DOCSLIB.ORG

Retinoid Receptor-Dependent and Independent Biological Activities of Novel Fenretinide Analogues and Metabolites

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Retinoid Receptor-Dependent and Independent Biological Activities of Novel Fenretinide Analogues and Metabolites 4606 Vol. 9, 4606–4613, October 1, 2003 Clinical Cancer Research Retinoid Receptor-Dependent and Independent Biological Activities of Novel Fenretinide Analogues and Metabolites Anita L. Sabichi, Hui Xu, Susan Fischer, dependent. 4-MPR, a major metabolite of 4-HPR, lacks a Changchan Zou, Xiulan Yang, Vernon E. Steele, charged group on the terminal phenylamine ring and did Gary J. Kelloff, Reuben Lotan, and not induce retinoid receptor-dependent effects, but did in- 1 duce cell growth inhibition. Thus, 4-MPR may play a role in John L. Clifford the clinical activity of 4-HPR. This study further reveals the Departments of Clinical Cancer Prevention [A. L. S., X. H., C. Z., mechanism of action of these novel phenylretinamides and X. Y., J. L. C.], Thoracic/Head and Neck Medical Oncology [R. L.], supports continued investigation into their development as and Carcinogenesis [S. F.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and National Cancer Institute, chemopreventive drugs. Bethesda, Maryland 20892 [V. E. S., G. J. K.] INTRODUCTION Retinoids are a class of chemical compounds, which in- ABSTRACT clude active metabolites of vitamin A (retinol) as well as a Fenretinide (4-HPR) is a retinoid analogue with antitu- diverse array of synthetic derivatives. Retinoids modulate a mor and chemopreventive activities. In addition to 4-HPR, wide variety of cellular processes, including proliferation, dif- there are several other new phenylretinamides bearing hy- ferentiation, homeostasis, malignant transformation, and apo- droxyl, carboxyl, or methoxyl residues on carbons 2, 3, and ptosis (1). Retinoids also act pharmacologically to restore reg- 4 of the terminal phenylamine ring [N-(2-hydroxyphenyl)- ulation of differentiation and growth in certain premalignant and retinamide (2-HPR), N-(3-hydroxyphenyl)retinamide, N-(2- malignant cells in vitro and in vivo. It is now well established carboxyphenyl)retinamide, N-(3-carboxyphenyl)retinamide, that retinoids exert their effects primarily through nuclear reti- N-(4-carboxyphenyl)retinamide, and N-(4-methoxyphenyl)- noid receptor proteins. Retinoid receptors comprise two families retinamide (4-MPR) ]. It is hypothesized that these agents of ligand-dependent, DNA-binding, transcriptional transactiva- can act independent of the nuclear retinoid receptor path- 2 tors, RARs and RXRs, both members of the nuclear steroid way. To test this hypothesis directly, we have analyzed the hormone receptor superfamily (1, 2). Fenretinide (4-HPR) is one activity of these phenylretinamides in vitro on a panel of F9 of the most promising retinoids for chemoprevention (3–5). It murine embryonal carcinoma cell lines, which includes wild- has a favorable toxicity profile, potent apoptosis-induction ac- type (F9-WT) and mutant cells that have disrupted genes for tivity, biological activity in several preclinical systems, includ- both retinoid X receptor ␣ and retinoic acid receptor ␥ ing all-trans- and 9-cis-retinoic acid-resistant neoplastic cells, retinoid receptors (F9-KO). The F9-KO cells lack almost all and significant clinical chemopreventive activity in randomized measurable response to all-trans-retinoic acid, the primary trials for breast cancer and oral carcinogenesis (6, 7). In addition biologically active retinoid. Two distinct effects of reti- to 4-HPR, there are several other new phenylretinamides bear- namides were identified. The first is a rapid, dose-dependent ing hydroxyl, carboxyl, or methoxyl residues on carbons 2, 3, induction of cell growth inhibition (reduced cell viability), and 4 of the terminal phenylamine ring (2-HPR, 3-HPR, 2-CPR, and the second is a slower induction of differentiation and 3-CPR, 4-CPR, and 4-MPR). One of these, 4-MPR, is a princi- accumulation of cells in the G phase of the cell cycle that 1 ple metabolite of 4-HPR in rodents and humans (8–10) and is ␮ was observed with a concentration of 1 M, for only those the only one of these that lacks a charged group on the terminal phenylretinamides bearing charged (hydroxyl or carboxyl) ring. To date there have been few studies aimed at determining groups on the terminal phenylamine ring. The induction of the activity of these compounds, with the exception of 4-CPR, differentiation and G accumulation was only observed in 1 which has been used extensively in Phase II clinical trials in the F9-WT cells, indicating that this effect is receptor- China (11). The activity of this group of phenylretinamides for the growth inhibition of human oral epithelial cells (12), bladder transitional cell carcinoma cells (13), head and neck squamous cell carcinoma cells and non-small cell lung cancer cells (14), Received 7/31/02; revised 5/14/03; accepted 5/21/03. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 2 The abbreviations used are: RAR, retinoic acid receptor; RXR, retinoid This work was supported in part by National Cancer Institute Grants 5 X receptor; 4-HPR, N-(4-hydroxyphenyl)retinamide; 2-HPR, N-(2- R29 CA78560, and 5 U01 CA77150, and National Institute of Environ- hydroxyphenyl)retinamide; 3-HPR, N-(3-hydroxyphenyl)retinamide; mental Health Sciences Grant 5 P30 ES07784. 2-CPR, N-(2-carboxyphenyl)retinamide; 3-CPR, N-(3-carboxyphenyl)- 1 To whom requests for reprints should be addressed, at Louisiana State retinamide; 4-CPR, N-(4-carboxyphenyl)retinamide; 4-MPR, N-(4- University Health Sciences Center and Feist-Weiller Cancer Center, methoxyphenyl)retinamide; RA, all-trans retinoic acid; WT, wild-type; Department of Biochemistry and Molecular Biology, 1501 Kings Hwy., F9-KO, F9 RXR␣Ϫ/Ϫ/RAR␥Ϫ/Ϫ; DAPI, 4Ј,6-diamidino-2-phenylin- P.O. Box 33932, Shreveport, LA 71130. Phone: (318) 675-8264; Fax: (318) dole; KO, knockout; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphe- 675-5180; E-mail: [email protected]. nyltetrazolium bromide. Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2003 American Association for Cancer Research. Clinical Cancer Research 4607 has been determined recently. These studies have shown that all each well followed by mild shaking to dissolve the insoluble of the novel phenylretinamides can induce cell death and sup- dark blue crystals. Absorbance was determined for each well press proliferation to various degrees, depending on the cell using a Biolumin 960 multiwell plate reader (Molecular Dy- type, and that these effects were often comparable with 4-HPR, namics Inc.) at an absorbance wavelength of 570 nM. Standard indicating that they may also have chemopreventive potential curves for cell number were generated for the F9-WT and (13). F9-KO cells by plating a broad range of known cell numbers Previous studies have shown that 4-HPR could induce (102-5 ϫ 104 cells/well) and performing the MTT assay in the apoptosis in cells that are resistant to the most biologically same day. Cell number for the treated cell samples was calcu- active retinoid, all-trans-RA, suggesting that this activity may lated from these curves. The percentage growth inhibition was not involve retinoid receptors in some cell types (15–19). To calculated using the equation: (1-R/C) ϫ 100, where R and C directly test the hypothesis that 4-HPR can act through a recep- represent the number of cells in retinoid-treated and control tor-independent mechanism, we used the F9 murine embryonal cultures, respectively. The cell cycle profile of F9-WT and carcinoma retinoid receptor KO system previously. The F9 cell F9-KO cells treated for 4 days with 1 ␮M retinoids was deter- line is a well-established model system for the study of RA- mined by cell cycle flow cytometry based on cellular DNA induced differentiation (20). Investigators have used homolo- content, using an Epics Profile II cell sorter (Coulter Electron- gous recombination-mediated gene targeting to generate F9 ics, Inc.), as described previously (13). The percentage of cells cells that lack expression of RARs ␣ and ␥, RXR␣, and pairwise in different phases of the cell cycle was determined from the raw combinations of RAR␣/RXR␣ and RAR␥/RXR␣ (Refs. 21, 22; data using the Epics Elite Flow Cytometry software. reviewed in Refs. 23, 24). It was determined that knocking out Western Blotting. Whole cell extracts were purified and the most abundant RXR (RXR␣) and the most abundant RAR Western blotting performed as described previously (21). Blots (RAR␥) in the same cell, abolishes almost all of the measurable were probed with a polyclonal goat antibody to mouse laminin retinoid receptor-mediated effects (22). By comparing the ef- B1 (Santa Cruz Biotechnology Inc.), stripped, and reprobed with fects of 4-HPR on cell growth and differentiation between the a mouse monoclonal antibody to ␤-actin (Amersham). Second- F9-WT and F9-KO cells, our group could show that 4-HPR had ary antibodies used were horseradish peroxidase-conjugated an- two distinct effects (25). The first was a rapid induction of tigoat or antimouse (Zymed). Chemiluminescence detection was apoptosis requiring a high concentration (10 ␮M), which was performed according to the manufacturer’s instructions (Amer- observed in both the F9-WT and F9-KO cells. The second was sham Life Science Inc.) followed by autoradiography. a slower induction of differentiation, accompanied by an accu- Immunocytochemical Staining. F9 cells were grown on mulation of cells in the G1 phase of the cell cycle, which is seen gelatinized glass coverslips in the presence or absence of the with a lower concentration (1 ␮M). This effect was only ob- indicated retinoids for 4 days. After fixation in 1% paraformal- served in the F9-WT cells, leading to the conclusion that the dehyde, coverslips were incubated with Superblock blocking rapid high concentration effects are receptor-independent and solution (Pierce) for1hatroom temperature to block nonspe- the delayed low concentration effects are receptor dependent.
Load more

Recommended publications
  • 4-Hydroxyphenyiretinamide
    Handbook 4 4-Hydroxyphenyiretinamide 1. Chemical and Physical Melting-point Characteristics 173-175 °C (Shealy etal., 1984; Budavari etal., 1996) 1.1. Nomenclature Solubility See General Remarks, section 1.4. Soluble in most organic solvents, fats, oils and aqueous micellar solutions; sparingly soluble in 1.2 Name water, e.g. 13 nmol/L at pH 6.5 (Li et al., 1996). Chemical Abstracts Services Registry Number 65646-68-6 Spectroscopy 1% UV and visible: ? 362 (methanol), E 1 IUPAC systematic name 1225, EM 47 900 (Budavari et al., 1996; Barua & N-[4-(all-E)-9, 13-Dimethyl-7-(1, 1,5-trimethylcy- Fun, 1998). Higher EM values, i.e. 57 100 and 56 clohex-5 -en-6-yl)nona- 7,9,11,1 3-tetraen- 15- 400, have also been reported (Formelli et al., 1996). oyl]aminophenol or N-[4-(all E)-3, 7-dimethyl-9- (2,2,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8- Nuclear magnetic resonance: tetraen-1-oyl]aminophenol 'H-NMR [(CD3)SO4, 100 MHz]: 8 1.03 (1,1-CH3), 1.3-1.8 (2-CH2, 3-CH), 1.70 (5-CH), 1.8-2.2 Synonyms (4-CH2), 1.99 (9-CH), 2.36 (13-CH), 6.03 (14-H), Fenretinide, 4-HPR, N-(4-hydroxyphenyl)reti- 6.1-6.6 (7-H, 8-H, 10-H, 12-H), 6.99 (11-H), namide, hydroxyphenyl-retinamide, N-(4-hydro- 6.6-6.8 and 7.3-7.6 (benzene ring -H), 9.15 (NH), xyphenyl)retinamide, N-(4-hydroxyphenyl)-all- 9.74 (OH) (Coburn et al., 1983; Shealy et al., tnins-retinamide 1984).
    [Show full text]
  • Role of Nuclear Receptors in Central Nervous System Development and Associated Diseases
    Role of Nuclear Receptors in Central Nervous System Development and Associated Diseases The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Olivares, Ana Maria, Oscar Andrés Moreno-Ramos, and Neena B. Haider. 2015. “Role of Nuclear Receptors in Central Nervous System Development and Associated Diseases.” Journal of Experimental Neuroscience 9 (Suppl 2): 93-121. doi:10.4137/JEN.S25480. http:// dx.doi.org/10.4137/JEN.S25480. Published Version doi:10.4137/JEN.S25480 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:27320246 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Journal name: Journal of Experimental Neuroscience Journal type: Review Year: 2015 Volume: 9(S2) Role of Nuclear Receptors in Central Nervous System Running head verso: Olivares et al Development and Associated Diseases Running head recto: Nuclear receptors development and associated diseases Supplementary Issue: Molecular and Cellular Mechanisms of Neurodegeneration Ana Maria Olivares1, Oscar Andrés Moreno-Ramos2 and Neena B. Haider1 1Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA. 2Departamento de Ciencias Biológicas, Facultad de Ciencias, Universidad de los Andes, Bogotá, Colombia. ABSTRACT: The nuclear hormone receptor (NHR) superfamily is composed of a wide range of receptors involved in a myriad of important biological processes, including development, growth, metabolism, and maintenance.
    [Show full text]
  • Microencapsulation of Amorphous Solid Dispersions of Fenretinide Enhances Drug Solubility and Release from PLGA in Vitro and in Vivo T ⁎ Kari Nietoa, Susan R
    International Journal of Pharmaceutics 586 (2020) 119475 Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm Microencapsulation of amorphous solid dispersions of fenretinide enhances drug solubility and release from PLGA in vitro and in vivo T ⁎ Kari Nietoa, Susan R. Malleryb, Steven P. Schwendemana,c, a Department of Pharmaceutical Sciences and The Biointerfaces Institute, University of Michigan, Ann Arbor, MI, United States b Division of Oral Maxillofacial Pathology & Radiology, College of Dentistry, Ohio State University, Columbus, OH, United States c Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States ARTICLE INFO ABSTRACT Keywords: The purpose of this study was to develop solid dispersions of fenretinide(4HPR), incorporate them into poly Fenretinide (4HPR) (lactic-co-glycolic)(PLGA) millicylindrical implants, and evaluate the resulting implants in vitro and in vivo for polyvinylpyrrolidone (PVP) future applications in oral cancer chemoprevention. Due to the extreme hydrophobicity of 4HPR, 4HPR-poly- amorphous solid dispersion (ASD) vinylpyrrolidone (PVP) amorphous solid dispersions(ASDs) were prepared for solubility enhancement. The Solubility enhancement optimal PVP-4HPR ratio of 9/1(w/w) provided a 50-fold solubility enhancement in aqueous media, which was Poly(lactic-co-glycolic) (PLGA) sustained over 1 week. PVP-4HPR ASD particles were loaded into PLGA millicylinders and drug release was In vivo release long-acting release (LAR) evaluated in vitro in PBST and in vivo by recovery from subcutaneous injection in rats. While initial formulations of PLGA PVP-4HPR millicylinders only released 10% 4HPR in vitro after 28 days, addition of the plasticizer triethyl-o-acetyl-citrate(TEAC) into PVP-4HPR ASDs resulted in a 5.6-fold total increase in drug release.
    [Show full text]
  • Agonist and Antagonist of Retinoic Acid Receptors Cause Similar Changes in Gene Expression and Induce Senescence-Like Growth Arrest in MCF-7 Breast Carcinoma Cells
    Research Article Agonist and Antagonist of Retinoic Acid Receptors Cause Similar Changes in Gene Expression and Induce Senescence-like Growth Arrest in MCF-7 Breast Carcinoma Cells Yuhong Chen,1 Milos Dokmanovic,1 Wilfred D. Stein,1,2 Robert J. Ardecky,3 and Igor B. Roninson1 1Cancer Center, Ordway Research Institute, Albany, New York; 2Institute of Life Sciences, Hebrew University, Jerusalem, Israel; and 3Ligand Pharmaceuticals, Inc., San Diego, California Abstract retinoids is most often attributed to the induction of differentia- Biological effects of retinoids are mediated via retinoic acid tion, but these compounds were also shown to stop the growth of (RA) receptors (RAR) and retinoid X receptors (RXR). The tumor cells by inducing apoptosis or accelerated senescence (1, 2). best-characterized mechanism of retinoid action is stimula- In particular, treatment of two human breast carcinoma cell lines tion of transcription from promoters containing RA response with all-trans retinoic acid (RA) or fenretinide, in vitro or in vivo, elements (RARE). Retinoids induce senescence-like growth induces a senescence-like phenotype characterized by increased h arrest in MCF-7 breast carcinoma cells; this effect is cell size and expression of senescence-associated -galactosidase h associated with the induction of several growth-inhibitory (SA- -gal; refs. 3, 4). This phenotype, as investigated in MCF-7 cells, genes. We have nowfound that these genes are induced by is associated with irreversible growth arrest and up-regulation of RAR-specific but not by RXR-specific ligands. Genome-scale several intracellular and secreted proteins with known growth- microarray analysis of gene expression was used to compare inhibitory activities.
    [Show full text]
  • Interplay Between P53 and Epigenetic Pathways in Cancer
    University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2016 Interplay Between P53 and Epigenetic Pathways in Cancer Jiajun Zhu University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Biology Commons, Cell Biology Commons, and the Molecular Biology Commons Recommended Citation Zhu, Jiajun, "Interplay Between P53 and Epigenetic Pathways in Cancer" (2016). Publicly Accessible Penn Dissertations. 2130. https://repository.upenn.edu/edissertations/2130 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2130 For more information, please contact [email protected]. Interplay Between P53 and Epigenetic Pathways in Cancer Abstract The human TP53 gene encodes the most potent tumor suppressor protein p53. More than half of all human cancers contain mutations in the TP53 gene, while the majority of the remaining cases involve other mechanisms to inactivate wild-type p53 function. In the first part of my dissertation research, I have explored the mechanism of suppressed wild-type p53 activity in teratocarcinoma. In the teratocarcinoma cell line NTera2, we show that wild-type p53 is mono-methylated at Lysine 370 and Lysine 382. These post-translational modifications contribute ot the compromised tumor suppressive activity of p53 despite a high level of wild-type protein in NTera2 cells. This study provides evidence for an epigenetic mechanism that cancer cells can exploit to inactivate p53 wild-type function. The paradigm provides insight into understanding the modes of p53 regulation, and can likely be applied to other cancer types with wild-type p53 proteins. On the other hand, cancers with TP53 mutations are mostly found to contain missense substitutions of the TP53 gene, resulting in expression of full length, but mutant forms of p53 that confer tumor-promoting “gain-of-function” (GOF) to cancer.
    [Show full text]
  • Epigenomic and Transcriptional Regulation of Hepatic Metabolism by REV-ERB and Hdac3
    University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2013 Epigenomic and Transcriptional Regulation of Hepatic Metabolism by REV-ERB and Hdac3 Dan Feng University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Genetics Commons, and the Molecular Biology Commons Recommended Citation Feng, Dan, "Epigenomic and Transcriptional Regulation of Hepatic Metabolism by REV-ERB and Hdac3" (2013). Publicly Accessible Penn Dissertations. 633. https://repository.upenn.edu/edissertations/633 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/633 For more information, please contact [email protected]. Epigenomic and Transcriptional Regulation of Hepatic Metabolism by REV-ERB and Hdac3 Abstract Metabolic activities are regulated by the circadian clock, and disruption of the clock exacerbates metabolic diseases including obesity and diabetes. Transcriptomic studies in metabolic organs suggested that the circadian clock drives the circadian expression of important metabolic genes. Here we show that histone deacetylase 3 (HDAC3) is recruited to the mouse liver genome in a circadian manner. Histone acetylation is inversely related to HDAC3 binding, and this rhythm is lost when HDAC3 is absent. Diurnal recruitment of HDAC3 corresponds to the expression pattern of REV-ERBα, an important component of the circadian clock. REV-ERBα colocalizes with HDAC3 near genes regulating lipid metabolism, and deletion of HDAC3 or Rev-erbα in mouse liver causes hepatic steatosis. Thus, genomic recruitment of HDAC3 by REV-ERBα directs a circadian rhythm of histone acetylation and gene expression required for normal hepatic lipid homeostasis. In addition, we reported that the REV-ERBα paralog, REV- ERBβ also displays circadian binding similar to that of REV-ERBα.
    [Show full text]
  • The Mechanisms of Fenretinide-Mediated Anti-Cancer Activity and Prevention of Obesity and Type-2 Diabetes
    *Manuscript Click here to view linked References The mechanisms of Fenretinide-mediated anti-cancer activity and 1 2 3 prevention of obesity and type-2 diabetes. 4 5 Authors: Nimesh Mody* and George D. Mcilroy. 6 7 8 Institute of Medical Sciences, College of Life Sciences & Medicine, University of Aberdeen, 9 10 Aberdeen, UK 11 12 * corresponding author 13 14 15 Running title: The synthetic retinoid, Fenretinide. 16 17 Abbreviations: Fenretinide, FEN; 18 19 20 Keywords: apoptosis, autophagy, reactive oxygen species, retinoic acid, adipogenesis, 21 22 obesity, type-2 diabetes. 23 24 25 Word count: 7169 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 1 63 64 65 ABSTRACT 1 2 3 4 Fenretinide remains the most investigated retinoid compound for the prevention of cancer. Its 5 6 clinical use remains a genuine possibility due to a favourable toxicological profile and 7 8 accumulation in fatty tissues. Like other well-characterised pharmacological therapies, 9 10 11 Fenretinide has been shown to affect multiple signalling pathways. Recent findings have 12 13 discovered additional beneficial properties the synthetic retinoid was not intentionally 14 15 16 designed for, including the prevention of high-fat diet-induced obesity and insulin resistance. 17 18 These preclinical findings in rodents are timely since obesity has reached pandemic 19 20 21 proportions and safe effective therapeutics are severely lacking. Recent investigations have 22 23 proposed various mechanisms of action for the beneficial effects of Fenretinide.
    [Show full text]
  • A Group of Chimeric Antigen Receptors (Cars)
    (19) *EP003632461A1* (11) EP 3 632 461 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 08.04.2020 Bulletin 2020/15 A61K 39/00 (2006.01) (21) Application number: 18198850.2 (22) Date of filing: 05.10.2018 (84) Designated Contracting States: (72) Inventors: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB • SALZER, Benjamin GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO 3744 Stockern (AT) PL PT RO RS SE SI SK SM TR •LEHNER, Manfred Designated Extension States: 1090 Vienna (AT) BA ME • TRAXLMAYR, Michael Designated Validation States: 1180 Vienna (AT) KH MA MD TN (74) Representative: Sonn & Partner Patentanwälte (71) Applicants: Riemergasse 14 • St. Anna Kinderkrebsforschung 1010 Wien (AT) 1090 Vienna (AT) • Universität für Bodenkultur Wien 1180 Wien (AT) (54) A GROUP OF CHIMERIC ANTIGEN RECEPTORS (CARS) (57) Disclosed is a group of chimeric antigen recep- regulating molecule and optionally reduced by another tors (CARs) consisting of two, three or four CAR mole- regulating molecule, or occurs in the absence of a regu- cules, lating molecule and is reduced by a regulating molecule, wherein the members of the group of CARs can be dif- and ferent or identical in their amino acid sequences to one wherein the ectodomain of each CAR molecule of the another, and group in its prevalent conformation is free of cysteine wherein each of the CAR molecules of the group com- amino acid moieties which are able to form intermolecular prise at least a transmembrane domain and an ectodo- disulphide bonds with other CAR molecules of the
    [Show full text]
  • The Effects of N-3 Fatty Acids and Bexarotene on Breast Cancer Cell Progression
    Journal of Cancer Therapy, 2011, 2, 710-714 doi:10.4236/jct.2011.25096 Published Online December 2011 (http://www.SciRP.org/journal/jct) The Effects of n-3 Fatty Acids and Bexarotene on Breast Cancer Cell Progression Jessica Trappmann, Susan N. Hawk Department of Nutrition, Exercise and Health Sciences, Central Washington University, Ellensburg, USA. E-mail: [email protected] Received September 28th, 2011; revised October 25th, 2011; accepted November 7th, 2011. ABSTRACT Breast cancer cell growth can be inhibited in vivo by retinoid X receptor (RXR) specific retinoids. In both animal and cell culture studies, omega-3 fatty acids share growth regulatory effects similar to those of RXR specific retinoids (rex- inoids). One synthetic rexinoid, bexarotene (LCD 1069, Targretin), is used clinically to treat cancer patients. Of con- cern is that some patients are unable to tolerate high doses of such treatment drugs. We hypothesized that n-3 fatty ac- ids and bexarotene may work synergistically to slow breast cancer cell growth. To test our hypothesis, we used MCF-7 human mammary carcinoma cells and an in vitro cell culture model. We investigated the relationship between the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) alone and in conjunction with bex- arotene in slowing MCF-7 cell growth. Following a 72 hr incubation with the respective treatments, bexarotene en- hanced cell growth (p < 0.05) while DHA showed a strong growth inhibitory effect which was not enhanced by the ad- dition of bexarotene (p < 0.05). EPA alone was not effective in altering cell growth (p < 0.05).
    [Show full text]
  • Circadian Modulation of Genome-Wide Rxr Binding in Mouse Liver Tissue
    Unicentre CH-1015 Lausanne http://serval.unil.ch Year : 2019 CIRCADIAN MODULATION OF GENOME-WIDE RXR BINDING IN MOUSE LIVER TISSUE Trang Khanh Bao Trang Khanh Bao, 2019, CIRCADIAN MODULATION OF GENOME-WIDE RXR BINDING IN MOUSE LIVER TISSUE Originally published at : Thesis, University of Lausanne Posted at the University of Lausanne Open Archive http://serval.unil.ch Document URN : urn:nbn:ch:serval-BIB_C4CE7516215F0 Droits d’auteur L'Université de Lausanne attire expressément l'attention des utilisateurs sur le fait que tous les documents publiés dans l'Archive SERVAL sont protégés par le droit d'auteur, conformément à la loi fédérale sur le droit d'auteur et les droits voisins (LDA). A ce titre, il est indispensable d'obtenir le consentement préalable de l'auteur et/ou de l’éditeur avant toute utilisation d'une oeuvre ou d'une partie d'une oeuvre ne relevant pas d'une utilisation à des fins personnelles au sens de la LDA (art. 19, al. 1 lettre a). A défaut, tout contrevenant s'expose aux sanctions prévues par cette loi. Nous déclinons toute responsabilité en la matière. Copyright The University of Lausanne expressly draws the attention of users to the fact that all documents published in the SERVAL Archive are protected by copyright in accordance with federal law on copyright and similar rights (LDA). Accordingly it is indispensable to obtain prior consent from the author and/or publisher before any use of a work or part of a work for purposes other than personal use within the meaning of LDA (art. 19, para.
    [Show full text]
  • Retinoid-Induced Apoptosis in Normal and Neoplastic Tissues
    Cell Death and Differentiation (1998) 5, 11 ± 19 1998 Stockton Press All rights reserved 13509047/98 $12.00 Review Retinoid-induced apoptosis in normal and neoplastic tissues Laszlo Nagy1,3,4, Vilmos A. Thomazy1, Richard A. Heyman2 retinoic acid receptor (RAR), which belongs to the superfamily and Peter J.A. Davies1,3 of ligand-activated transcription factors (nuclear receptors) revolutionized our understanding as to how retinoids exert 1 Department of Pharmacology, University of Texas-Houston, Medical School, their pleiotropic effects (for reviews see Chambon (1996); Houston, Texas 77225 USA Mangelsdorf et al (1994)). Members of the nuclear receptor 2 Ligand Pharmaceuticals, San Diego, California, 92121 USA superfamily mediate the biological effects of many hormones, 3 Corresponding author: PJAD, tel: 713-500-7480; fax: 713-500-7455; vitamins and drugs (i.e. steroid hormones, thyroid hormones, e-mail: [email protected] 4 vitamin D, prostaglandin-J (PG-J ) and drugs that activate Present address for correspondence: The Salk Institute for Biological Studies, 2 2 Gene Expression Laboratory, La Jolla, California 92037; peroxisomal proliferation). There are two families of retinoid tel: (619) 453-4100 fax:(619) 455-1349; e-mail: [email protected] receptors, Retinoid X Receptors (RXRs) that bind 9-cis retinoic acid (9-cis RA) and Retinoic Acid Receptors (RARs) Received 18.8.97; revised 19.9.97; accepted 22.9.97 that bind both 9-cis RA and all-trans retinoic acid (ATRA) (for Edited by M. Piacentini reviews see Chambon 1996; Mangelsdorf et al, 1994)). Each of these receptor families includes at least three distinct genes, (RARa,b and g; RXRa,b and g) that through differential Abstract promoter usage and alternative splicing, give rise to a large number of distinct retinoid receptor proteins (for reviews see Vitamin A and its derivatives (collectively referred to as Chambon 1996; Mangelsdorf et al, 1994).
    [Show full text]
  • Retinoid X Receptor Is Necessary to Establish the S-Opsin Gradient In
    Retinoid X Receptor ␥ Is Necessary to Establish the S-opsin Gradient in Cone Photoreceptors of the Developing Mouse Retina Melanie R. Roberts,1,2 Anita Hendrickson,2 Christopher R. McGuire,2 and Thomas A. Reh2 PURPOSE. The retinoid X receptors (RXRs) are members of the tion, they also have demonstrated some isoform-specific family of ligand-dependent nuclear hormone receptors. One of functions. For example, RXR␣ heterodimerizes with retinoic these genes, RXR␥, is expressed in highly restricted regions of acid receptors (RARs) to regulate retinal growth and cardiac the developing central nervous system (CNS), including the development.4 retina. Although previous studies have localized RXR␥ to de- Although all three isoforms are expressed in the developing veloping cone photoreceptors in several species, its function nervous system, RXR␥ has the most restricted and develop- in these cells is unknown. A prior study showed that thyroid mentally regulated expression. It is expressed in the develop- hormone receptor ␤2 (TR␤2) is necessary to establish proper ing striatum, part of the tegmentum, the pituitary, the ventral cone patterning in mice by activating medium-wavelength (M) horns of the spinal cord,3,5 and the retina.6 RXR␥-null mice cone opsin and suppressing short-wavelength (S) cone opsin. show isoform-specific defects in both striatal and hippocampal Thyroid hormone receptors often regulate gene transcription function, although RXR␤ can partially compensate for the loss as heterodimeric complexes with RXRs. of RXR␥ in the striatum.2,7,8 RXR␥ has also been identified in 6,9,10 METHODS. To determine whether RXR␥ cooperates with TR␤2 the developing retina of Xenopus, chicks, and mice.
    [Show full text]