Download PDF
CC BY 4.0 · TH Open 2019; 03(03): e230-e243
DOI: 10.1055/s-0039-1693710
Original Article
Georg Thieme Verlag KG Stuttgart · New York

Topically Applied Etamsylate: A New Orphan Drug for HHT-Derived Epistaxis (Antiangiogenesis through FGF Pathway Inhibition)

Virginia Albiñana
1   Molecular Biomedicine Department, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain
2   Centro de Investigación Biomédica en Red, CIBERER, Instituto de Salud Carlos III, Madrid, Spain
,
Guillermo Giménez-Gallego
1   Molecular Biomedicine Department, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain
,
Angela García-Mato
1   Molecular Biomedicine Department, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain
,
Patricia Palacios
1   Molecular Biomedicine Department, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain
,
Lucia Recio-Poveda
1   Molecular Biomedicine Department, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain
,
Angel-M Cuesta
1   Molecular Biomedicine Department, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain
2   Centro de Investigación Biomédica en Red, CIBERER, Instituto de Salud Carlos III, Madrid, Spain
,
José-Luis Patier
3   Department of Internal Medicine, University Hospital Ramón y Cajal; Department of Medicine and Medical Specialities, Faculty of Medicine, University of Alcalá, IRYCIS, Madrid, Spain
,
Luisa-María Botella
1   Molecular Biomedicine Department, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain
2   Centro de Investigación Biomédica en Red, CIBERER, Instituto de Salud Carlos III, Madrid, Spain
› Author Affiliations Funding The present work was funded by public projects of the Spanish Ministry of Economy and Competitiveness: MINECO SAF 2014 52374 R and SAF2017–83351 to L.M. Botella as the main researcher; PIE-201820E073 CSIC to Lucia Recio, CIBER Rare Diseases ISCIII, Madrid, Spain, funded Virginia Albiñana, and the Spanish HHT association acted as a sponsor of the clinical trial.
Further Information

Publication History

07 February 2019

13 June 2019

Publication Date:
26 July 2019 (online)

Also available at
   Permissions and Reprints

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia characterized by recurrent and spontaneous epistaxis (nose bleeds), telangiectases on skin and mucosa, internal organ arteriovenous malformations, and dominant autosomal inheritance. Mutations in Endoglin and ACVRL1/ALK1, genes mainly expressed in endothelium, are responsible in 90% of the cases for the pathology. These genes are involved in the transforming growth factor-β(TGF-β) signaling pathway. Epistaxis remains as one of the most common symptoms impairing the quality of life of patients, becoming life-threatening in some cases. Different strategies have been used to decrease nose bleeds, among them is antiangiogenesis. The two main angiogenic pathways in endothelial cells depend on vascular endothelial growth factor and fibroblast growth factor (FGF). The present work has used etamsylate, the diethylamine salt of the 2,5-dihydroxybenzene sulfonate anion, also known as dobesilate, as a FGF signaling inhibitor. In endothelial cells, in vitro experiments show that etamsylate acts as an antiangiogenic factor, inhibiting wound healing and matrigel tubulogenesis. Moreover, etamsylate decreases phosphorylation of Akt and ERK1/2. A pilot clinical trial (EudraCT: 2016–003982–24) was performed with 12 HHT patients using a topical spray of etamsylate twice a day for 4 weeks. The epistaxis severity score (HHT-ESS) and other pertinent parameters were registered in the clinical trial. The significant reduction in the ESS scale, together with the lack of significant side effects, allowed the designation of topical etamsylate as a new orphan drug for epistaxis in HHT (EMA/OD/135/18).

Keywords

HHT - Endoglin - Alk1 - antiangiogenesis - etamsylate - epistaxis - FGF pathway - TGF-β signaling pathway
 

  • References

  • 1 Abdalla SA, Letarte M. Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease. J Med Genet 2006; 43 (02) 97-110
    PubMedSearch in Google Scholar
  • 2 Govani FS, Shovlin CL. Hereditary haemorrhagic telangiectasia: a clinical and scientific review. Eur J Hum Genet 2009; 17 (07) 860-871
    CrossrefPubMedSearch in Google Scholar
  • 3 Shovlin CL. Hereditary haemorrhagic telangiectasia: pathophysiology, diagnosis and treatment. Blood Rev 2010; 24 (06) 203-219
    CrossrefPubMedSearch in Google Scholar
  • 4 Shovlin CL, Buscarini E, Kjeldsen AD. , et al. European Reference Network for Rare Vascular Diseases (VASCERN) outcome measures for hereditary haemorrhagic telangiectasia (HHT). Orphanet J Rare Dis 2018; 13 (01) 136-140
    CrossrefPubMedSearch in Google Scholar
  • 5 Shovlin CL, Guttmacher AE, Buscarini E. , et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet 2000; 91 (01) 66-67
    CrossrefPubMedSearch in Google Scholar
  • 6 Plauchu H, de Chadarévian JP, Bideau A, Robert JM. Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population. Am J Med Genet 1989; 32 (03) 291-297
    CrossrefPubMedSearch in Google Scholar
  • 7 McAllister KA, Grogg KM, Johnson DW. , et al. Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet 1994; 8 (04) 345-351
    CrossrefPubMedSearch in Google Scholar
  • 8 Johnson DW, Berg JN, Baldwin MA. , et al. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet 1996; 13 (02) 189-195
    CrossrefPubMedSearch in Google Scholar
  • 9 Cole SG, Begbie ME, Wallace GM, Shovlin CL. A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5. J Med Genet 2005; 42 (07) 577-582
    CrossrefPubMedSearch in Google Scholar
  • 10 Bayrak-Toydemir P, McDonald J, Akarsu N. , et al. A fourth locus for hereditary hemorrhagic telangiectasia maps to chromosome 7. Am J Med Genet A 2006; 140 (20) 2155-2162
    PubMedSearch in Google Scholar
  • 11 Wooderchak-Donahue WL, McDonald J, O'Fallon B. , et al. BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia. Am J Hum Genet 2013; 93 (03) 530-537
    CrossrefPubMedSearch in Google Scholar
  • 12 Albiñana V, Recio-Poveda L, Zarrabeitia R, Botella LM. Current and emerging pharmacotherapies for hereditary hemorrhagic telangiectasia. Expert Opin Orphan Drugs 2017; 5: 665-675
    PubMedSearch in Google Scholar
  • 13 Albiñana V, Bernabeu-Herrero ME, Zarrabeitia R, Bernabéu C, Botella LM. Estrogen therapy for hereditary haemorrhagic telangiectasia (HHT): effects of raloxifene, on Endoglin and ALK1 expression in endothelial cells. Thromb Haemost 2010; 103 (03) 525-534
    PubMedSearch in Google Scholar
  • 14 Albiñana V, Sanz-Rodríguez F, Recio-Poveda L, Bernabéu C, Botella LM. Immunosuppressor FK506 increases endoglin and activin receptor-like kinase 1 expression and modulates transforming growth factor-β1 signaling in endothelial cells. Mol Pharmacol 2011; 79 (05) 833-843
    CrossrefPubMedSearch in Google Scholar
  • 15 Zarrabeitia R, Ojeda-Fernandez L, Recio L. , et al. Bazedoxifene, a new orphan drug for the treatment of bleeding in hereditary haemorrhagic telangiectasia. Thromb Haemost 2016; 115 (06) 1167-1177
    Thieme ConnectPubMedSearch in Google Scholar
  • 16 Albiñana V, Recio-Poveda L, Zarrabeitia R, Bernabéu C, Botella LM. Propranolol as antiangiogenic candidate for the therapy of hereditary haemorrhagic telangiectasia. Thromb Haemost 2012; 108 (01) 41-53
    Thieme ConnectPubMedSearch in Google Scholar
  • 17 Fernández IS, Cuevas P, Angulo J. , et al. Gentisic acid, a compound associated with plant defense and a metabolite of aspirin, heads a new class of in vivo fibroblast growth factor inhibitors. J Biol Chem 2010; 285 (15) 11714-11729
    CrossrefPubMedSearch in Google Scholar
  • 18 Olsen SK, Garbi M, Zampieri N. , et al. Fibroblast growth factor (FGF) homologous factors share structural but not functional homology with FGFs. J Biol Chem 2003; 278 (36) 34226-34236
    CrossrefPubMedSearch in Google Scholar
  • 19 Itoh N, Ornitz DM. Evolution of the Fgf and Fgfr gene families. Trends Genet 2004; 20 (11) 563-569
    CrossrefPubMedSearch in Google Scholar
  • 20 Baird A, Bohlen P. Peptide growth factors and their receptors. In: Sporn MB, Roberts AB. , eds. Handbook of Experimental Pharmacology. Berlin: Springer-Verlag; 1990. 95: 369-418
    Search in Google Scholar
  • 21 Giménez-Gallego G, Cuevas P. Fibroblast growth factors, proteins with a broad spectrum of biological activities. Neurol Res 1994; 16 (04) 313-316
    CrossrefPubMedSearch in Google Scholar
  • 22 Cuevas P, García-Calvo M, Carceller F. , et al. Correction of hypertension by normalization of endothelial levels of fibroblast growth factor and nitric oxide synthase in spontaneously hypertensive rats. Proc Natl Acad Sci U S A 1996; 93 (21) 11996-12001
    CrossrefPubMedSearch in Google Scholar
  • 23 Cuevas P, Reimers D, Carceller F, Xiaobing F, Gimenez-Gallego G. Second messengers and protein phosphorylation in health and disease. In: Martín Municio A, Miras-Portugal MT. , eds. Cell Signal Transduction. New York, NY: Plenum Press; 1996: 161-167
    Search in Google Scholar
  • 24 Abuharbeid S, Czubayko F, Aigner A. The fibroblast growth factor-binding protein FGF-BP. Int J Biochem Cell Biol 2006; 38 (09) 1463-1468
    CrossrefPubMedSearch in Google Scholar
  • 25 Finetti F, Solito R, Morbidelli L, Giachetti A, Ziche M, Donnini S. Prostaglandin E2 regulates angiogenesis via activation of fibroblast growth factor receptor-1. J Biol Chem 2008; 283 (04) 2139-2146
    CrossrefPubMedSearch in Google Scholar
  • 26 Jackson A, Friedman S, Zhan X, Engleka KA, Forough R, Maciag T. Heat shock induces the release of fibroblast growth factor 1 from NIH 3T3 cells. Proc Natl Acad Sci U S A 1992; 89 (22) 10691-10695
    CrossrefPubMedSearch in Google Scholar
  • 27 Shin JT, Opalenik SR, Wehby JN. , et al. Serum-starvation induces the extracellular appearance of FGF-1. Biochim Biophys Acta 1996; 1312 (01) 27-38
    CrossrefPubMedSearch in Google Scholar
  • 28 Matsunaga H, Ueda H. Voltage-dependent N-type Ca2+ channel activity regulates the interaction between FGF-1 and S100A13 for stress-induced non-vesicular release. Cell Mol Neurobiol 2006; 26 (03) 237-246
    CrossrefPubMedSearch in Google Scholar
  • 29 Thomas KA, Rios-Candelore M, Giménez-Gallego G. , et al. Pure brain-derived acidic fibroblast growth factor is a potent angiogenic vascular endothelial cell mitogen with sequence homology to interleukin 1. Proc Natl Acad Sci U S A 1985; 82 (19) 6409-6413
    CrossrefPubMedSearch in Google Scholar
  • 30 Esch F, Baird A, Ling N. , et al. Primary structure of bovine pituitary basic fibroblast growth factor (FGF) and comparison with the amino-terminal sequence of bovine brain acidic FGF. Proc Natl Acad Sci U S A 1985; 82 (19) 6507-6511
    CrossrefPubMedSearch in Google Scholar
  • 31 Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100 (01) 57-70
    CrossrefPubMedSearch in Google Scholar
  • 32 Jonca F, Ortéga N, Gleizes PE, Bertrand N, Plouët J. Cell release of bioactive fibroblast growth factor 2 by exon 6-encoded sequence of vascular endothelial growth factor. J Biol Chem 1997; 272 (39) 24203-24209
    CrossrefPubMedSearch in Google Scholar
  • 33 Pàez-Ribes M, Allen E, Hudock J. , et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 2009; 15 (03) 220-231
    CrossrefPubMedSearch in Google Scholar
  • 34 Loges S, Mazzone M, Hohensinner P, Carmeliet P. Silencing or fueling metastasis with VEGF inhibitors: antiangiogenesis revisited. Cancer Cell 2009; 15 (03) 167-170
    CrossrefPubMedSearch in Google Scholar
  • 35 Fernández-Tornero C, Lozano RM, Redondo-Horcajo M. , et al. Leads for development of new naphthalenesulfonate derivatives with enhanced antiangiogenic activity: crystal structure of acidic fibroblast growth factor in complex with 5-amino-2-naphthalene sulfonate. J Biol Chem 2003; 278 (24) 21774-21781
    CrossrefPubMedSearch in Google Scholar
  • 36 Andrés G, Leali D, Mitola S. , et al. A pro-inflammatory signature mediates FGF2-induced angiogenesis. J Cell Mol Med 2009; 13 (8B): 2083-2108
    CrossrefPubMedSearch in Google Scholar
  • 37 Cha YI, DuBois RN. NSAIDs and cancer prevention: targets downstream of COX-2. Annu Rev Med 2007; 58: 239-252
    CrossrefPubMedSearch in Google Scholar
  • 38 Haritoglou C, Gerss J, Sauerland C, Kampik A, Ulbig MW. ; CALDIRET study group. Effect of calcium dobesilate on occurrence of diabetic macular oedema (CALDIRET study): randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2009; 373 (9672): 1364-1371
    CrossrefPubMedSearch in Google Scholar
  • 39 Zhang X, Liu W, Wu S, Jin J, Li W, Wang N. Calcium dobesilate for diabetic retinopathy: a systematic review and meta-analysis. Sci China Life Sci 2015; 58 (01) 101-107
    CrossrefPubMedSearch in Google Scholar
  • 40 Angulo J, Peiró C, Romacho T. , et al. Inhibition of vascular endothelial growth factor (VEGF)-induced endothelial proliferation, arterial relaxation, vascular permeability and angiogenesis by dobesilate. Eur J Pharmacol 2011; 667 (1–3): 153-159
    CrossrefPubMedSearch in Google Scholar
  • 41 Cuevas P, Díaz-González D, García-Martín-Córdova C. , et al. Dobesilate diminishes activation of the mitogen-activated protein kinase ERK1/2 in glioma cells. J Cell Mol Med 2006; 10 (01) 225-230
    CrossrefPubMedSearch in Google Scholar
  • 42 Cuevas P, Carceller F, Angulo J, González-Corrochano R, Cuevas-Bourdier A, Giménez-Gallego G. Antiglioma effects of a new, low molecular mass, inhibitor of fibroblast growth factor. Neurosci Lett 2011; 491 (01) 1-7
    CrossrefPubMedSearch in Google Scholar
  • 43 Fernandez-L A, Sanz-Rodriguez F, Zarrabeitia R. , et al. Blood outgrowth endothelial cells from hereditary haemorrhagic Telangiectasia patients reveal abnormalities compatible with vascular lesions. Cardiovasc Res 2005; 68 (02) 235-248
    CrossrefPubMedSearch in Google Scholar
  • 44 Fernandez-L A, Garrido-Martin EM, Sanz-Rodriguez F. , et al. Gene expression fingerprinting for human hereditary hemorrhagic telangiectasia. Hum Mol Genet 2007; 16 (13) 1515-1533
    CrossrefPubMedSearch in Google Scholar
  • 45 Hoag JB, Terry P, Mitchell S, Reh D, Merlo CA. An epistaxis severity score for hereditary hemorrhagic telangiectasia. Laryngoscope 2010; 120 (04) 838-843
    CrossrefPubMedSearch in Google Scholar
  • 46 Somanath PR, Razorenova OV, Chen J, Byzova TV. Akt1 in endothelial cell and angiogenesis. Cell Cycle 2006; 5 (05) 512-518
    CrossrefPubMedSearch in Google Scholar
  • 47 Hata Y, Rook SL, Aiello LP. Basic fibroblast growth factor induces expression of VEGF receptor KDR through a protein kinase C and p44/p42 mitogen-activated protein kinase-dependent pathway. Diabetes 1999; 48 (05) 1145-1155
    CrossrefPubMedSearch in Google Scholar
  • 48 Murakami M, Nguyen LT, Hatanaka K. , et al. FGF-dependent regulation of VEGF receptor 2 expression in mice. J Clin Invest 2011; 121 (07) 2668-2678
    CrossrefPubMedSearch in Google Scholar
  • 49 Shovlin CL, Sulaiman NL, Govani FS, Jackson JE, Begbie ME. Elevated factor VIII in hereditary haemorrhagic telangiectasia (HHT): association with venous thromboembolism. Thromb Haemost 2007; 98 (05) 1031-1039
    Thieme ConnectPubMedSearch in Google Scholar