Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study shows the effect of combined dietary deprivation of fat and vitamin A on benzo(a)pyrene (BaP) induced lung carcinogenesis in male Wistar rats. Lung tumors were induced by intratracheal instillation of BaP-Fe2O3 in normal saline. The tumor incidence and tumor burden in control animals were 82% and 2.28 respectively. Fat deficiency decreased the tumor incidence to 57% and tumor burden to 1.66. On the other hand, in vitamin A deficiency these were 83% and 4.02 respectively. Fat deprivation in the diet of animals fed with vitamin A deficient diet decreased the tumor incidence and tumor burden to 69.6% and 2.7 respectively. The results suggest a protective role of low intake of fat in vitamin A deficiency for BaP-induced lung tumorigenesis in rats.
 ...
PMID:Influence of combined deficiency of fat and vitamin A on benzo(a)pyrene-induced lung carcinogenesis in rats. 804 12

The epithelium of the oral cavity is mostly nonkeratinizing. However, it undergoes an abnormal squamous differentiation with keratinization during vitamin A deficiency or oral carcinogenesis. Vitamin A analogues (retinoids) were found to be effective in preventing oral premalignant lesions and second primary cancers in the upper aerodigestive tract. Further development of retinoids for prevention and therapy of squamous cell carcinoma (SCC) requires a better understanding of their mechanism action on the growth and differentiation of SCC cells. We used cultured head and neck SCC (HNSCC) cell lines as a model system. Treatment of HNSCC cells with beta-all-trans-retinoic acid resulted in inhibition of growth (proliferation and colony formation) and suppression of squamous differentiation to varying degrees in the different cell lines. Because some of the malignant HNSCC cells recapitulate the main characteristics of keratinocyte squamous differentiation and responsiveness to retinoids, they can serve as a model for investigating the mechanism underlying the effects of retinoids on cell growth and differentiation. It is thought that nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs) mediate the above effects of retinoids by acting as DNA-binding transcription-modulating factors. We found that HNSCC cell lines express several nuclear RAR and that their level could be modulated by retinoids in some cell lines. An inverse relationship was found between RAR-beta expression and squamous differentiation. An analysis of RAR mRNA expression in head and neck cancer specimens revealed a decrease in RAR-beta in premalignant and malignant tissues relative to normal mucosa. The expression of this receptor increased in vivo after treatment with 13-cis-retinoic acid. These results implicate the loss of RAR-beta expression in the development of head and neck cancer and suggest that RAR-beta could serve as an intermediate marker in prevention trials.
 ...
PMID:Suppression of squamous cell carcinoma growth and differentiation by retinoids. 813 25

It has become evident that retinoids control differentiation, embryonal development, and tumorigenesis. In animal models, skin tumorigenesis has been shown to be prevented by retinoids, which in this organ function as antitumor promoters in the two-stage system using 7,12-dimethylbenz(a)anthracene (DMBA) as the initiator, and 12-tetradecanoyl-phorbol-13-acetate (TPA) as tumor promoter. Even though pharmacological doses applied topically appear to inhibit tumor formation, we found that papilloma and keratoacanthoma growth required physiological concentrations of retinoic acid and that vitamin A deficiency was even more effective than excess retinoid in inhibiting SENCAR mouse skin tumorigenesis. In human beings, oral administration of retinoic acid after tumor resection was effective in inhibiting the appearance of new tumors on the skin of four patients with Xeroderma Pigmentosum, and was effective in preventing new primary tumor formations in patients treated for head and neck cancer. The newly-discovered nuclear receptors for retinoic acid function as transcriptional activators for several genes. In patients with acute promyelocytic leukemia presenting with a reciprocal translocation of chromosome 17 to chromosome 15, the breakpoint has been identified in the retinoic acid receptor alpha gene, which forms a fusion gene with a new gene termed myl, on chromosome 15. Treatment of the patients with retinoic acid causes complete remission of the APL. It also appears to generate cells that do not bear the translocation. Therefore, retinoids may well function as modulators of carcinogenesis both at the promotion level as well as by causing differentiation of neoplastically transformed cells.
 ...
PMID:Multiple mechanisms: the example of vitamin A. 830 28

Natural and synthetic vitamin A metabolites and analogs (retinoids) were found to suppress head and neck and lung carcinogenesis in animal models and inhibit carcinogenesis in individuals with premalignant lesions and a high risk to develop cancer of the aerodigestive tract. Likewise, retinoids prevent the development of second primary cancers in head and neck and lung cancer patients who had been treated for the first primary. These effects are thought to result from changes in the expression of genes that regulate cell growth and differentiation. Most of the effects of retinoids on gene expression are mediated by nuclear retinoic acid receptors RARs (alpha, beta, and gamma) and retinoid X receptors (RXR alpha, beta, and gamma), which function as retinoid-activated transcription factors. Like vitamin A deficiency, alterations in receptor expression or function could interfere with the retinoid signaling pathway and thereby enhance cancer development even in vitamin A sufficient individuals. We found that the expression of RAR beta was suppressed in more than 50% of oral and lung premalignant lesions in individuals without cancer (e.g., oral leukoplakia and squamous metaplasia), in dysplastic lesions adjacent to cancer, and in malignant oral and lung carcinomas. The expression of the other receptors was not different among normal, dysplastic, and malignant oral tissues. However, the expression of RAR gamma and RXR beta was somewhat decreased in lung cancers. These results show that RAR beta expression is lost at early stages of carcinogenesis in the aerodigestive tract and support the hypothesis that the loss of RAR beta expression may facilitate the development of some of these cancers.
 ...
PMID:Retinoids and chemoprevention of aerodigestive tract cancers. 943 44

We report here that ultraviolet irradiation substantially reduced the mRNA and protein of the two major nuclear retinoid receptors, RAR-gamma and RXR-alpha, in human skin in vivo. Pre-treatment with retinoic acid mitigated this loss of nuclear retinoid receptors. Ultraviolet irradiation caused a near-total loss of retinoic acid induction of two RAR/RXR target genes, cellular retinoic acid binding protein-II and RA 4-hydroxylase, but did not affect 1,25-dihydroxyvitamin D3 induction of the vitamin D receptor/RXR-regulated gene vitamin D 24-hydroxylase. In effect, ultraviolet irradiation causes a functional vitamin A deficiency that may have deleterious effects on skin function, contributing to skin photo-aging and carcinogenesis.
 ...
PMID:Ultraviolet irradiation of human skin causes functional vitamin A deficiency, preventable by all-trans retinoic acid pre-treatment. 1020 19

Isozymes of alcohol and other dehydrogenases convert ethanol and retinol to their corresponding aldehydes in vitro. In addition, new pathways of retinol metabolism have been described in hepatic microsomes that involve, in part, cytochrome P450s, which can also metabolize various drugs. In view of these overlapping metabolic pathways, it is not surprising that multiple interactions between retinol, ethanol, and other drugs occur. Accordingly, prolonged use of alcohol, drugs, or both, results not only in decreased dietary intake of retinoids and carotenoids, but also accelerates the breakdown of retinol through cross-induction of degradative enzymes. There is also competition between ethanol and retinoic acid precursors. Depletion ensues, with associated hepatic and extrahepatic pathology, including carcinogenesis and contribution to fetal defects. Correction of deficiency through vitamin A supplementation has been advocated. It is, however, complicated by the intrinsic hepatotoxicity of retinol, which is potentiated by concomitant alcohol consumption. By contrast, beta-carotene, a precursor of vitamin A, was considered innocuous until recently, when it was found to also interact with ethanol, which interferes with its conversion to retinol. Furthermore, the combination of beta-carotene with ethanol results in hepatotoxicity. Moreover, in smokers who also consume alcohol, beta-carotene supplementation promotes pulmonary cancer and, possibly, cardiovascular complications. Experimentally, beta-carotene toxicity was exacerbated when administered as part of beadlets. Thus ethanol, while promoting a deficiency of vitamin A also enhances its toxicity as well as that of beta-carotene. This narrowing of the therapeutic window for retinol and beta-carotene must be taken into account when formulating treatments aimed at correcting vitamin A deficiency, especially in drinking populations.
 ...
PMID:Alcohol, vitamin A, and beta-carotene: adverse interactions, including hepatotoxicity and carcinogenicity. 1035 25

Retinoids play an important role in regulating the growth and differentiation of normal, premalignant and malignant cell types, especially epithelial cells, mainly through interaction with two types of nuclear receptors: retinoic acid receptors (RARalpha, beta and gamma) and retinoid X receptors (RXRalpha, beta and gamma). Vitamin A deficiency in experimental animals has been associated with a higher incidence of cancer and with increased susceptibility to chemical carcinogens. This is in agreement with the epidemiological studies indicating that individuals with a lower dietary vitamin A intake are at a higher risk to develop cancer. At the molecular level, aberrant expression and function of nuclear retinoid receptors have been found in various types of cancer including premalignant lesions. Thus, aberrations in retinoid signaling are early events in carcinogenesis. Retinoids at pharmacological doses exhibit a variety of effects associated with cancer prevention. They suppress transformation of cells in vitro, inhibit carcinogenesis in various organs in animal models, reduce premalignant human epithelial lesions and prevent second primary tumors following curative therapy for epithelial malignancies such as head and neck, lung, liver, and breast cancer.
 ...
PMID:Retinoids and their receptors in cancer development and chemoprevention. 1179 31

We tested the hypothesis that adolescent dietary vitamin A intake impacts mammary gland development and subsequent sensitivity to carcinogenesis. Sprague-Dawley rats were fed a purified diet that was vitamin A deficient, adequate (2.2 mg retinyl palmitate/kg diet), or supranutritional (16 mg retinyl palmitate/kg diet) from 21 to 63 days of age, the period of adolescent mammary gland development. At 73 days of age, rats were given 1-methyl-1-nitrosourea (25 mg/kg body wt i.p.) and monitored for mammary tumors. Tumors appeared earlier and more frequently in rats fed vitamin A-deficient or -supplemented diets. Vitamin A deficiency during adolescence was associated with alveolar mammary gland development and precocious milk protein expression, while supplementation was associated with ductal gland development and suppression of milk protein expression. Differences in circulating estradiol and mammary gland estrogen receptor-alpha, and estrogen-responsive progesterone receptor mRNA were not observed, suggesting that the effects of vitamin A on mammary gland development and carcinogenesis are estrogen independent. Mammary expression of another hormone receptor that regulates milk protein expression, the glucocorticoid receptor, was also unaffected. These results demonstrate that vitamin A intake during adolescence alters mammary gland differentiation and indicate that a narrow range of vitamin A intake during adolescence protects against carcinogenesis.
 ...
PMID:Adolescent vitamin A intake alters susceptibility to mammary carcinogenesis in the Sprague-Dawley rat. 1223 54

Vitamin A deficiency has been associated with increased incidence of certain types of cancer; however, the mechanisms by which vitamin A depletion promotes tumorigenesis are poorly understood. In addition all-trans-retinoic acid (RA), the most active form of vitamin A metabolites, has been shown to limit carcinogenesis in animal models and to trigger programmed cell death (apoptosis) in certain types of tumor cells. On the other hand, we show here that various cell lines overexpressing CYP26A1, a cytochrome P450 enzyme specifically involved in the catabolic inactivation of RA, exhibit increased resistance to various apoptogenic factors, including death receptor ligands such as tumor necrosis factor-related apoptosis-inducing ligand. This resistance could be reversed by pretreatment with ketoconazole, a broad-spectrum inhibitor of cytochrome P450 enzymes. In addition, synthetic retinoids Am80 (4[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid) and Am580 [4(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtamido)benzoic acid], which are resistant to CYP26A1 metabolism, can restore the sensitivity of these cells to apoptogens. Thus, these findings support the idea that CYP26 expression levels may play a role in determining cellular commitment to apoptosis, and increased RA metabolism may be at least partially responsible for these observed effects.
 ...
PMID:Expression of the retinoic acid-metabolizing enzyme CYP26A1 limits programmed cell death. 1570 82

Vitamin A deficiency is associated with carcinogenesis, and upregulation of CYP26A1, a major retinoic acid (RA)-catabolizing enzyme, has recently been shown in cancer. We have previously demonstrated alterations of RA biosynthesis in Barrett's oesophagus, the precursor lesion to oesophageal adenocarcinoma. The aims of this study were to determine CYP26A1 expression levels and functional effects in Barrett's associated carcinogenesis. Retinoic acid response element reporter cells were used to determine RA levels in non-dysplastic and dysplastic Barrett's cell lines and endoscopic biopsies. CYP26A1 expression levels, with or without induction by RA and lithocholic acid, were determined by quantitative reverse transcriptase-PCR (RT-PCR) and immunohistochemistry. CYP26A1 promoter activity was determined by a luciferase reporter construct. CYP26A1 was stably overexpressed in GihTERT cells, which were evaluated for gene-expression changes (pathway array and quantitative RT-PCR), cellular proliferation (cytometric DNA profile and colorimetric assay) and invasion (in vitro matrigel assay) with or without the CYP inhibitor ketaconazole. RA levels decreased progressively with the degree of dysplasia (P<0.05) and were inversely correlated with CYP26A1 gene levels and activity (P<0.01). CYP26A1 expression was increased synergistically by RA and lithocholic acid (P<0.05). Overexpression of CYP26A1 led to induction of c-Myc, epidermal growth factor receptor and matrix metalloproteinase 3 as well as downregulation of tissue inhibitor metalloproteinase 1 and 3. Functional effects of CYP26A1 overexpression were increased proliferation (P<0.01) and invasion in vitro (P<0.01), which were inhibited by ketaconazole. Overexpression of CYP26A1 causes intracellular RA depletion and drives the cell into a highly proliferative and invasive state with induction of other known oncogenes.
 ...
PMID:A novel role for the retinoic acid-catabolizing enzyme CYP26A1 in Barrett's associated adenocarcinoma. 1805 32


<< Previous 1 2 3 4 Next >>