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

Angulo J, Cuevas P, Cuevas B, El Youssef M, Fernández A, Martínez-Salamanca E, González-Corrochano R, Giménez-Gallego G - J Transl Med (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Hospital Universitario Ramón y Cajal, Madrid, Spain. javier.angulo@hrc.es.

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.

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Related in: MedlinePlus

Chemical structures of potassium 2,5-dihydroxyphenyl sulfonate (DHPS: A) and potassium 2,5-diacetoxyphenyl sulfonate (DAPS: B). Panels C and D show representative images illustrating the effects of DHPS (C) and DAPS (D) on dermatitis of rat ears induced by the application of benzalkonium chloride. After induction of dermatitis in both ears, the right ear was treated topically with DHPS (5% w/v; eq. to 0.22 mmol/ml) or DAPS (5% w/v; eq. to 0.16 mmol/ml), and the left ear with the vehicle alone (glycerol). The extent of dermatitis (vascular hyperpermeability) was revealed by intravenous injection of Evans blue dye. In panel E the inhibitory effects of DHPS (5%; eq. to 0.22 mmol/ml) and DAPS (2.5% and 5%; eq. to 0.08 and 0.16 mmol/ml) on dermatitis are quantified, expressing the data as the mean ± SEM of the percentage of blue-stained area relative to the total area of the ear. The number of animals used for each determination is shown in parentheses: ***p < 0.001 vs. vehicle, † p < 0.05 vs DHPS by one-factor ANOVA followed by Student-Newmann-Keuls test.
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Fig1: Chemical structures of potassium 2,5-dihydroxyphenyl sulfonate (DHPS: A) and potassium 2,5-diacetoxyphenyl sulfonate (DAPS: B). Panels C and D show representative images illustrating the effects of DHPS (C) and DAPS (D) on dermatitis of rat ears induced by the application of benzalkonium chloride. After induction of dermatitis in both ears, the right ear was treated topically with DHPS (5% w/v; eq. to 0.22 mmol/ml) or DAPS (5% w/v; eq. to 0.16 mmol/ml), and the left ear with the vehicle alone (glycerol). The extent of dermatitis (vascular hyperpermeability) was revealed by intravenous injection of Evans blue dye. In panel E the inhibitory effects of DHPS (5%; eq. to 0.22 mmol/ml) and DAPS (2.5% and 5%; eq. to 0.08 and 0.16 mmol/ml) on dermatitis are quantified, expressing the data as the mean ± SEM of the percentage of blue-stained area relative to the total area of the ear. The number of animals used for each determination is shown in parentheses: ***p < 0.001 vs. vehicle, † p < 0.05 vs DHPS by one-factor ANOVA followed by Student-Newmann-Keuls test.

Mentions: Potassium 2,5-dihydroxyphenyl sulfonate (DHPS) was obtained from Sigma-Aldrich (Saint Louis, MO) and reagent-grade potassium 2,5-diacetoxyphenyl sulfonate (DAPS) was purchased from Aurigene (Bangalore, India). The chemical structures are shown in Figure 1A.Figure 1


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

Angulo J, Cuevas P, Cuevas B, El Youssef M, Fernández A, Martínez-Salamanca E, González-Corrochano R, Giménez-Gallego G - J Transl Med (2015)

Chemical structures of potassium 2,5-dihydroxyphenyl sulfonate (DHPS: A) and potassium 2,5-diacetoxyphenyl sulfonate (DAPS: B). Panels C and D show representative images illustrating the effects of DHPS (C) and DAPS (D) on dermatitis of rat ears induced by the application of benzalkonium chloride. After induction of dermatitis in both ears, the right ear was treated topically with DHPS (5% w/v; eq. to 0.22 mmol/ml) or DAPS (5% w/v; eq. to 0.16 mmol/ml), and the left ear with the vehicle alone (glycerol). The extent of dermatitis (vascular hyperpermeability) was revealed by intravenous injection of Evans blue dye. In panel E the inhibitory effects of DHPS (5%; eq. to 0.22 mmol/ml) and DAPS (2.5% and 5%; eq. to 0.08 and 0.16 mmol/ml) on dermatitis are quantified, expressing the data as the mean ± SEM of the percentage of blue-stained area relative to the total area of the ear. The number of animals used for each determination is shown in parentheses: ***p < 0.001 vs. vehicle, † p < 0.05 vs DHPS by one-factor ANOVA followed by Student-Newmann-Keuls test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4318172&req=5

Fig1: Chemical structures of potassium 2,5-dihydroxyphenyl sulfonate (DHPS: A) and potassium 2,5-diacetoxyphenyl sulfonate (DAPS: B). Panels C and D show representative images illustrating the effects of DHPS (C) and DAPS (D) on dermatitis of rat ears induced by the application of benzalkonium chloride. After induction of dermatitis in both ears, the right ear was treated topically with DHPS (5% w/v; eq. to 0.22 mmol/ml) or DAPS (5% w/v; eq. to 0.16 mmol/ml), and the left ear with the vehicle alone (glycerol). The extent of dermatitis (vascular hyperpermeability) was revealed by intravenous injection of Evans blue dye. In panel E the inhibitory effects of DHPS (5%; eq. to 0.22 mmol/ml) and DAPS (2.5% and 5%; eq. to 0.08 and 0.16 mmol/ml) on dermatitis are quantified, expressing the data as the mean ± SEM of the percentage of blue-stained area relative to the total area of the ear. The number of animals used for each determination is shown in parentheses: ***p < 0.001 vs. vehicle, † p < 0.05 vs DHPS by one-factor ANOVA followed by Student-Newmann-Keuls test.
Mentions: Potassium 2,5-dihydroxyphenyl sulfonate (DHPS) was obtained from Sigma-Aldrich (Saint Louis, MO) and reagent-grade potassium 2,5-diacetoxyphenyl sulfonate (DAPS) was purchased from Aurigene (Bangalore, India). The chemical structures are shown in Figure 1A.Figure 1

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Hospital Universitario Ramón y Cajal, Madrid, Spain. javier.angulo@hrc.es.

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.

Show MeSH
Related in: MedlinePlus