions and can reduce the risk of second primary non-small-cell lung cancer (NSCLC). The effects of retinoids are mediated by nuclear receptors, i.e., the retinoic acid receptors (RARalpha, RARbeta, and RARgamma) and the retinoid X receptors (RXRalpha, RXRbeta, and RXRgamma). We investigated whether abnormalities in the in vivo expression of retinoid receptors are observed in NSCLC. METHODS: Expression of retinoid receptors in paired specimens of normal and cancerous tissues from the lungs of 76 patients with NSCLC was studied by use of antiretinoid receptor antibodies (except those against RXRgamma) and immunohistochemistry. RAR messenger RNAs were analyzed by use of in situ hybridization and by reverse transcription-polymerase chain reaction (RT-PCR). Samples were also studied for loss of heterozygosity (LOH) at chromosome 3p24. All P values are two-sided. RESULTS: All studied receptors were expressed in normal lung cells and in high- risk non-neoplastic lesions. In tumor cells, overexpression of RXRalpha and RARalpha was frequently observed. In contrast, RXRbeta expression decreased in 18% of the tumor specimens. Furthermore, there was a marked decrease in the expression of RARbeta in 63% of the tumors (P<.0001). Decreased expression of RARgamma was observed by RT-PCR in 41% of the tumors (P<.0001). LOH at 3p24 was observed in 41% of the tumor specimens from informative patients and in 20% of the non-neoplastic lesions. CONCLUSIONS: Expression of RARalpha and RXRalpha is either normal or elevated in NSCLC. In contrast, a large percentage of tumors show a marked decrease in the expression of RARbeta, RARgamma, and RXRbeta as well as a high frequency of LOH at 3p24, which was also observed in non-neoplastic lesions. These data suggest that altered retinoid receptor expression may play a role in lung carcinogenesis.

Aged↗
PubMed2005

Altered retinoid metabolism in female Long-Evans and Han/Wistar rats following long-term 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treatment.

This study investigated the effects of long-term low-dose 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure on retinoid, thyroid hormone, and vitamin D homeostasis in Long-Evans and Han/Wistar rats using a tumor promotion exposure protocol. Female rats (ten/group) were partially hepatectomized, initiated with nitrosodiethylamine (NDEA), and given TCDD once per week by sc injection for 20 weeks at calculated daily doses of 0, 1, 10, 100, or 1000 ng/kg bw/day. Groups of nonhepatectomized/uninitiated rats (five/group) were identically maintained. After 20 weeks, the rats were killed, and apolar retinoid levels were determined in the liver and kidneys. No consistent differences were seen between partially hepatectomized/initiated and nonhepatectomized/uninitiated animals with respect to apolar retinoid levels or hepatic TCDD concentration. Further analyses of polar and apolar retinoid levels in liver, plasma, and kidney, as well as free thyroxine (FT4) and vitamin D (25-OH-D(3)) concentrations were carried out in partially hepatectomized/inititated animals. In Long-Evans rats, TCDD exposure dose-dependently decreased hepatic retinyl ester concentrations at doses of 1-100 ng/kg bw/day. Likewise, hepatic all-trans-retinoic acid (all-trans-RA) concentration was decreased 39 and 54% at 10 and 100 ng/kg bw/day respectively, whereas 9-cis-4-oxo-13,14-dihydro-retinoic acid (9-cis-4-oxo-13,14-dihydro-RA), a recently discovered retinoic acid metabolite, was decreased approximately 60% in the liver at 1 ng/kg bw/day. TCDD dose-dependently increased plasma retinol and kidney retinol concentrations, whereas all-trans-RA concentration was also increased in the plasma and kidney at 10 and 100 ng/kg bw/day. Plasma 9-cis-4-oxo-13,14-dihydro-RA was decreased to below detection limits from doses of 1 ng/kg bw/day TCDD. A qualitatively similar pattern of retinoid disruption was observed in the Han/Wistar rat strain following TCDD exposure. FT4 was decreased to a similar extent in both strains, whereas 25-OH-D(3) was decreased only at 100 ng/kg bw/day in Long-Evans rats. Together these results show that TCDD disrupts both retinoid storage and metabolism of retinoic acid and retinoic acid metabolites in liver, kidney, and plasma from doses as low as 1 ng/kg bw/day. Furthermore, 9-cis-4-oxo-13,14-dihydro-RA was identified as a novel and sensitive indicator of TCDD exposure, in a resistant and sensitive rat strain, thereby extending the database of low-dose TCDD effects.

Animals↗