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

Javier Angulo,Begoña Cuevas,Mohammad El Youssef,Eduardo Martínez-Salamanca,Rocío González-Corrochano,Argentina Fernández,Pedro Cuevas,Guillermo Giménez-Gallego

doi:10.1186/s12967-015-0413-4

Abstract

BackgroundDobesilate (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).MethodsAnti-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.ResultsTopical 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.ConclusionsBy 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.

Highlights

Prostaglandins (PGs) are local mediators of inflammation, the synthesis of which is controlled by cyclooxygenases (COXs)
diacetoxyphenyl sulfonate (DAPS) is more effective than dihydroxyphenyl sulfonate (DHPS) in inhibiting dermatitis-induced inflammation The dermatitis induced in rat ears by 5% benzalkonium chloride (BZK) was associated with an increase in vascular permeability, evident through the extravasation of Evans blue dye that stains the ears in blue (Figure 1C-D, left ears)
Dermatomyositis was observed in the erector muscle of the ear after BZK-induced dermatitis (Figure 2I) and likewise, it was prevented by DAPS administration (Figure 2J)

Summary

Introduction

Prostaglandins (PGs) are local mediators of inflammation, the synthesis of which is controlled by cyclooxygenases (COXs). Non-steroidal anti-inflammatory drugs (NSAIDs), such as acetylsalicylic acid (ASA; aspirin), achieve their anti-inflammatory effects, at least in part, by inhibiting prostaglandin production [2]. COXs have been widely implicated in tumorigenesis, a process to which they contribute by upregulating the expression of pro-angiogenic cytokines, vascular endothelial cell growth factor (VEGF) and fibroblast growth factor (FGF) [4,5,6,7], making them responsible for the pathological neovascularization of tumors. VEGF and FGF can induce the expression of COX-2 and phospholipase A2, as well as the ensuing production of PG in endothelial cells, creating a positive feedback loop typical of chronic diseases [8,9]. 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)

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