Diacetyloxyl derivatization of the fibroblast growth factor inhibitor dobesilate enhances its anti-inflammatory, anti-angiogenic and anti-tumoral activities

Journal of Translational Medicine

Guillermo Giménez-Gallego¹  Rocío González-Corrochano¹  Eduardo Martínez-Salamanca²  Argentina Fernández²  Mohammad El Youssef²  Begoña Cuevas²  Pedro Cuevas²  Javier Angulo² 

[1] Departamento de Estructura y Función de Proteínas, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Avda Ramiro de Maeztu 9, Madrid, ES-28040, Spain;Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Hospital Universitario Ramón y Cajal, Madrid, Spain

关键词: Inflammation;    Fibroblast growth factor;    Dobesilate;    Cyclooxygenase;    Cancer;    Angiogenesis;   

Others  :  1137649
DOI  :  10.1186/s12967-015-0413-4

 received in 2014-11-05, accepted in 2015-01-20,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Angulo et al.; licensee BioMed Central.

【 图 表 】

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