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Glucocorticoids are steroid hormones that exert most of their effects through their binding to the glucocorticoid receptor (GR), a ligand regulated transcription factor. Although glucocorticoids are widely used in the clinic, their usage in chronic therapies provokes severe adverse reactions. In the quest for safer glucocorticoids a dissociated model was established that proposes a disconnection between GR activated pathways responsible of desired pharmacological effects and pathways involved in adverse GR reactions. Under this model, a myriad of steroidal and non-steroidal compounds has been characterized, with most of them still producing side effects. X-ray crystallographic studies followed by molecular dynamics analysis led research to insights on the receptor Ligand Binding Domain (LBD), which undergoes specific ligand dependent conformational changes that influence receptor activities. In this sense, the flexibility of the ligand structure would contribute to the final GR outcome. Here, we review different data of 21-hydroxy-6,19-epoxyprogesterone (21OH-6,19OP), a rigid steroid with potential pharmaceutical interest due to its anti-inflammatory and immunosuppressive activities, lacking several GR adverse reactions. The rigid structure endows this compound with an enhanced selectivity towards GR. Molecular characterization of the GR/21OH-6,19OP complex revealed specific intermediate conformations adopted by the receptor that would explain the influence on GR dimerization and the recruitment of a specific set of GR transcription modulators. We summarize recent data that will contribute to understand the complexity of glucocorticoid response. © 2016 Bentham Science Publishers.


Documento: Artículo
Título:21-hydroxy-6,19-epoxyprogesterone: A promising therapeutic agent and a molecular tool for deciphering glucocorticoid action
Autor:Pecci, A.; Alvarez, L.D.; Presman, D.M.; Burton, G.
Filiación:Dpto. Química Biológica/IFIBYNE-CONICET, Facultad de Ciencias Exactas y Naturales (FCEN), Universidad de Buenos Aires (UBA), Buenos Aires, Argentina
Dpto. Química Orgánica/UMYMFOR-CONICET, Facultad de Ciencias Exactas y Naturales (FCEN), Universidad de Buenos Aires (UBA), Buenos Aires, Argentina
Laboratory of Receptor Biology and Gene Expression, National Cancer Institute NIH, Bethesda, United States
Palabras clave:21-hydroxy-6,19-epoxyprogesterone; Dissociated ligands; Glucocorticoid mechanism of action; Glucocorticoid receptor; Molecular dynamics; Rigid steroids; 21 hydroxy 6 19 epoxyprogesterone; dexamethasone; glucocorticoid; mifepristone; paclitaxel; progesterone derivative; unclassified drug; 21-hydroxy-6,19-oxidoprogesterone; glucocorticoid; glucocorticoid receptor; immunosuppressive agent; nonsteroid antiinflammatory agent; progesterone; anxiety; apoptosis; biological activity; breast cancer; conformational transition; crystal structure; depression; dimerization; gene expression; gene overexpression; hydrogen bond; hypertension; immunosurveillance; inflammation; ligand binding; lung cancer; molecular biology; molecular docking; molecular dynamics; oligomerization; point mutation; protein interaction; Review; spectroscopy; therapy effect; X ray crystallography; analogs and derivatives; chemical structure; chemistry; human; metabolism; molecular model; Anti-Inflammatory Agents, Non-Steroidal; Glucocorticoids; Humans; Immunosuppressive Agents; Models, Molecular; Molecular Structure; Progesterone; Receptors, Glucocorticoid
Título revista:Mini-Reviews in Medicinal Chemistry
Título revista abreviado:Mini-Rev. Med. Chem.
CAS:dexamethasone, 50-02-2; mifepristone, 84371-65-3; paclitaxel, 33069-62-4; progesterone, 57-83-0; 21-hydroxy-6,19-oxidoprogesterone; Anti-Inflammatory Agents, Non-Steroidal; Glucocorticoids; Immunosuppressive Agents; Progesterone; Receptors, Glucocorticoid


  • Kadmiel, M., Cidlowski, J.A., Glucocorticoid receptor signaling in health and disease (2013) Trends Pharmacol Sci, 34 (9), pp. 518-530
  • McMaster, A., Ray, D.W., Modelling the glucocorticoid receptor and producing therapeutic agents with anti-inflammatory effects but reduced side-effects (2007) Exp Physiol, 92 (2), pp. 299-309
  • De Bosscher, K., Selective Glucocorticoid Receptor modulators (2010) J Steroid Biochem Mol Biol, 120 (2-3), pp. 96-104
  • Schacke, H., Docke, W.D., Asadullah, K., Mechanisms involved in the side effects of glucocorticoids (2002) Pharmacol Ther, 96 (1), pp. 23-43
  • Manolagas, S.C., Weinstein, R.S., New developments in the pathogenesis and treatment of steroid--‐induced osteoporosis (1999) J Bone Miner Res, 14, pp. 1061-1066
  • Mitić, Z.J., Najman, S.J., Cakić, M.D., Ajduković, Z.R., Ignjatovic, N.L., Nikolić, R.S., Nikolić, G.M., Trajanović, M.D., Spectroscopic characterization of bone tissue of experimental animals after glucocorticoid treatment and recovery period (2014) J Mol Struct, 1074, pp. 315-320
  • Weinstein, R.S., Glucocorticoid-induced osteonecrosis (2012) Endocrine, 41, pp. 183-190
  • Schneiter, P., Tappy, L., Kinetics of dexamethasone-induced alterations of glucose metabolism in healthy humans (1998) Am J Physiol, 275, pp. E806-E813
  • Andrews, R.C., Walker, B.R., Glucocorticoids and insulin resistance: Old hormones, new targets (1999) Clin Sci, 96, pp. 513-523
  • Burt, M.G., Roberts, G.W., Aguilar-Loza, N.R., Frith, P., Stranks, S.N., Continuous monitoring of circadian glycemic patterns in patients receiving prednisolone for COPD (2011) J Clin Endocrinol Metab, 96, pp. 1789-1796
  • Hall, R.C., Popkin, M.K., Stickney, S.K., Gardner, E.R., Presentation of the steroid psychosis (1979) J Nerv Ment Dis, 167, pp. 229-236
  • Swinburn, C.R., Wakefield, J.M., Newman, S.P., Jones, P.W., Evidence of prednisolone induced mood change (‘steroid euphoria’) in patients with chronic obstructive airways disease (1988) Br J Clin Pharmacol, 26, pp. 709-713
  • Turner, R., Elson, E., Sleep disorders. Steroids cause sleep disturbance (1993) BMJ, 306, pp. 1477-1478
  • Bolanos, S.H., Khan, D.A., Hanczyc, M., Bauer, M.S., Dhanani, N., Brown, E.S., Assessment of mood states in patients receiving long-term corticosteroid therapy and in controls with patient-rated and clinician rated scales (2004) Ann Allergy Asthma Immunol, 92, pp. 500-505
  • Warrington, T.P., Bostwick, J.M., Psychiatric adverse effects of corticosteroids (2006) Mayo Clin Proc, 81, pp. 1361-1367
  • Wolkowitz, O.M., Burke, H., Epel, E.S., Reus, V.I., Glucocorticoids. Mood, memory, and mechanisms (2009) Ann N Y Acad Sci, 1179, pp. 19-40
  • Schäcke, H., Döcke, W.D., Asadullah, K., Mechanisms involved in the side effects of glucocorticoids (2002) Pharmacol Ther, 96 (1), pp. 23-43
  • Poetker, D.M., Reh, D.D., A comprehensive review of the adverse effects of systemic corticosteroids (2010) Otolaryngol Clin North Am, 43, pp. 753-768
  • Sholter, D.E., Armstrong, P.W., Adverse effects of corticosteroids on the cardiovascular system (2000) Can J Cardiol, 16, pp. 505-511
  • Souverein, P.C., Berard, A., Van Staa, T.P., Cooper, C., Egberts, A.C., Leufkens, H.G., Walker, B.R., Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a population based case-control study (2004) Heart, 90, pp. 859-865
  • Van Der Hooft, C.S., Heeringa, J., Brusselle, G.G., Hofman, A., Witteman, J.C., Kingma, J.H., Sturkenboom, M.C., Stricker, B.H., Corticosteroids and the risk of atrial fibrillation (2006) Arch Intern Med, 166, pp. 1016-1020
  • Price, S.R., Du, J.D., Bailey, J.L., Mitch, W.E., Molecular mechanisms regulating protein turnover in muscle (2001) Am J Kidney Dis, 37 (1), pp. S112-S114
  • West, K.M., Johnson, P.C., Kyriakapoulos, A.A., Bahr, W.J., Bloedow, C.E., The physiologic effects of dexamethasone (1960) Arthritis Rheum, 3, pp. 129-139
  • Fardet, L., Cabane, J., Lebbé, C., Morel, P., Flahault, A., Incidence and risk factors for corticosteroid-induced lipodystrophy: A prospective study (2007) J am Acad Dermatol, 57, pp. 604-609
  • Urban, R.C., Jr., Cotlier, E., Corticosteroid-induced cataracts (1986) Surv Ophthalmol, 31, pp. 102-110
  • Mitchell, P., Cumming, R.G., Mackey, D.A., Inhaled cortico--‐ steroids, family history, and risk of glaucoma (1999) Ophthalmology, 106, pp. 2301-2306
  • Stanbury, R.M., Graham, E.M., Systemic corticosteroid therapy--‐side effect and their management (1998) Br J Ophthamol, 82, pp. 704-708
  • Henzen, C., Suter, A., Lerch, E., Urbinelli, R., Schorno, X.H., Briner, V.A., Suppression and recovery of adrenal response after short-term, high-dose glucocorticoid treatment (2000) Lancet, 355, pp. 542-545
  • Lionakis, M.S., Kontoyiannis, D.P., Glucocorticoids and invasive fungal infections (2003) Lancet, 362, pp. 1828-1838
  • Clark, A.R., Anti-inflammatory functions of glucocorticoid induced genes (2007) Mol Cell Endocrinol, 275 (1-2), pp. 79-97
  • Strehl, C., Buttgereit, F., Optimized glucocorticoid therapy: Teaching old drugs new tricks (2013) Mol Cell Endocrinol, 380 (1-2), pp. 32-40
  • Liu, D., Ahmet, A., Ward, L., Krishnamoorthy, P., Mandelcorn, E.D., Leigh, R., Brown, J.P., Kim, H., A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy Allergy (2013) Asthma & Clinical Immunology, 9, pp. 30-55
  • Rosen, J., Miner, J.N., The search for safer glucocorticoid receptor ligands (2005) Endocr Rev, 26 (3), pp. 452-464
  • Kleiman, A., Tuckermann, J.P., Glucocorticoid receptor action in beneficial and side effects of steroid therapy: Lessons from conditional knockout mice (2007) Mol Cell Endocrinol, 275 (1-2), pp. 98-108
  • Barnes, P.J., Glucocorticosteroids: Current and future directions (2011) Br J Pharmacol, 163 (1), pp. 29-43
  • Chrousos, G.P., Stress as a medical and scientific idea and its implications (1998) Adv Pharmacol, 42, pp. 552-556
  • Nieman, L.K., Chrousos, G.P., Kellner, C., Spitz, I.M., Nisula, B.C., Cutler, G.B., Merriam, G.R., Loriaux, D.L., Successful treatment of Cushing's syndrome with the glucocorticoid antagonist RU 486 (1985) J Clin Endocrinol Metab, 61 (3), pp. 536-540
  • Schulte, H.M., Chrousos, G.P., Gold, P.W., Booth, J.D., Oldfield, E.H., Cutler, G.B., Jr., Loriaux, D.L., Continuous administration of synthetic ovine corticotropin-releasing factor in man. Physiological and pathophysiological implications (1985) J Clin Invest, 75 (6), pp. 1781-1785
  • Bai, C., Schmidt, A., Freedman, L.P., Steroid hormone receptors and drug discovery: Therapeutic opportunities and assay designs (2003) Assay Drug Dev Technol, 1 (6), pp. 843-852
  • Chen, J., Wang, J., Shao, J., Gao, Y., Xu, J., Yu, S., Liu, Z., Jia, L., The unique pharmacological characteristics of mifepristone (RU486): From terminating pregnancy to preventing cancer metastasis (2014) Med Res Rev, 34 (5), pp. 979-1000
  • Grad, I., Picard, D., The glucocorticoid responses are shaped by molecular chaperones (2007) Mol Cell Endocrinol, 275 (1-2), pp. 2-12
  • Beato, M.H.P., Schütz, G., Steroid hormone receptors: Many Actors in search of a plot (1995) Cell, 83, pp. 851-857
  • John, S., Sabo, P.J., Thurman, R.E., Sung, M.H., Biddie, S.C., Johnson, T.A., Hager, G.L., Stamatoyannopoulos, J.A., Chromatin accessibility pre-determines glucocorticoid receptor binding patterns (2011) Nat Genet, 43 (3), pp. 264-268
  • Grontved, L., John, S., Baek, S., Liu, Y., Buckley, J.R., Vinson, C., Aguilera, G., Hager, G.L., C/EBP maintains chromatin accessibility in liver and facilitates glucocorticoid receptor recruitment to steroid response elements (2013) EMBO J, 32 (11), pp. 1568-1583
  • Meijsing, S.H., Pufall, M.A., So, A.Y., Bates, D.L., Chen, L., Yamamoto, K.R., DNA binding site sequence directs glucocorticoid receptor structure and activity (2009) Science, 324 (5925), pp. 407-410
  • Watson, L.C., Kuchenbecker, K.M., Schiller, B.J., Gross, J.D., Pufall, M.A., Yamamoto, K.R., The glucocorticoid receptor dimer interface allosterically transmits sequence-specific DNA signals (2013) Nat Struct Mol Biol, 20 (7), pp. 876-883
  • Kassel, O., Herrlich, P., Crosstalk between the glucocorticoid receptor and other transcription factors: Molecular aspects (2007) Mol Cell Endocrinol, 275 (1-2), pp. 13-29
  • Belvisi, M.G., Brown, T.J., Wicks, S., Foster, M.L., New Glucocorticosteroids with an improved therapeutic ratio? (2001) Pulm Pharmacol Ther, 14 (3), pp. 221-227
  • Reichardt, H.M., Kaestner, K.H., Tuckermann, J., Kretz, O., Wessely, O., Bock, R., Gass, P., Schutz, G., DNA binding of the glucocorticoid receptor is not essential for survival (1998) Cell, 93, pp. 531-541
  • Hübner, S., Dejager, L., Libert, C., Tuckermann, J.P., The glucocorticoid receptor in inflammatory processes: Transrepression is not enough (2015) Biological Chemistry
  • Heck, S., Kullmann, M., Gast, A., Ponta, H., Rahmsdorf, H.J., Herrlich, P., Cato, A.C., A distinct modulating domain in glucocorticoid receptor monomers in the repression of activity of the transcription factor AP-1 (1994) EMBO J, 13 (17), pp. 4087-4095
  • Clark, A.R., Belvisi, M.G., Maps and legends: The quest for dissociated ligands of the glucocorticoid receptor (2012) Pharmacol Ther, 134 (1), pp. 54-67
  • Jewell, C.M., Scoltock, A.B., Hamel, B.L., Yudt, M.R., Cidlowski, J.A., Complex human glucocorticoid receptor dim mutations define glucocorticoid induced apoptotic resistance in bone cells (2012) Mol Endocrinol, 26 (2), pp. 244-256
  • Presman, D.M., Levi, V., Pignataro, O.P., Pecci, A., Melatonin inhibits glucocorticoid-dependent GR-TIF2 interaction in newborn hamster kidney (BHK) cells (2012) Mol Cell Endocrinol, 349 (2), pp. 214-221
  • Adams, M., Meijer, O.C., Wang, J., Bhargava, A., Pearce, D., Homodimerization of the glucocorticoid receptor is not essential for response element binding: Activation of the phenylethanolamine N-methyltransferase gene by dimerization-defective mutants (2003) Mol Endocrinol, 17 (12), pp. 2583-2592
  • Schiller, B.J., Chodankar, R., Watson, L.C., Stallcup, M.R., Yamamoto, K.R., Glucocorticoid receptor binds half sites as a monomer and regulates specific target genes (2014) Genome Biol, 15 (7), pp. 418-434
  • Lim, H.W., Uhlenhaut, N.H., Rauch, A., Weiner, J., Hubner, S., Hubner, N., Won, K.J., Steger, D.J., Genomic redistribution of GR monomers and dimers mediates transcriptional response to exogenous glucocorticoid in vivo (2015) Genome Res
  • Newton, R., Holden, N.S., Separating transrepression and transactivation: A distressing divorce for the glucocorticoid receptor? (2007) Mol Pharmacol, 72 (4), pp. 799-809
  • Kumar, R., Thompson, E.B., Gene regulation by the glucocorticoid receptor: Structure: Function relationship (2005) J Steroid Biochem Mol Biol, 94 (5), pp. 383-394
  • Gronemeyer, H., Gustafsson, J.A., Laudet, V., Principles for modulation of the nuclear receptor superfamily (2004) Nat Rev Drug Discov, 3 (11), pp. 950-964
  • Bledsoe, R.K., Montana, V.G., Stanley, T.B., Delves, C.J., Apolito, C.J., McKee, D.D., Consler, T.G., Xu, H.E., Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition (2002) Cell, 110 (1), pp. 93-105
  • Kauppi, B., Jakob, C., Farnegardh, M., Yang, J., Ahola, H., Alarcon, M., Calles, K., Carlquist, M., The three-dimensional structures of antagonistic and agonistic forms of the glucocorticoid receptor ligand-binding domain: RU-486 induces a transconformation that leads to active antagonism (2003) J Biol Chem, 278 (25), pp. 22748-22754
  • Madauss, K.P., Bledsoe, R.K., McLay, I., Stewart, E.L., Uings, I.J., Weingarten, G., Williams, S.P., The first X-ray crystal structure of the glucocorticoid receptor bound to a non-steroidal agonist (2008) Bioorg Med Chem Lett, 18 (23), pp. 6097-6099
  • Suino-Powell, K., Xu, Y., Zhang, C., Tao, Y.G., Tolbert, W.D., Simons, S.S., Jr., Xu, H.E., Doubling the size of the glucocorticoid receptor ligand binding pocket by deacylcortivazol (2008) Mol Cell Biol, 28 (6), pp. 1915-1923
  • Biggadike, K., Bledsoe, R.K., Hassell, A.M., Kirk, B.E., McLay, I.M., Shewchuk, L.M., Stewart, E.L., X-ray crystal structure of the novel enhanced-affinity glucocorticoid agonist fluticasone furoate in the glucocorticoid receptor-ligand binding domain (2008) J Med Chem, 51 (12), pp. 3349-3352
  • Veleiro, A.S., Alvarez, L.D., Eduardo, S.L., Burton, G., Structure of the glucocorticoid receptor, a flexible protein that can adapt to different ligands (2010) Chemmedchem, 5 (5), pp. 649-659
  • Pecci, A., Alvarez, L.D., Veleiro, A.S., Ceballos, N.R., Lantos, C.P., Burton, G., New lead compounds in the search for pure antiglucocorticoids and the dissociation of antiglucocorticoid effects (2009) J Steroid Biochem Mol Biol, 113 (3-5), pp. 155-162
  • Vicent, G.P., Monteserin, M.C., Veleiro, A.S., Burton, G., Lantos, C.P., Galigniana, M.D., 21-Hydroxy-6,19-oxidoprogesterone: A novel synthetic steroid with specific antiglucocorticoid properties in the rat (1997) Mol Pharmacol, 52 (4), pp. 749-753
  • Schoch, G.A., D'arcy, B., Stihle, M., Burger, D., Bar, D., Benz, J., Thoma, R., Ruf, A., Molecular switch in the glucocorticoid receptor: Active and passive antagonist conformations (2010) J Mol Biol, 395 (3), pp. 568-577
  • Souza, P.C., Barra, G.B., Velasco, L.F., Ribeiro, I.C., Simeoni, L.A., Togashi, M., Webb, P., Polikarpov, I., Helix 12 dynamics and thyroid hormone receptor activity: Experimental and molecular dynamics studies of Ile280 mutants (2011) J Mol Biol, 412 (5), pp. 882-893
  • Shen, J., Li, W., Liu, G., Tang, Y., Jiang, H., Computational insights into the mechanism of ligand unbinding and selectivity of estrogen receptors (2009) J Phys Chem B, 113 (30), pp. 10436-10444
  • Teotico, D.G., Frazier, M.L., Ding, F., Dokholyan, N.V., Temple, B.R., Redinbo, M.R., Active nuclear receptors exhibit highly correlated AF-2 domain motions (2008) Plos Comput Biol, 4 (7)
  • Alvarez, L.D., Marti, M.A., Veleiro, A.S., Presman, D.M., Estrin, D.A., Pecci, A., Burton, G., Exploring the molecular basis of action of the passive antiglucocorticoid 21-hydroxy-6,19-epoxyprogesterone (2008) J Med Chem, 51 (5), pp. 1352-1360
  • Presman, D.M., Alvarez, L.D., Levi, V., Eduardo, S., Digman, M.A., Marti, M.A., Veleiro, A.S., Pecci, A., Insights on glucocorticoid receptor activity modulation through the binding of rigid steroids (2010) Plos One, 5 (10)
  • Pratt, W.B., Galigniana, M.D., Harrell, J.M., Defranco, D.B., Role of hsp90 and the hsp90-binding immunophilins in signalling protein movement (2004) Cell Signal, 16 (8), pp. 857-872
  • Robertson, S., Rohwer, J.M., Hapgood, J.P., Louw, A., Impact of glucocorticoid receptor density on ligand-independent dimerization, cooperative ligand-binding and basal priming of transactivation: A cell culture model (2013) Plos One, 8 (5)
  • Reichardt, H.M., Tuckermann, J.P., Gottlicher, M., Vujic, M., Weih, F., Angel, P., Herrlich, P., Schutz, G., Repression of inflammatory responses in the absence of DNA binding by the glucocorticoid receptor (2001) EMBO J, 20 (24), pp. 7168-7173
  • Presman, D.M., Ogara, M.F., Stortz, M., Alvarez, L.D., Pooley, J.R., Schiltz, R.L., Grontved, L., Pecci, A., Live cell imaging unveils multiple domain requirements for in vivo dimerization of the glucocorticoid receptor (2014) Plos Biol, 12 (3)
  • Brelivet, Y., Rochel, N., Moras, D., Structural analysis of nuclear receptors: From isolated domains to integral proteins (2012) Mol Cell Endocrinol, 348 (2), pp. 466-473
  • Helsen, C., Claessens, F., Looking at nuclear receptors from a new angle (2014) Mol Cell Endocrinol, 382 (1), pp. 97-106
  • Bledsoe, R.K., Stewart, E.L., Pearce, K.H., Structure and function of the glucocorticoid receptor ligand binding domain (2004) Vitam Horm, 68, pp. 49-91
  • Digman, M.A., Dalal, R., Horwitz, A.F., Gratton, E., Mapping the number of molecules and brightness in the laser scanning microscope (2008) Biophys J, 94 (6), pp. 2320-2332
  • Van Der Laan, S., Meijer, O.C., Pharmacology of glucocorticoids: Beyond receptors (2008) Eur J Pharmacol, 585 (2-3), pp. 483-491
  • Viegas, L.R., Hoijman, E., Beato, M., Pecci, A., Mechanisms involved in tissue-specific apopotosis regulated by glucocorticoids (2008) J Steroid Biochem Mol Biol, 109 (3-5), pp. 273-278
  • Patel, F.A., Funder, J.W., Challis, J.R., Mechanism of cortisol/progesterone antagonism in the regulation of 15-hydroxyprostaglandin dehydrogenase activity and messenger ribonucleic acid levels in human chorion and placental trophoblast cells at term (2003) J Clin Endocrinol Metab, 88 (6), pp. 2922-2933
  • Xiao, D., Huang, X., Yang, S., Zhang, L., Direct chronic effect of steroid hormones in attenuating uterine arterial myogenic tone: Role of protein kinase c/extracellular signal-regulated kinase 1/2 (2009) Hypertension, 54 (2), pp. 352-358
  • Spallanzani, R.G., Dalotto-Moreno, T., Raffo Iraolagoitia, X.L., Ziblat, A., Domaica, C.I., Avila, D.E., Rossi, L.E., Zwirner, N.W., Expansion of CD11b(+)Ly6G (+)Ly6C (int) cells driven by medroxyprogesterone acetate in mice bearing breast tumors restrains NK cell effector functions (2013) Cancer Immunol Immunother, 62 (12), pp. 1781-1795
  • Orqueda, A.J., Dansey, M.V., Espanol, A., Veleiro, A.S., Bal De Kier Joffe, E., Sales, M.E., Burton, G., Pecci, A., The rigid steroid 21-hydroxy-6,19-epoxyprogesterone (21OH-6,19OP) is a dissociated glucocorticoid receptor modulator potentially useful as a novel coadjuvant in breast cancer chemotherapy (2014) Biochem Pharmacol, 89 (4), pp. 526-535
  • Jantzen, H.M., Strahle, U., Gloss, B., Stewart, F., Schmid, W., Boshart, M., Miksicek, R., Schutz, G., Cooperativity of glucocorticoid response elements located far upstream of the tyrosine aminotransferase gene (1987) Cell, 49 (1), pp. 29-38
  • Amsterdam, A., Tajima, K., Sasson, R., Cell-specific regulation of apoptosis by glucocorticoids: Implication to their antiinflammatory action (2002) Biochem Pharmacol, 64 (5-6), pp. 843-850
  • Schorr, K., Furth, P.A., Induction of bcl-xL expression in mammary epithelial cells is glucocorticoid-dependent but not signal transducer and activator of transcription 5-dependent (2000) Cancer Res, 60 (21), pp. 5950-5953
  • Berg, M.N., Dharmarajan, A.M., Waddell, B.J., Glucocorticoids and progesterone prevent apoptosis in the lactating rat mammary gland (2002) Endocrinology, 143 (1), pp. 222-227
  • Pecci, A., Scholz, A., Pelster, D., Beato, M., Progestins prevent apoptosis in a rat endometrial cell line and increase the ratio of bcl-XL to bcl-XS (1997) J Biol Chem, 272 (18), pp. 11791-11798
  • Hillier, S.G., Tetsuka, M., An anti-inflammatory role for glucocorticoids in the ovaries? (1998) J Reprod Immunol, 39 (1-2), pp. 21-27
  • Yamamoto, M., Fukuda, K., Miura, N., Suzuki, R., Kido, T., Komatsu, Y., Inhibition by dexamethasone of transforming growth factor beta1-induced apoptosis in rat hepatoma cells: A possible association with Bcl-xL induction (1998) Hepatology, 27 (4), pp. 959-966
  • Gascoyne, D.M., Kypta, R.M., Vivanco, M.M., Glucocorticoids inhibit apoptosis during fibrosarcoma development by transcriptionally activating Bcl-xL (2003) J Biol Chem, 278 (20), pp. 18022-18029
  • Viegas, L.R., Vicent, G.P., Baranao, J.L., Beato, M., Pecci, A., Steroid hormones induce bcl-X gene expression through direct activation of distal promoter P4 (2004) J Biol Chem, 279 (11), pp. 9831-9839
  • Vicent, G.P., Pecci, A., Ghini, A., Piwien-Pilipuk, G., Galigniana, M.D., Differences in nuclear retention characteristics of agonist-activated glucocorticoid receptor may determine specific responses (2002) Exp Cell Res, 276 (2), pp. 142-154
  • Delfino, D.V., Agostini, M., Spinicelli, S., Vito, P., Riccardi, C., Decrease of Bcl-xL and augmentation of thymocyte apoptosis in GILZ overexpressing transgenic mice (2004) Blood, 104 (13), pp. 4134-4141
  • Abraham, S.M., Lawrence, T., Kleiman, A., Warden, P., Medghalchi, M., Tuckermann, J., Saklatvala, J., Clark, A.R., Antiinflammatory effects of dexamethasone are partly dependent on induction of dual specificity phosphatase 1 (2006) J Exp Med, 203 (8), pp. 1883-1889
  • Ayroldi, E., Riccardi, C., Glucocorticoid-induced leucine zipper (GILZ): A new important mediator of glucocorticoid action (2009) FASEB J, 23 (11), pp. 3649-3658
  • Smoak, K., Cidlowski, J.A., Glucocorticoids regulate tristetraprolin synthesis and posttranscriptionally regulate tumor necrosis factor alpha inflammatory signaling (2006) Mol Cell Biol, 26 (23), pp. 9126-9135
  • Chivers, J.E., Gong, W., King, E.M., Seybold, J., Mak, J.C., Donnelly, L.E., Holden, N.S., Newton, R., Analysis of the dissociated steroid RU24858 does not exclude a role for inducible genes in the anti-inflammatory actions of glucocorticoids (2006) Mol Pharmacol, 70 (6), pp. 2084-2095
  • Korhonen, R., Lahti, A., Hamalainen, M., Kankaanranta, H., Moilanen, E., Dexamethasone inhibits inducible nitric-oxide synthase expression and nitric oxide production by destabilizing mRNA in lipopolysaccharide-treated macrophages (2002) Mol Pharmacol, 62 (3), pp. 698-704
  • Zhang, J.Z., Cavet, M.E., Vandermeid, K.R., Salvador-Silva, M., Lopez, F.J., Ward, K.W., BOL-303242-X, a novel selective glucocorticoid receptor agonist, with full anti-inflammatory properties in human ocular cells (2009) Mol Vis, 15, pp. 2606-2616
  • Cluning, C., Ward, B.K., Rea, S.L., Arulpragasam, A., Fuller, P.J., Ratajczak, T., The helix 1-3 loop in the glucocorticoid receptor LBD is a regulatory element for FKBP cochaperones (2013) Mol Endocrinol, 27 (7), pp. 1020-1035
  • Rogatsky, I., Zarember, K.A., Yamamoto, K.R., Factor recruitment and TIF2/GRIP1 corepressor activity at a collagenase-3 response element that mediates regulation by phorbol esters and hormones (2001) EMBO J, 20 (21), pp. 6071-6083
  • Reily, M.M., Pantoja, C., Hu, X., Chinenov, Y., Rogatsky, I., The GRIP1:IRF3 interaction as a target for glucocorticoid receptormediated immunosuppression (2006) EMBO J, 25 (1), pp. 108-117
  • Simons, S.S., Jr., Edwards, D.P., Kumar, R., Minireview: Dynamic structures of nuclear hormone receptors: New promises and challenges (2014) Mol Endocrinol, 28 (2), pp. 173-182


---------- APA ----------
Pecci, A., Alvarez, L.D., Presman, D.M. & Burton, G. (2016) . 21-hydroxy-6,19-epoxyprogesterone: A promising therapeutic agent and a molecular tool for deciphering glucocorticoid action. Mini-Reviews in Medicinal Chemistry, 16.
---------- CHICAGO ----------
Pecci, A., Alvarez, L.D., Presman, D.M., Burton, G. "21-hydroxy-6,19-epoxyprogesterone: A promising therapeutic agent and a molecular tool for deciphering glucocorticoid action" . Mini-Reviews in Medicinal Chemistry 16 (2016).
---------- MLA ----------
Pecci, A., Alvarez, L.D., Presman, D.M., Burton, G. "21-hydroxy-6,19-epoxyprogesterone: A promising therapeutic agent and a molecular tool for deciphering glucocorticoid action" . Mini-Reviews in Medicinal Chemistry, vol. 16, 2016.
---------- VANCOUVER ----------
Pecci, A., Alvarez, L.D., Presman, D.M., Burton, G. 21-hydroxy-6,19-epoxyprogesterone: A promising therapeutic agent and a molecular tool for deciphering glucocorticoid action. Mini-Rev. Med. Chem. 2016;16.