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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 oral administration of potassium 2,5-diacetoxyphenyl sulfonate (DAPS) on the progression, angiogenesis and apoptosis of tumors established in rats by subcutaneous implantation of rat glioma C6 cells (5 × 105cells). Treatment began once the presence of a tumor was verified on the fifth day after glioma cell implantation (arrow in panel A). Tumors were removed after 10 days of treatment with vehicle (VEH, tap water; n = 8) or DAPS (200 mg/kg/d; eq. to 0.73 mmol/kg/d; n = 10) by oral gavage. Panel A shows the time-course of subcutaneous glioma size in rats treated with vehicle or DAPS. Panel B shows representative images of macroscopic aspect of tumors excised from rats treated with vehicle or DAPS while the quantification and comparison of the volumes and weights are shown in the same row. Panel C shows representative images illustrating the intense leukocyte extravasation and infiltration observed in peritumoral vessels of gliomas obtained from vehicle-treated rats that is markedly reduced in gliomas from rats treated with DAPS. Panel D shows representative images illustrating the intense vascularization in tumors from vehicle-treated rats which is notably reduced in DAPS-treated rats, as confirmed by functional vessel quantification displayed at the right side. Panel E shows representative images illustrating the scarce presence of apoptotic nuclei detected by TUNEL assay in sections of tumors from vehicle-treated rats that markedly increased in DAPS-treated rats, as confirmed by quantification of the percentage of tumoral apoptotic nuclei displayed at the right side. The data are expressed as the mean ± SEM: *p < 0.05; **p < 0.01; ***p < 0.001 vs. VEH by unpaired Student’s t test.
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Fig7: Effects of oral administration of potassium 2,5-diacetoxyphenyl sulfonate (DAPS) on the progression, angiogenesis and apoptosis of tumors established in rats by subcutaneous implantation of rat glioma C6 cells (5 × 105cells). Treatment began once the presence of a tumor was verified on the fifth day after glioma cell implantation (arrow in panel A). Tumors were removed after 10 days of treatment with vehicle (VEH, tap water; n = 8) or DAPS (200 mg/kg/d; eq. to 0.73 mmol/kg/d; n = 10) by oral gavage. Panel A shows the time-course of subcutaneous glioma size in rats treated with vehicle or DAPS. Panel B shows representative images of macroscopic aspect of tumors excised from rats treated with vehicle or DAPS while the quantification and comparison of the volumes and weights are shown in the same row. Panel C shows representative images illustrating the intense leukocyte extravasation and infiltration observed in peritumoral vessels of gliomas obtained from vehicle-treated rats that is markedly reduced in gliomas from rats treated with DAPS. Panel D shows representative images illustrating the intense vascularization in tumors from vehicle-treated rats which is notably reduced in DAPS-treated rats, as confirmed by functional vessel quantification displayed at the right side. Panel E shows representative images illustrating the scarce presence of apoptotic nuclei detected by TUNEL assay in sections of tumors from vehicle-treated rats that markedly increased in DAPS-treated rats, as confirmed by quantification of the percentage of tumoral apoptotic nuclei displayed at the right side. The data are expressed as the mean ± SEM: *p < 0.05; **p < 0.01; ***p < 0.001 vs. VEH by unpaired Student’s t test.

Mentions: Furthermore, DAPS displayed anti-tumoral efficacy also when orally administered (Figure 7). Oral administration of DAPS (200 mg/kg/d) resulted in reduced progression of subcutaneous gliomas induced by C6 cell implantation in rats (Figure 7A). This was confirmed by the significant reduction in tumor volume and weight after the treatment with DAPS (Figure 7B). A strong leukocyte infiltration from peritumoral vessels was observed in vehicle-treated rats that was notably reduced in rats treated with DAPS (Figure 7C). Inhibition of tumoral progression by oral DAPS was accompanied by a reduction of tumor vascularization (Figure 7D) and an increase in tumor apoptosis (Figure 7E). Oral treatment with DAPS for 10 days did not cause signs of toxicity since weight gain of animals treated with DAPS was not different from that observed in vehicle treated animals. Baseline weights just before C6 implantation were 332 ± 12 g and 319 ± 14 g for vehicle- and DAPS-treated groups, respectively, while final weights 15 days afterwards, including the 10-days treatment period, were 374 ± 15 g and 373 ± 13 g for vehicle- and DAPS-treated groups, respectively.Figure 7


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 oral administration of potassium 2,5-diacetoxyphenyl sulfonate (DAPS) on the progression, angiogenesis and apoptosis of tumors established in rats by subcutaneous implantation of rat glioma C6 cells (5 × 105cells). Treatment began once the presence of a tumor was verified on the fifth day after glioma cell implantation (arrow in panel A). Tumors were removed after 10 days of treatment with vehicle (VEH, tap water; n = 8) or DAPS (200 mg/kg/d; eq. to 0.73 mmol/kg/d; n = 10) by oral gavage. Panel A shows the time-course of subcutaneous glioma size in rats treated with vehicle or DAPS. Panel B shows representative images of macroscopic aspect of tumors excised from rats treated with vehicle or DAPS while the quantification and comparison of the volumes and weights are shown in the same row. Panel C shows representative images illustrating the intense leukocyte extravasation and infiltration observed in peritumoral vessels of gliomas obtained from vehicle-treated rats that is markedly reduced in gliomas from rats treated with DAPS. Panel D shows representative images illustrating the intense vascularization in tumors from vehicle-treated rats which is notably reduced in DAPS-treated rats, as confirmed by functional vessel quantification displayed at the right side. Panel E shows representative images illustrating the scarce presence of apoptotic nuclei detected by TUNEL assay in sections of tumors from vehicle-treated rats that markedly increased in DAPS-treated rats, as confirmed by quantification of the percentage of tumoral apoptotic nuclei displayed at the right side. The data are expressed as the mean ± SEM: *p < 0.05; **p < 0.01; ***p < 0.001 vs. VEH by unpaired Student’s t test.
© Copyright Policy - open-access
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Fig7: Effects of oral administration of potassium 2,5-diacetoxyphenyl sulfonate (DAPS) on the progression, angiogenesis and apoptosis of tumors established in rats by subcutaneous implantation of rat glioma C6 cells (5 × 105cells). Treatment began once the presence of a tumor was verified on the fifth day after glioma cell implantation (arrow in panel A). Tumors were removed after 10 days of treatment with vehicle (VEH, tap water; n = 8) or DAPS (200 mg/kg/d; eq. to 0.73 mmol/kg/d; n = 10) by oral gavage. Panel A shows the time-course of subcutaneous glioma size in rats treated with vehicle or DAPS. Panel B shows representative images of macroscopic aspect of tumors excised from rats treated with vehicle or DAPS while the quantification and comparison of the volumes and weights are shown in the same row. Panel C shows representative images illustrating the intense leukocyte extravasation and infiltration observed in peritumoral vessels of gliomas obtained from vehicle-treated rats that is markedly reduced in gliomas from rats treated with DAPS. Panel D shows representative images illustrating the intense vascularization in tumors from vehicle-treated rats which is notably reduced in DAPS-treated rats, as confirmed by functional vessel quantification displayed at the right side. Panel E shows representative images illustrating the scarce presence of apoptotic nuclei detected by TUNEL assay in sections of tumors from vehicle-treated rats that markedly increased in DAPS-treated rats, as confirmed by quantification of the percentage of tumoral apoptotic nuclei displayed at the right side. The data are expressed as the mean ± SEM: *p < 0.05; **p < 0.01; ***p < 0.001 vs. VEH by unpaired Student’s t test.
Mentions: Furthermore, DAPS displayed anti-tumoral efficacy also when orally administered (Figure 7). Oral administration of DAPS (200 mg/kg/d) resulted in reduced progression of subcutaneous gliomas induced by C6 cell implantation in rats (Figure 7A). This was confirmed by the significant reduction in tumor volume and weight after the treatment with DAPS (Figure 7B). A strong leukocyte infiltration from peritumoral vessels was observed in vehicle-treated rats that was notably reduced in rats treated with DAPS (Figure 7C). Inhibition of tumoral progression by oral DAPS was accompanied by a reduction of tumor vascularization (Figure 7D) and an increase in tumor apoptosis (Figure 7E). Oral treatment with DAPS for 10 days did not cause signs of toxicity since weight gain of animals treated with DAPS was not different from that observed in vehicle treated animals. Baseline weights just before C6 implantation were 332 ± 12 g and 319 ± 14 g for vehicle- and DAPS-treated groups, respectively, while final weights 15 days afterwards, including the 10-days treatment period, were 374 ± 15 g and 373 ± 13 g for vehicle- and DAPS-treated groups, respectively.Figure 7

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