DOCSLIB.ORG

A Novel Role for the Retinoic Acid-Catabolizing Enzyme CYP26A1 in Barrett’S Associated Adenocarcinoma

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Novel Role for the Retinoic Acid-Catabolizing Enzyme CYP26A1 in Barrett’S Associated Adenocarcinoma Oncogene (2008) 27, 2951–2960 & 2008 Nature Publishing Group All rights reserved 0950-9232/08 $30.00 www.nature.com/onc ORIGINAL ARTICLE A novel role for the retinoic acid-catabolizing enzyme CYP26A1 in Barrett’s associated adenocarcinoma C-L Chang1,2, E Hong1, P Lao-Sirieix1 and RC Fitzgerald1 1MRC-Cancer Cell Unit, MRC/Hutchison Research Centre, Cambridge, UK and 2Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan Vitamin A deficiency is associated with carcinogenesis, Introduction and upregulation of CYP26A1, a major retinoic acid (RA)-catabolizing enzyme, has recently been shown in The incidence of oesophageal adenocarcinoma has in- cancer. We have previously demonstrated alterations of creased rapidly in the western world over the last two RA biosynthesis in Barrett’s oesophagus, the precursor decades (Pohl and Welch, 2005). The 5-year survival rate is lesion to oesophageal adenocarcinoma. The aims of this an abysmal 13% because the majority of patients present study were to determine CYP26A1 expression levels and with locally advanced disease (Medical Research Council functional effects in Barrett’s associated carcinogenesis. Oesophageal Cancer Working (MRCOCW) Group, 2002). Retinoic acid response element reporter cells were used to Since most oesophageal adenocarcinomas arise on the determine RA levels in non-dysplastic and dysplastic background of Barrett’s metaplasia, which gradually Barrett’s cell lines and endoscopic biopsies. CYP26A1 progresses to carcinoma through a metaplasia–dyspla- expression levels, with or without induction by RA and sia–carcinoma sequence, this provides the opportunity lithocholic acid, were determined by quantitative reverse to intervene at an early stage. A greater understanding transcriptase-PCR (RT–PCR) and immunohistochemis- of the pathogenesis of Barrett’s associated cancer is try. CYP26A1 promoter activity was determined by a required to develop effective chemopreventive strategies. luciferase reporter construct. CYP26A1 was stably over- An association between vitamin A (retinoic acid, RA) expressed in GihTERT cells, which were evaluated for deficiency and carcinogenesis has been known since the gene-expression changes (pathway array and quantitative 1920s when vitamin A-deficient rats were observed to RT–PCR), cellular proliferation (cytometric DNA profile develop squamous metaplasia of the lung mimicking the and colorimetric assay) and invasion (in vitro matrigel changes caused by smoking (Wolbach and Howe, 1925). assay) with or without the CYP inhibitor ketaconazole. Since then, a number of experimental animal models have RA levels decreased progressively with the degree of demonstrated that vitamin A deficiency is associated with dysplasia (Po0.05) and were inversely correlated with increased susceptibility to carcinogenesis (Bertram, 1993; CYP26A1 gene levels and activity (Po0.01). CYP26A1 Avidan et al., 2002). In humans, epidemiological data expression was increased synergistically by RA and have demonstrated a relationship between low levels of lithocholic acid (Po0.05). Overexpression of CYP26A1 serum b-carotene and vitamin A intake and the risk of led to induction of c-Myc, epidermal growth factor various human cancers including cervical pre-cancerous receptor and matrix metalloproteinase 3 as well as lesions (Saffiotti et al., 1967; Wald et al., 1980; Smith and downregulation of tissue inhibitor metalloproteinase 1 Waller, 1991). These effects have been shown to occur and 3. Functional effects of CYP26A1 overexpression through defects in DNA repair (Webster et al., 1996), were increased proliferation (Po0.01) and invasion in increased cell proliferation (Reifen et al., 1998) and a vitro (Po0.01), which were inhibited by ketaconazole. number of genotoxic events (Klamt et al., 2003). Overexpression of CYP26A1 causes intracellular RA Disruption of normal retinoid signalling may occur as depletion and drives the cell into a highly proliferative and a result of reduced expression of retinoid receptors, invasive state with induction of other known oncogenes. reduced transcriptional responses of RA target genes Oncogene (2008) 27, 2951–2960; doi:10.1038/sj.onc.1210969; and increased RA metabolism (Freemantle et al., 2003). published online 3 December 2007 A member of the cytochrome P450 family, CYP26A1, has recently been identified as a major RA-catabolizing Keywords: vitamin A; oesophageal adenocarcinoma; enzyme, which converts RA to biologically inactive proliferation; invasion; bile acids hydroxylated retinoid derivatives (Niederreither et al., 2002). CYP26A1 has been shown to be upregulated in human familial adenomatous polyposis adenomas, sporadic colon cancers and primary ovarian cancer Correspondence: Dr RC Fitzgerald, MRC-Cancer Cell Unit, MRC/ (Downie et al., 2005; Shelton et al., 2006). Furthermore, Hutchison Research Centre, Hills Road, Cambridge, Cambs CB2 the pattern of retinoid gene expression, including 2XZ, UK. E-mail: [email protected] CYP26A1, has been shown to correlate with retinoid Received 3 May 2007; revised 11 October 2007; accepted 6 November sensitivity in a panel of breast and lung cancer cell lines 2007; published online 3 December 2007 (Liu et al., 2005). Role of CYP26A1 in Barrett’s carcinogenesis C-L Chang et al 2952 Apart from the connection between RA deficiency states and cancer, there are several reasons why CYP26A1 might be implicated in Barrett’s oesophagus and associated carcinogenesis. First, Barrett’s oesopha- gus may be considered as an abnormal re-activation of embryonic patterning since the oesophagus undergoes a columnar to squamous transition at 18 weeks gestation. CYP26A1 is necessary for the establishment of the anterior–posterior axis in embryogenesis (Abu-Abed et al., 1998), and we have recently shown that alterations in RA concentration levels can affect differentiation of human oesophagus ex vivo (Chang et al., 2007). Second, chronic exposure to duodeno-gastro-oesophageal reflux- ate is the only well-established risk factor for Barrett’s carcinogenesis (Winters et al., 1987), and the bile acid lithocholic acid (LCA) has recently been demonstrated to compete efficiently with 9-cis-RA for the retinoid X receptor (RXR)-binding sites on the promoter region of the CYP26A1 gene (Radominska-Pandya and Chen, 2002). Therefore, the specific aims of this study were to determine the relative levels of RA and CYP26A1 expression in neoplastic compared with non-neoplastic Barrett’s cells in vitro and in vivo, to evaluate the effects of LCA on CYP26A1 expression and to examine the molecular and functional effects of CYP26A1 over- expression using an in vitro model system. Results Decreased retinoid levels in neoplastic relative to non-dysplastic Barrett’s cells Figure 1 Retinoic acid concentration in a Barrett’s oesophagus First, we determined the relative levels of RA in cells and tissues. Cell lines representative of Barrett’s carcinogenic sequence (a) or Barrett’s metaplasia (BE) and adenocarcinoma (Ca) Barrett’s carcinogenesis. Barrett’s telomerase-immorta- patients (b) were cultured for 24 and 18 h respectively with 100 nM lized cell lines were treated with 10À7 M RA over 24 h and retinal in serum-free medium. The resultant medium (100 ml) from then examined for RA levels using retinoic acid response cell or biopsy culture was then added to a 96-well plate containing element (RARE) reporter cells. The results demon- 3T3 RARE-SEAP reporter cells and incubated for 24 h. SEAP concentration in the medium was determined by Great EscApe strated that non-dysplastic Barrett’s cell lines, BAR detection kit. Relative RA levels were calculated by comparison À11 À11 (7.16 Â 10 ±2.20 Â 10 M) and QhTERT (2.91 Â with a standard curve using serial RA concentrations and then 10À11±1.38 Â 10À11 M), had higher retinoid levels, com- adjusted for the protein content of the cells. In panel a, for each cell pared to dysplastic cell lines, ChTERT (1.51 Â 10À11± line, three biological replicates (each with three technical replicates) 0.09 Â 10À11 M), GohTERT (6.73 Â 10À12±4.29 Â were performed. For panel b, the level of RA was determined in triplicate in each biopsy sample (***Po0.0001 and **Po0.01). 10À12 M) and GihTERT (2.40 Â 10À12±1.53 Â 10À12 M, Po0.0001; Figure 1a), and transformed normal oeso- À12± À12 phagus cell lines Het1a (2.43 Â 10 1.28 Â 10 M) the expression levels of the main RA-producing enzyme À12± À12 and NES (1.60 Â 10 0.32 Â 10 M). We confirmed RALDH2 in Barrett’s cell lines and tissues did not the in vivo relevance of these changes using oesophageal reveal any differences (data not shown). Therefore, we tissues from patients with non-dysplastic Barrett’s and next examined the expression levels of the main adenocarcinoma. Specifically, the mean retinoid level in catabolizing enzyme, CYP26A1. The constitutive ex- Barrett’s oesophageal biopsies (5.92 Â 10À11±1.28 Â À11 pression of CYP26A1 in all the cell lines is very low, but 10 M) was increased 13-fold compared to normal detectable by real-time PCR. We demonstrated that À12± À12 oesophagus (1.94 Â 10 0.73 Â 10 M) and 5.5-fold CYP26A1 mRNA transcript levels were induced by RA compared to adenocarcinoma biopsies (1.04 Â 10À11± À11 in the GihTERT cell line in a dose-dependent manner 0.9 Â 10 M, P ¼ 0.033; Figure 1b). À5 À10 (10 –10 M all-trans retinoic acid (ATRA)), (data not shown) and therefore, 10À8 M was chosen for subsequent Increased CYP26A1 gene expression in Barrett’s experiments. Across the panel of cell lines, RA led to a carcinogenesis significant induction of this gene, which was most Cellular retinoid activity is modulated via the balance marked in the dysplastic cell lines (GohTERT, ChTERT between production and metabolism. Measurement of and GihTERT) compared to the non-dysplastic Oncogene Role of CYP26A1 in Barrett’s carcinogenesis C-L Chang et al 2953 Barrett’s cell lines, BAR and QhTERT (Po0.01; staining was also seen to increase in the epithelial Figure 2a). Measurement of the promoter activity, using compartment throughout the metaplasia–dysplasia– a luciferase reporter vector containing a 354-bp prox- adenocarcinoma sequence (Figure 3b).
Load more

Recommended publications
  • Detailed Review Paper on Retinoid Pathway Signalling
    1 1 Detailed Review Paper on Retinoid Pathway Signalling 2 December 2020 3 2 4 Foreword 5 1. Project 4.97 to develop a Detailed Review Paper (DRP) on the Retinoid System 6 was added to the Test Guidelines Programme work plan in 2015. The project was 7 originally proposed by Sweden and the European Commission later joined the project as 8 a co-lead. In 2019, the OECD Secretariat was added to coordinate input from expert 9 consultants. The initial objectives of the project were to: 10 draft a review of the biology of retinoid signalling pathway, 11 describe retinoid-mediated effects on various organ systems, 12 identify relevant retinoid in vitro and ex vivo assays that measure mechanistic 13 effects of chemicals for development, and 14 Identify in vivo endpoints that could be added to existing test guidelines to 15 identify chemical effects on retinoid pathway signalling. 16 2. This DRP is intended to expand the recommendations for the retinoid pathway 17 included in the OECD Detailed Review Paper on the State of the Science on Novel In 18 vitro and In vivo Screening and Testing Methods and Endpoints for Evaluating 19 Endocrine Disruptors (DRP No 178). The retinoid signalling pathway was one of seven 20 endocrine pathways considered to be susceptible to environmental endocrine disruption 21 and for which relevant endpoints could be measured in new or existing OECD Test 22 Guidelines for evaluating endocrine disruption. Due to the complexity of retinoid 23 signalling across multiple organ systems, this effort was foreseen as a multi-step process.
    [Show full text]
  • Liarozole Hydrochloride (BANM, USAN, Rinnm) Kinetin Hidrocloruro De Liarozol; Liarozole, Chlorhydrate De; Liarozoli 1
    Isotretinoin/Liarozole 1603 Malignant neoplasms. Retinoids such as isotretinoin have 9. Matthay KK, et al. Treatment of high-risk neuroblastoma with Profile been studied in the treatment of various neoplastic or preneoplas- intensive chemotherapy, radiotherapy, autologous bone marrow Kinetin is a plant growth hormone that has been promoted in transplantation, and 13-cis-retinoic acid. N Engl J Med 1999; tic disorders. Although oral tretinoin is used for remission induc- 341: 1165–73. products for the management of photodamaged skin and hyper- tion in acute promyelocytic leukaemia (see p.1619), other retin- 10. Kohler JA, et al. A randomized trial of 13-cis retinoic acid in pigmentation but good evidence of efficacy appears to be lack- oids do not have an established role in the treatment of cancer. children with advanced neuroblastoma after high-dose therapy. ing. There may, however, be a place for the use of retinoids in the Br J Cancer 2000; 83: 1124–7. Preparations chemoprevention of some malignancies. Skin disorders. Apart from its established role in the treatment Proprietary Preparations (details are given in Part 3) There has been particular interest in the potential for retinoids to of acne (above), isotretinoin has been tried in many other skin Arg.: Kinerase†; Braz.: Kinerase; Hong Kong: Kinerase; Malaysia: Kin- prevent the formation of skin cancers (p.672) in patients at in- disorders not responding to usual therapy.1,2 Clinical responses to erase†; Mex.: Kinerase; Singapore: Kinerase; USA: Kinerase. creased risk. Maintenance immunosuppression may increase the oral isotretinoin have been reported1 in small numbers of patients incidence of pre-malignant and malignant skin lesions in solid with anogenital warts (p.1584), rosacea (p.1583), and lichen pla- organ transplant recipients; large numbers of lesions can develop nus (p.1580).
    [Show full text]
  • Progress Towards Genetic and Pharmacological Therapies for Keratin Genodermatoses: Current Perspective and Future Promise
    15 March 2005 Use of Articles in the Pachyonychia Congenita Bibliography The articles in the PC Bibliography may be restricted by copyright laws. These have been made available to you by PC Project for the exclusive use in teaching, scholar- ship or research regarding Pachyonychia Congenita. To the best of our understanding, in supplying this material to you we have followed the guidelines of Sec 107 regarding fair use of copyright materials. That section reads as follows: Sec. 107. - Limitations on exclusive rights: Fair use Notwithstanding the provisions of sections 106 and 106A, the fair use of a copyrighted work, including such use by reproduction in copies or phonorecords or by any other means specified by that section, for purposes such as criticism, comment, news reporting, teaching (including multiple copies for classroom use), scholarship, or research, is not an infringement of copyright. In determining whether the use made of a work in any particular case is a fair use the factors to be considered shall include - (1) the purpose and character of the use, including whether such use is of a commercial nature or is for nonprofit educational purposes; (2) the nature of the copyrighted work; (3) the amount and substantiality of the portion used in relation to the copyrighted work as a whole; and (4) the effect of the use upon the potential market for or value of the copyrighted work. The fact that a work is unpublished shall not itself bar a finding of fair use if such finding is made upon consideration of all the above factors.
    [Show full text]
  • Robert Foti to Cite This Version
    Characterization of xenobiotic substrates and inhibitors of CYP26A1, CYP26B1 and CYP26C1 using computational modeling and in vitro analyses Robert Foti To cite this version: Robert Foti. Characterization of xenobiotic substrates and inhibitors of CYP26A1, CYP26B1 and CYP26C1 using computational modeling and in vitro analyses. Agricultural sciences. Université Nice Sophia Antipolis, 2016. English. NNT : 2016NICE4033. tel-01376678 HAL Id: tel-01376678 https://tel.archives-ouvertes.fr/tel-01376678 Submitted on 5 Oct 2016 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Université de Nice-Sophia Antipolis Thèse pour obtenir le grade de DOCTEUR DE L’UNIVERSITE NICE SOPHIA ANTIPOLIS Spécialité : Interactions Moléculaires et Cellulaires Ecole Doctorale : Sciences de la Vie et de la Santé (SVS) Caractérisation des substrats xénobiotiques et des inhibiteurs des cytochromes CYP26A1, CYP26B1 et CYP26C1 par modélisation moléculaire et études in vitro présentée et soutenue publiquement par Robert S. Foti Le 4 Juillet 2016 Membres du jury Dr. Danièle Werck-Reichhart Rapporteur Dr. Philippe Roche Rapporteur Pr. Serge Antonczak Examinateur Dr. Philippe Breton Examinateur Pr. Philippe Diaz Examinateur Dr. Dominique Douguet Directrice de thèse 1 1. Table of Contents 1. Table of Contents ..............................................................................................................................
    [Show full text]
  • Effects of Retinoids on the TGF-ß System and Extracellular Matrix In
    J Am Soc Nephrol 12: 2300–2309, 2001 Effects of Retinoids on the TGF-␤ System and Extracellular Matrix in Experimental Glomerulonephritis CHRISTIAN MORATH,* CLAUDIUS DECHOW,* INGO LEHRKE,* VOLKER HAXSEN,* RUDIGER¨ WALDHERR,* JURGEN¨ FLOEGE,† EBERHARD RITZ,* and JURGEN¨ WAGNER* *Department of Nephrology, University of Heidelberg, Heidelberg, Germany; and †Department of Nephrology, University of Aachen, Aachen, Germany. Abstract. Transforming growth factor–␤1 (TGF-␤1) overex- compared with untreated animals (P Ͻ 0.025). Cortical expres- pression plays a key role in the glomerular accumulation of sion of TGF receptor II, but not receptor I gene expression, was extracellular matrix proteins in renal disease. Retinoids have significantly lower in animals treated with all-trans retinoic previously been shown to significantly limit glomerular dam- acid or isotretinoin (P Ͻ 0.05). In all-trans retinoic acid–treated age in rat experimental glomerulonephritis. Therefore, the ef- animals with Thy-GN, the increase of glomerular TGF-␤1 fects of all-trans retinoic acid and isotretinoin on the compo- protein (P Ͻ 0.008) and TGF-␤1(P Ͻ 0.025) and TGF nents of the TGF-␤ system and extracellular matrix proteins in receptor II mRNA (P Ͻ 0.015) was significantly less. Immu- anti-Thy1.1-nephritis (Thy-GN) were investigated. Vehicle- nohistochemistry revealed less glomerular staining for TGF-␤1 injected control rats were compared with rats treated with daily and TGF receptor II in the presence of all-trans retinoic acid. subcutaneous injections of 10 mg/kg body wt all-trans retinoic TGF-␤1 immunostaining was not restricted to monocytes and acid or 40 mg/kg body wt isotretinoin (n ϭ 9 per group) either macrophages, as indicated by double-staining.
    [Show full text]
  • Immunofluorescence Localization of Nuclear Retinoid Receptors In
    Acta Derm Venereol 2004; 84: 363–369 INVESTIGATIVE REPORT Immunofluorescence Localization of Nuclear Retinoid Receptors in Psoriasis Versus Normal Human Skin Teresa KARLSSON, Ola ROLLMAN, Anders VAHLQUIST and Hans TO¨ RMA¨ Department of Medical Sciences, Section of Dermatology and Venereology, Uppsala University, Sweden Psoriasis responds favourably to treatment with retinoids retinoids (1). A second class of retinoid receptors, but the cellular pathways mediating these effects are RXRa,-b and -c, are activated by 9-cis-RA and poorly understood. Retinoids regulate keratinocyte pro- phytanic acid, and function as auxilliary heterodimer- liferation and maturation via binding to nuclear retinoic ization partners for RARs, as well as for the vitamin D acid receptors (mainly RARa and RARc) which form receptor, liver X receptors, peroxisome proliferator- heterodimers with the 9-cis-RA receptor, RXRa.We activated receptors (PPARs) and other members of a have previously shown that mRNA expression of RARa superfamily of nuclear receptors (1). The retinoid- and RXRa is down-regulated in psoriatic lesions as activated RAR-RXR heterodimers recognize and bind compared with non-lesional human skin. In the present to RA-response elements (RAREs) in the promoter study, we investigated the protein expression of RARa, region of certain genes, thereby recruiting co-activators RARc and RXRa in normal and psoriatic skin using leading to transcriptional induction of the adjacent indirect immunofluorescence analysis. Epidermal kerati- gene (1). Retinoids may also interact with other nocytes of normal and non-lesional psoriatic skin signalling pathways, e.g. activator protein-1 (AP-1), displayed similar nuclear localization of all three which has been put forward as a key transcriptional receptors; RARa was detected with decreasing intensity regulator in the expression of many marker genes of from basal to suprabasal layers, RARc showed the keratinocyte differentiation.
    [Show full text]
  • Federal Register / Vol. 60, No. 80 / Wednesday, April 26, 1995 / Notices DIX to the HTSUS—Continued
    20558 Federal Register / Vol. 60, No. 80 / Wednesday, April 26, 1995 / Notices DEPARMENT OF THE TREASURY Services, U.S. Customs Service, 1301 TABLE 1.ÐPHARMACEUTICAL APPEN- Constitution Avenue NW, Washington, DIX TO THE HTSUSÐContinued Customs Service D.C. 20229 at (202) 927±1060. CAS No. Pharmaceutical [T.D. 95±33] Dated: April 14, 1995. 52±78±8 ..................... NORETHANDROLONE. A. W. Tennant, 52±86±8 ..................... HALOPERIDOL. Pharmaceutical Tables 1 and 3 of the Director, Office of Laboratories and Scientific 52±88±0 ..................... ATROPINE METHONITRATE. HTSUS 52±90±4 ..................... CYSTEINE. Services. 53±03±2 ..................... PREDNISONE. 53±06±5 ..................... CORTISONE. AGENCY: Customs Service, Department TABLE 1.ÐPHARMACEUTICAL 53±10±1 ..................... HYDROXYDIONE SODIUM SUCCI- of the Treasury. NATE. APPENDIX TO THE HTSUS 53±16±7 ..................... ESTRONE. ACTION: Listing of the products found in 53±18±9 ..................... BIETASERPINE. Table 1 and Table 3 of the CAS No. Pharmaceutical 53±19±0 ..................... MITOTANE. 53±31±6 ..................... MEDIBAZINE. Pharmaceutical Appendix to the N/A ............................. ACTAGARDIN. 53±33±8 ..................... PARAMETHASONE. Harmonized Tariff Schedule of the N/A ............................. ARDACIN. 53±34±9 ..................... FLUPREDNISOLONE. N/A ............................. BICIROMAB. 53±39±4 ..................... OXANDROLONE. United States of America in Chemical N/A ............................. CELUCLORAL. 53±43±0
    [Show full text]
  • FROM ACNE to RETINOIDS and LYMPHOMAS Composed by Anders Vahlquist, Editor-In-Chief
    ISSN 0001-5555 Volume 92 2012 No. 3 Theme Section A Non-profit International Journal for Skin Research, Clinical Dermatology and Sexually Transmitted Diseases Official Journal of - The International Forum for the Study of Itch - European Society for Dermatology and Psychiatry THEME ISSUE: FROM ACNE TO RETINOIDS AND LYMPHOMAS COMPOSED BY ANDERS VAHLQUIST, Editor-IN-CHIEF Acta Dermato-Venereologica www.medicaljournals.se/adv Acta Derm Venereol 2012; 92: 227–289 THEME ISSUE: FROM ACNE TO RETINOIDS AND LYMPHOMAS Composed by Anders Vahlquist, Editor-in-Chief This theme issue of Acta Dermato-Venereologica bridges two bexarotene exert positive and negative effects far beyond seemingly unrelated diseases, acne and lymphoma, by inclu- those of pure RAR agonists. For the former drug, this is il- ding papers on retinoid therapy for both conditions. Beginning lustrated in a large trial on chronic hand eczema (p. 251) and with acne vulgaris, accumulating evidence suggests that diet in a pilot study of its use for congenital ichthyosis (p. 256). after all plays a role, which is ventilated in a commentary (p. For bexarotene, a new Finnish study shows 10 years expe- 228) of a prospective study using low- and high-calorie diets rience of this therapy in severe cutaneous lymphoma (p. 258). in adolescents with acne (p. 241). Acne treatment regimes Depending on the stage of the disease, lymphomas can also usually differ from one country to another; a Korean survey be treated for instance with photodynamic therapy (p. 264) (p. 236) combined with a review on how to treat post-acne and methotrexate (p. 276).
    [Show full text]
  • Synthesis of Biotinylated Retinoids for Cross-Linking and Isolation of Retinol Binding Proteins
    Tetrahedron 58 (2002) 6577–6584 Synthesis of biotinylated retinoids for cross-linking and isolation of retinol binding proteins Nasri Nesnas,a Robert R. Randob,* and Koji Nakanishia,* aDepartment of Chemistry, Columbia University, New York, NY 10027, USA bDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA Received 11 June 2002; accepted 21 June 2002 This article is dedicated to Professor Yoshito Kishi on his receipt of the Tetrahedron Prize Abstract—The synthesis of (3R )-3-[Boc-Lys(biotinyl)-O ]-11-cis-retinol bromoacetate and 3-[Boc-Lys(biotinyl)-O ]-all trans-retinol chloroacetate is described. These biotinylated retinoids are instrumental in labeling the retinol binding proteins (RBPs) via a nucleophilic displacement of the haloacetate by a residue in the binding site of the protein. The covalently linked biotin will allow for a facile isolation and purification of the protein on a streptavidin column thus rendering the protein ready for a tryptic digest followed by mass spectrometric analysis. The 11-cis retinoid was synthesized via metal reduction of an alkyne intermediate generated from a Horner–Wadsworth–Emmons (HWE) reaction whereas the all-trans was synthesized via two consecutive HWE couplings. q 2002 Elsevier Science Ltd. All rights reserved. 1. Introduction some are involved in catalyzing esterification, hydrolysis, and isomerization of retinols at various stages in the visual Retinoids are derivatives of vitamin A (all trans-retinol) cycle. A summary of the mammalian visual cycle is which can generally be synthesized for studies directed to a presented in Fig. 2. The visual protein, rhodopsin, is better understanding of human and non-human vision.
    [Show full text]
  • Study on Cytochrome P-450 Dependent Retinoic Acid Metabolism and Its Inhibitors As Potential Agents for Cancer Therapy
    Sci Pharm www.scipharm.at Research article Open Access Study on Cytochrome P-450 Dependent Retinoic Acid Metabolism and its Inhibitors as Potential Agents for Cancer Therapy Mobasher AHMAD University College of Pharmacy, University of the Punjab (Old Campus), the Mall, Lahore, Pakistan. E-mail: [email protected] Sci Pharm. 2011; 79: 921–935 doi:10.3797/scipharm.1106-18 Published: August 12th 2011 Received: June 24th 2011 Accepted: August 12th 2011 This article is available from: http://dx.doi.org/10.3797/scipharm.1106-18 © Ahmad; licensee Österreichische Apotheker-Verlagsgesellschaft m. b. H., Vienna, Austria. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract The relative lack of clinical success with conventional anticancer agents may be due in part to the traditional concept of cancer being a biological state rather than a dynamic process. Redefining cancer as a dynamic disease commencing with carcinogenesis introduces the possibility of chemoprevention. Retinoids offer the promise of a therapeutic option based on differentiation of premalignant as well as malignant cells. Research to date has concentrated on the use of exogenous retinoids in cancer. Although this research continues with new retinoid derivatives, an alternative approach to overcoming the drawbacks associated with exogenous retinoids has been to increase the levels of endogenous retinoic acid (RA) by inhibiting the cytochrome P450- mediated catabolism of RA using a novel class of agents known as retinoic acid metabolism blocking agents (RAMBAs which increase the level of endogenous retinoic acid (RA) within the tumor cells by blocking their metabolism.
    [Show full text]
  • The Retinoid X Receptor Agonist 9-Cis-Retinoic Acid and the 24-Hydroxylase Inhibitor Ketoconazole Increase Activity of 1,25-Dihydroxyvitamin D3 in Human Skin in Vivo
    The Retinoid X Receptor Agonist 9-cis-Retinoic Acid and the 24-Hydroxylase Inhibitor Ketoconazole Increase Activity of 1,25-Dihydroxyvitamin D3 in Human Skin In Vivo Sewon Kang, Xiao-Yan Li , Elizabeth A. Duell, and Jolm J. Voorhees Department of Dermatology, U niversity o f Micltigan M edical Center Ann Arbor. Michigan. U .S .A. 1,25-Dihydroxyvitamin D 3 [1,25(OHhD31 transacti­ 1,25(OH}zD3' however, caused a synergistic increase vates its target genes via the vitamin D receptor in 24-0Hase mRNA. Similarly, 1,25(OH)2D3 plus (VDR). VDR functions in physiology as a dimer ketoconazole increased 24-0Hase mRNA synergisti­ complexed with retinoid X receptor (RXR), whose cally. Ket oconazole inhibited ex vil10 1,25(OH}zD3- natural ligand is 9-cis-retinoic acid (9-c-RA). Inacti­ induced epidermal 24-0Hase activity. Thus, 24- vation of 1,25(OH}zD3 occurs through a cytochrome OHase mRNA induction is a sensitive reporter of P-450 24-hydroxylase (OHase). The promoter of the 1,25(OH}zD3 activity ill vivo; RXR bound to VDR is human 24-0Hase gene contains a 1,25(OH)2D 3-re- not a silent partner ill vivo, because 9-c-RA enhances sponsive enhancer element (VDRE). We have used 1,25(OHhDrliganded RXRJVDR stimulation of the this VDRE containing gene as an endogenous re­ VDRE containing 24-0Hase gene; ketoconazole in­ porter for vitamin D 3-mediated gene activation ;11 hibition of 24-0Hase enhances 1,25(OH}zD3 activity vivo. Normal adult human skin was keratomed after a by impeding its breakdown.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2002/0177609 A1 Swindell Et Al
    US 2002O177609A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2002/0177609 A1 Swindell et al. (43) Pub. Date: Nov. 28, 2002 (54) FATTY ALCOHOL DRUG CONJUGATES Related U.S. Application Data (60) Provisional application No. 60/278,457, filed on Mar. (76) Inventors: Charles S. Swindell, Merion, PA (US); 23, 2001. Glenn J. Fegley, Eagleville, PA (US) Publication Classification Correspondence Address: (51) Int. Cl." ..................... A61K 31/4453; A61K 31/40; Edward R. Gates, Esq. A61K 31/15 Chantal Morgan D'Apuzzo (52) U.S. Cl. ......................... 514/329; 514/426; 514/640; Wolf, Greenfield & Sacks, P.C. 546/244; 548/558; 564/256 600 Atlantic Ave Boston, MA 02210 (US) (57) ABSTRACT The invention provides conjugates of fatty alcohols and (21)21) AppAppl. No.: 10/107,537/107, p harmaceutical agents9. useful in treating9. cancer, Viruses, psychiatric disorders. Compositions, pharmaceutical prepa rations, and methods of preparation of the fatty alcohols 22) Filled: Mar. 25, 2002 p harmaceutical agent9. coniugatesJug are pprovided. US 2002/0177609 A1 Nov. 28, 2002 FATTY ALCOHOL DRUG CONJUGATES was observed (for an adenosine receptor agonist), and it was postulated that the pendant lipid molecule interacted with RELATED APPLICATION the phospholipid membrane to act as a distal anchor for the 0001. This application claims priority under 35 U.S.C. S receptor ligand in the membrane micro environment of the 119 (e) from U.S. provisional patent application Serial No. receptor. This increase in potency, however, was not 60/278,457, filed on Mar. 23, 2001, entitled Fatty Alcohol observed when the same lipid derivatives of adenosine Drug Conjugates.
    [Show full text]