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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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Effects of intraperitoneal injection of potassium 2,5-dihydroxyphenyl sulfonate (DHPS; 100 mg/kg; eq. to 0.44 mmol/kg) or potassium 2,5-diacetoxyphenyl sulfonate (DAPS; 100 mg/kg; eq. to 0.32 mmol/kg) on the lipopolysaccharide (LPS)-induced increase in tumor necrosis factor-α (TNF-α; A), interleukin-6 (IL-6; B) and interleukin-1ß (IL-1ß; C) concentrations in rat serum. Serum samples were obtained 6 h after LPS injection (5 mg/kg; i.p.) and the data are expressed as the mean ± SEM concentration of cytokine in pg/ml or ng/ml: * p < 0.05, **p < 0.01 vs. LPS + vehicle, † p < 0.05 vs. LPS+DHPS, by one-factor ANOVA followed by Student-Newmann-Keuls test.
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Fig4: Effects of intraperitoneal injection of potassium 2,5-dihydroxyphenyl sulfonate (DHPS; 100 mg/kg; eq. to 0.44 mmol/kg) or potassium 2,5-diacetoxyphenyl sulfonate (DAPS; 100 mg/kg; eq. to 0.32 mmol/kg) on the lipopolysaccharide (LPS)-induced increase in tumor necrosis factor-α (TNF-α; A), interleukin-6 (IL-6; B) and interleukin-1ß (IL-1ß; C) concentrations in rat serum. Serum samples were obtained 6 h after LPS injection (5 mg/kg; i.p.) and the data are expressed as the mean ± SEM concentration of cytokine in pg/ml or ng/ml: * p < 0.05, **p < 0.01 vs. LPS + vehicle, † p < 0.05 vs. LPS+DHPS, by one-factor ANOVA followed by Student-Newmann-Keuls test.

Mentions: Since, in addition to mediating local inflammatory processes, FGF and COX could have an impact on systemic inflammation, we evaluated the effect of DHPS (100 mg/kg; i.p.) and DAPS (100 mg/kg; i.p.) on the level of TNF-α, IL-6 and IL-1ß in a rat model of systemic inflammation. Precisely, the marked increase of the serum levels of TNF-α caused by intraperitoneal injection of LPS (5 mg/kg) was significantly attenuated by DHPS, and to a larger extent, by DAPS administration (Figure 4A). LPS also markedly increased serum concentrations of IL-6 and IL-1ß. Although DHPS showed a trend to reduce the elevation of these cytokines, only DAPS was able to significantly reduce the increase in IL-6 and IL-1ß caused by LPS (Figure 4B-C).Figure 4


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)

Effects of intraperitoneal injection of potassium 2,5-dihydroxyphenyl sulfonate (DHPS; 100 mg/kg; eq. to 0.44 mmol/kg) or potassium 2,5-diacetoxyphenyl sulfonate (DAPS; 100 mg/kg; eq. to 0.32 mmol/kg) on the lipopolysaccharide (LPS)-induced increase in tumor necrosis factor-α (TNF-α; A), interleukin-6 (IL-6; B) and interleukin-1ß (IL-1ß; C) concentrations in rat serum. Serum samples were obtained 6 h after LPS injection (5 mg/kg; i.p.) and the data are expressed as the mean ± SEM concentration of cytokine in pg/ml or ng/ml: * p < 0.05, **p < 0.01 vs. LPS + vehicle, † p < 0.05 vs. LPS+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

Fig4: Effects of intraperitoneal injection of potassium 2,5-dihydroxyphenyl sulfonate (DHPS; 100 mg/kg; eq. to 0.44 mmol/kg) or potassium 2,5-diacetoxyphenyl sulfonate (DAPS; 100 mg/kg; eq. to 0.32 mmol/kg) on the lipopolysaccharide (LPS)-induced increase in tumor necrosis factor-α (TNF-α; A), interleukin-6 (IL-6; B) and interleukin-1ß (IL-1ß; C) concentrations in rat serum. Serum samples were obtained 6 h after LPS injection (5 mg/kg; i.p.) and the data are expressed as the mean ± SEM concentration of cytokine in pg/ml or ng/ml: * p < 0.05, **p < 0.01 vs. LPS + vehicle, † p < 0.05 vs. LPS+DHPS, by one-factor ANOVA followed by Student-Newmann-Keuls test.
Mentions: Since, in addition to mediating local inflammatory processes, FGF and COX could have an impact on systemic inflammation, we evaluated the effect of DHPS (100 mg/kg; i.p.) and DAPS (100 mg/kg; i.p.) on the level of TNF-α, IL-6 and IL-1ß in a rat model of systemic inflammation. Precisely, the marked increase of the serum levels of TNF-α caused by intraperitoneal injection of LPS (5 mg/kg) was significantly attenuated by DHPS, and to a larger extent, by DAPS administration (Figure 4A). LPS also markedly increased serum concentrations of IL-6 and IL-1ß. Although DHPS showed a trend to reduce the elevation of these cytokines, only DAPS was able to significantly reduce the increase in IL-6 and IL-1ß caused by LPS (Figure 4B-C).Figure 4

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