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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

Effects of acetylsalicylic acid (ASA; 1 to 100 μM), potassium 2,5-dihydroxyphenyl sulfonate (DHPS; 1 to 100 μM) and potassium 2,5-diacetoxyphenyl sulfonate (DAPS; 1 to 100 μM) on cyclooxygenase (COX)-1 (A) and COX-2 (B) activity. Data are expressed as the percentage of the total COX activity obtained in the absence of inhibitors and the results are the mean ± SEM of two independent experiments performed in duplicate. Panel C shows the effects of intravenously administered ASA (10 mg/kg; eq. to 0.05 mmol/kg), DHPS (10 mg/kg; eq. to 0.04 mmol/kg) and DAPS (10 mg/kg; eq. to 0.03 mmol/kg) on bleeding time (BT) in anesthetized rats. The data are expressed as the mean ± SEM of the percentage of increase in BT with respect to the basal determination for each animal. The numbers of rats used for the measurements are indicated in parentheses: *p < 0.05 vs. ASA; † p < 0.05 vs. DHPS, by one-factor ANOVA followed by Student-Newmann-Keuls test.
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Fig3: Effects of acetylsalicylic acid (ASA; 1 to 100 μM), potassium 2,5-dihydroxyphenyl sulfonate (DHPS; 1 to 100 μM) and potassium 2,5-diacetoxyphenyl sulfonate (DAPS; 1 to 100 μM) on cyclooxygenase (COX)-1 (A) and COX-2 (B) activity. Data are expressed as the percentage of the total COX activity obtained in the absence of inhibitors and the results are the mean ± SEM of two independent experiments performed in duplicate. Panel C shows the effects of intravenously administered ASA (10 mg/kg; eq. to 0.05 mmol/kg), DHPS (10 mg/kg; eq. to 0.04 mmol/kg) and DAPS (10 mg/kg; eq. to 0.03 mmol/kg) on bleeding time (BT) in anesthetized rats. The data are expressed as the mean ± SEM of the percentage of increase in BT with respect to the basal determination for each animal. The numbers of rats used for the measurements are indicated in parentheses: *p < 0.05 vs. ASA; † p < 0.05 vs. DHPS, by one-factor ANOVA followed by Student-Newmann-Keuls test.

Mentions: DHPS (1 to 100 μM) had no significant inhibitory effect on COX activity, whereas the acetyloxy derivative DAPS (1 to 100 μM) induced significant concentration-dependent inhibition of both COX-1 and COX-2 (Figure 3A-B). In fact, DAPS was as potent as ASA in inhibiting COX-1 activity, and even more efficient than ASA in inhibiting COX-2 (Figure 2A-B).Figure 3


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 acetylsalicylic acid (ASA; 1 to 100 μM), potassium 2,5-dihydroxyphenyl sulfonate (DHPS; 1 to 100 μM) and potassium 2,5-diacetoxyphenyl sulfonate (DAPS; 1 to 100 μM) on cyclooxygenase (COX)-1 (A) and COX-2 (B) activity. Data are expressed as the percentage of the total COX activity obtained in the absence of inhibitors and the results are the mean ± SEM of two independent experiments performed in duplicate. Panel C shows the effects of intravenously administered ASA (10 mg/kg; eq. to 0.05 mmol/kg), DHPS (10 mg/kg; eq. to 0.04 mmol/kg) and DAPS (10 mg/kg; eq. to 0.03 mmol/kg) on bleeding time (BT) in anesthetized rats. The data are expressed as the mean ± SEM of the percentage of increase in BT with respect to the basal determination for each animal. The numbers of rats used for the measurements are indicated in parentheses: *p < 0.05 vs. ASA; † 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

Fig3: Effects of acetylsalicylic acid (ASA; 1 to 100 μM), potassium 2,5-dihydroxyphenyl sulfonate (DHPS; 1 to 100 μM) and potassium 2,5-diacetoxyphenyl sulfonate (DAPS; 1 to 100 μM) on cyclooxygenase (COX)-1 (A) and COX-2 (B) activity. Data are expressed as the percentage of the total COX activity obtained in the absence of inhibitors and the results are the mean ± SEM of two independent experiments performed in duplicate. Panel C shows the effects of intravenously administered ASA (10 mg/kg; eq. to 0.05 mmol/kg), DHPS (10 mg/kg; eq. to 0.04 mmol/kg) and DAPS (10 mg/kg; eq. to 0.03 mmol/kg) on bleeding time (BT) in anesthetized rats. The data are expressed as the mean ± SEM of the percentage of increase in BT with respect to the basal determination for each animal. The numbers of rats used for the measurements are indicated in parentheses: *p < 0.05 vs. ASA; † p < 0.05 vs. DHPS, by one-factor ANOVA followed by Student-Newmann-Keuls test.
Mentions: DHPS (1 to 100 μM) had no significant inhibitory effect on COX activity, whereas the acetyloxy derivative DAPS (1 to 100 μM) induced significant concentration-dependent inhibition of both COX-1 and COX-2 (Figure 3A-B). In fact, DAPS was as potent as ASA in inhibiting COX-1 activity, and even more efficient than ASA in inhibiting COX-2 (Figure 2A-B).Figure 3

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