Context Pancreatic cancer cells produce various proteases involved in invasion, angiogenesis and metastatic spread. Gabexate mesylate (GM), a serine protease inhibitor, may reduce invasive capabilities and enhance chemotherapy effects. Objective To evaluate the effect of treatment with GM and gemcitabine (GEM), alone or combined. Materials and methods Studies have been performed on cancer cell lines PANC-1, SW1990 and endothelial cell EA.hy926. Treatment consisted of GM (50-100 µM for 24 h), alone or followed by GEM (250 µM for 24 h). Aspects studied included: cell viability (MTT assay), cell invasiveness and migration (Boyden chambers chemoinvasion and chemotaxis assay), angiogenesis (endothelial tube formation assay) and VEGF levels (ELISA) in EA.hy926 cell, MMP-2 and MMP-9 activity (gelatin zymography). Results Cell viability: this parameter decreased by 40% with GM alone only in EA.hy926 cells (P<0.05). Cell invasiveness: GM alone inhibited SW1990 and EA.hy926 cell line invasiveness by about 75% (P<0.001). GM and GEM reduced invasiveness of PANC-1 and SW1990 cells by 55-65%. Angiogenesis and VEGF: inhibition of angiogenesis (from 60 to 90%) was observed in EA.hy926 cells incubated with the supernatant of PANC-1 and SW1990 cells treated with GM, alone or followed by GEM. Similar result was found for VEGF levels, strongly decreased in all cell lines treated with GM, alone or followed by GEM (P<0.001). The inhibitory effect of GM on PANC-1 and SW1990 was superior to bevacizumab (P<0.05). MMP-9 and MMP-2 activity: MMP-9 and MMP-2 activities were decreased by 40% after combined treatment (GM and GEM) in both PANC-1 and SW1990 cells. In EA.hy926 cells GM alone was more effective than the combination in inhibiting MMP-2 (P<0.001). Conclusion These in vitro data indicate that GM can effectively inhibit pancreatic cancer cell invasiveness and angiogenesis, also enhancing the effect of gemcitabine.

The Protease Inhibitor Gabexate Mesylate Reduces Invasiveness and Angiogenesis in Pancreatic Cancer Cell Lines, Enhancing Gemcitabine Action

MACCHINI, MARINA;BRANDI, GIOVANNI;TAVOLARI, SIMONA;GUARNIERI, TIZIANA;DE ROSA, FRANCESCO;PATERINI, PAOLA;DI MARCO, MARIACRISTINA;DI CICILIA, ROBERTO;NOBILI, ELISABETTA;BIASCO, GUIDO
2010

Abstract

Context Pancreatic cancer cells produce various proteases involved in invasion, angiogenesis and metastatic spread. Gabexate mesylate (GM), a serine protease inhibitor, may reduce invasive capabilities and enhance chemotherapy effects. Objective To evaluate the effect of treatment with GM and gemcitabine (GEM), alone or combined. Materials and methods Studies have been performed on cancer cell lines PANC-1, SW1990 and endothelial cell EA.hy926. Treatment consisted of GM (50-100 µM for 24 h), alone or followed by GEM (250 µM for 24 h). Aspects studied included: cell viability (MTT assay), cell invasiveness and migration (Boyden chambers chemoinvasion and chemotaxis assay), angiogenesis (endothelial tube formation assay) and VEGF levels (ELISA) in EA.hy926 cell, MMP-2 and MMP-9 activity (gelatin zymography). Results Cell viability: this parameter decreased by 40% with GM alone only in EA.hy926 cells (P<0.05). Cell invasiveness: GM alone inhibited SW1990 and EA.hy926 cell line invasiveness by about 75% (P<0.001). GM and GEM reduced invasiveness of PANC-1 and SW1990 cells by 55-65%. Angiogenesis and VEGF: inhibition of angiogenesis (from 60 to 90%) was observed in EA.hy926 cells incubated with the supernatant of PANC-1 and SW1990 cells treated with GM, alone or followed by GEM. Similar result was found for VEGF levels, strongly decreased in all cell lines treated with GM, alone or followed by GEM (P<0.001). The inhibitory effect of GM on PANC-1 and SW1990 was superior to bevacizumab (P<0.05). MMP-9 and MMP-2 activity: MMP-9 and MMP-2 activities were decreased by 40% after combined treatment (GM and GEM) in both PANC-1 and SW1990 cells. In EA.hy926 cells GM alone was more effective than the combination in inhibiting MMP-2 (P<0.001). Conclusion These in vitro data indicate that GM can effectively inhibit pancreatic cancer cell invasiveness and angiogenesis, also enhancing the effect of gemcitabine.
JOP. JOURNAL OF THE PANCREAS
512
512
Macchini M; Brandi G; Tavolari S; Guarnieri T; de Rosa F; Paterini P; Di Girolamo S; Agostini V; Di Marco M; Vecchiarelli S; Di Cicilia R; Nobili E; Biasco G.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/95070
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