title: Diacetyloxyl derivatization of the fibroblast growth factor inhibitor dobesilate enhances its anti-inflammatory, anti-angiogenic and anti-tumoral activities.
abstract: BACKGROUND
  Dobesilate (2,5-dihydroxyphenyl sulfonate, DHPS) was recently identified as the most potent member of a family of fibroblast growth factor (FGF) inhibitors headed by gentisic acid, one of the main catabolites of aspirin. Although FGFs were first described as inducers of angiogenesis, they were soon recognized as broad spectrum mitogens. Furthermore, in the last decade these proteins have been shown to participate directly in the onset of inflammation, and their potential angiogenic activity often contributes to the inflammatory process in vivo. The aim of this work was to evaluate the anti-inflammatory, anti-angiogenic and anti-tumoral activities of the derivative of DHPS obtained by acetoxylation of its two hydroxyl groups (2,5-diacetoxyphenyl sulfonate; DAPS).
  
  
  METHODS
  Anti-inflammatory, anti-angiogenic and anti-tumoral activities of DHPS and DAPS were compared using in vivo assays of dermatitis, angiogenesis and tumorigenesis. The effects of both compounds on myeloperoxidase (MPO) and cyclooxygenase (COX) activities, cytokine production and FGF-induced fibroblast proliferation were also determined.
  
  
  RESULTS
  Topical DAPS is more effective than DHPS in preventing inflammatory signs (increased vascular permeability, edema, leukocyte infiltration, MPO activation) caused by contact dermatitis induction in rat ears. DAPS, but not DHPS, effectively inhibits COX-1 and COX-2 activities. DAPS also reduces the increase in serum cytokine concentration induced by lipopolysaccharide in rats. Furthermore, DAPS displays higher in vivo efficacy than DHPS in inhibiting FGF-induced angiogenesis and heterotopic glioma progression, with demonstrated oral efficacy to combat both processes.
  
  
  CONCLUSIONS
  By inhibiting both FGF-signaling and COX-mediated prostaglandin synthesis, DAPS efficiently breaks the vicious circle created by the reciprocal induction of FGF and prostaglandins, which probably sustains undesirable inflammation in many circumstances. Our findings define the enhancement of anti-inflammatory, anti-angiogenic and anti-tumoral activities by diacetyloxyl derivatization of the FGF inhibitor, dobesilate.
authors: Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Hospital Universitario Ramón y Cajal, Madrid, Spain. javier.angulo@hrc.es.
authors: Javier
authors: J
authors: Angulo
authors: Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Hospital Universitario Ramón y Cajal, Madrid, Spain. pedro.cuevas44@gmail.com.
authors: Pedro
authors: P
authors: Cuevas
authors: Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Hospital Universitario Ramón y Cajal, Madrid, Spain. begona.cuevas@hrc.es.
authors: Begoña
authors: B
authors: Cuevas
authors: Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Hospital Universitario Ramón y Cajal, Madrid, Spain. mrachidy@sympatico.ca.
authors: Mohammad
authors: M
authors: El Youssef
authors: Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Hospital Universitario Ramón y Cajal, Madrid, Spain. argentina.fernandez@hrc.es.
authors: Argentina
authors: A
authors: Fernández
authors: Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Hospital Universitario Ramón y Cajal, Madrid, Spain. edumartinez86@yahoo.es.
authors: Eduardo
authors: E
authors: Martínez-Salamanca
authors: Departamento de Estructura y Función de Proteínas, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Avda Ramiro de Maeztu 9, ES-28040, Madrid, Spain. rocio_gonzalezcorrochano@yahoo.es.
authors: Rocío
authors: R
authors: González-Corrochano
authors: Departamento de Estructura y Función de Proteínas, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Avda Ramiro de Maeztu 9, ES-28040, Madrid, Spain. gimenez_gallego@cib.csic.es.
authors: Guillermo
authors: G
authors: Giménez-Gallego
mesh_terms: D000107:Acetylation; D000284:Administration, Oral; D000287:Administration, Topical; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003872:Dermatitis / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007249:Inflammation / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008297:Male; D008934:Mitogens / Q000494:pharmacology; D017207:Rats, Sprague-Dawley
chemical_list: C571011:2,5-dihydroxyphenylsulfonate; D020533:Angiogenesis Inhibitors; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D016207:Cytokines; D018836:Inflammation Mediators; D008934:Mitogens; C557994:potassium dobesilate; D005346:Fibroblast Growth Factors; D051546:Cyclooxygenase 2
references: Cell. 1991 Feb 22;64(4):841-8
references: 1847668
references: J Pharm Pharmacol. 2009 Nov;61(11):1505-10
references: 19903376
references: J Biol Chem. 2011 Dec 2;286(48):41230-45
references: 21990352
references: Science. 1991 Jun 21;252(5013):1705-8
references: 1646484
references: Am J Ther. 2004 Mar-Apr;11(2):141-3
references: 14999366
references: J Biol Chem. 2010 Apr 9;285(15):11714-29
references: 20145243
references: Mediators Inflamm. 2012;2012:382082
references: 22577248
references: J Cell Biochem. 1991 Feb;45(2):167-76
references: 1711529
references: J Cell Mol Med. 2008 Apr;12(2):459-70
references: 18182066
references: Matrix Biol. 2014 Apr;35:174-81
references: 24398134
references: Proc Natl Acad Sci U S A. 1975 Aug;72(8):3073-6
references: 810797
references: J Cell Mol Med. 2009 Aug;13(8B):2083-108
references: 18624773
references: BMJ Case Rep. 2011;2011. pii: bcr0620114351. doi: 10.1136/bcr.06.2011.4351
references: 22688482
references: Cell. 2010 Mar 19;140(6):883-99
references: 20303878
references: Turk Neurosurg. 2011 Jan;21(1):27-35
references: 21294088
references: Anticancer Res. 2013 Oct;33(10):4463-8
references: 24123016
references: Genes Dev. 2007 Nov 1;21(21):2683-710
references: 17974913
references: BMJ Case Rep. 2012;2012. pii: bcr0220125942. doi: 10.1136/bcr.02.2012.5942
references: 22729337
references: FASEB J. 1998 Sep;12(12):1063-73
references: 9737710
references: Int J Oncol. 2013 Oct;43(4):1073-9
references: 23900502
references: Cancer Control. 2004 May-Jun;11(3):152-64
references: 15153839
references: Biomed Pharmacother. 2005 Oct;59 Suppl 2:S289-92
references: 16507395
references: Transplantation. 1995 Apr 15;59(7):1005-10
references: 7535956
references: J Cell Sci. 1997 Sep;110 ( Pt 18):2293-302
references: 9378778
references: Eur J Med Res. 2005 Sep 12;10(9):369-72
references: 16183547
references: J Immunol. 1999 May 15;162(10):5853-9
references: 10229820
references: Adv Exp Med Biol. 2014;816:75-105
references: 24818720
references: Am J Gastroenterol. 2001 Mar;96(3):822-8
references: 11280558
references: Sci Transl Med. 2014 Jun 25;6(242):242ra84
references: 24964992
references: Med Hypotheses. 2011 Nov;77(5):726-33
references: 21862232
references: Annu Rev Med. 2007;58:239-52
references: 17100552
references: J Biol Chem. 2003 Jun 13;278(24):21774-81
references: 12676958
references: Neurosci Lett. 2011 Mar 10;491(1):1-7
references: 21193016
references: J Med Chem. 1998 Nov 19;41(24):4800-18
references: 9822550
references: Lancet. 2009 Apr 18;373(9672):1364-71
references: 19376452
references: J Dermatolog Treat. 2011 Dec;22(6):348-52
references: 21756148
references: Front Oncol. 2014 Jul 02;4:131
references: 25072019
references: PLoS Biol. 2012 Jul;10(7):e1001361
references: 22815649
references: Allergy Asthma Clin Immunol. 2010 Sep 05;6(1):25
references: 20815913
references: Nature. 2012 Jan 19;481(7381):278-86
references: 22258606
references: J Cell Mol Med. 2006 Jan-Mar;10(1):225-30
references: 16563234
references: Thromb Res. 2003 Jun 15;110(5-6):255-8
references: 14592543
references: N Engl J Med. 2005 Mar 10;352(10):987-96
references: 15758009
references: Kidney Int. 2005 Dec;68(6):2621-8
references: 16316338
references: J Cell Biochem. 2011 Dec;112(12):3594-603
references: 21809372
references: Oncol Lett. 2014 Oct;8(4):1628-1634
references: 25202381
references: J Cell Mol Med. 2003 Jul-Sep;7(3):207-22
references: 14594546
references: J Cell Mol Med. 2011 Sep;15(9):1857-64
references: 21029368
references: Drug Saf. 2004;27(9):649-60
references: 15230646
references: PLoS One. 2014;9(7):e103432
references: 25054228
references: Eur Cytokine Netw. 2009 Jun;20(2):39-50
references: 19541589
references: Graefes Arch Clin Exp Ophthalmol. 2006 Dec;244(12):1591-600
references: 16763797
references: Anticancer Res. 2010 Apr;30(4):1209-15
references: 20530430
references: J Pharmacol Exp Ther. 2004 May;309(2):607-15
references: 14762098
references: J Transl Med. 2008;6:57
references: 18844982
references: J Cell Biol. 1990 Apr;110(4):1417-26
references: 1691192
references: Eur J Pharmacol. 2011 Sep 30;667(1-3):153-9
references: 21703259
references: FASEB J. 2004 Feb;18(2):300-10
references: 14769824
references: Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11996-2001
references: 8876251
references: BMJ Case Rep. 2012;2012. pii: bcr2012007128. doi: 10.1136/bcr-2012-007128
references: 23076703
references: Vascul Pharmacol. 2012 Aug 19;57(1):3-9
references: 22361334
references: J Transl Med. 2011;9:142
references: 21867538
references: Mol Carcinog. 2007 Dec;46(12):971-80
references: 17477358
references: Mol Pharmacol. 2003 Feb;63(2):450-5
references: 12527817
references: Neurol Res. 1994 Aug;16(4):313-6
references: 7527128
references: Eur J Med Res. 2005 Sep 12;10(9):373-6
references: 16183548
references: Nature. 2008 Jul 24;454(7203):436-44
references: 18650914
references: Prostaglandins Other Lipid Mediat. 2013 Oct;106:99-105
references: 23624019
references: Int J Cell Biol. 2012;2012:723419
references: 22505934