RESUMO
Neovascularization is a critical process in the pathophysiology of neovascular eye diseases. Although anti-VEGF therapy has achieved remarkable curative effects, complications, limited efficacy and drug resistance remain the prominent problems. DCZ3301, an aryl-guanidino compound, was reported to have anti-tumor activity in the previous studies. Here, we demonstrated the effects of DCZ3301 on human umbilical vein endothelial cell (HUVEC) in vitro, and performed choroid microvascular sprouting assay ex vivo and alkali-burn induced corneal neovascularization mouse model in vivo. We found that DCZ3301 inhibited the proliferation, migration, and tube formation of HUVECs, while inducing the spontaneous apoptosis of HUVECs by suppressing the activation of PI3K/AKT and ERK1/2 pathways. Furthermore, DCZ3301 inhibited the choroid microvascular sprouting, diminished the area of corneal neovascularization and attenuated the edema of corneal stroma after alkali burn. Together, these results suggested that DCZ3301 exerted anti-angiogenic properties, and might be regarded as a potential candidate for ocular neovascularization.
Assuntos
Amidas/farmacologia , Neovascularização da Córnea/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células , Células Cultivadas , Neovascularização da Córnea/tratamento farmacológico , Neovascularização da Córnea/patologia , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais/efeitos dos fármacosRESUMO
INTRODUCTION: Polyamines play a fundamental role during embryogenesis by regulating cell growth and proliferation and by interacting with RNA, DNA and protein. The polyamine pools are regulated by metabolism and uptake from exogenous sources. The use of certain inhibitors of polyamine synthesis causes similar defects to those seen in alcohol exposure e.g. retarded embryo growth and endothelial cell sprouting. METHODS: CD-1 mice received two intraperitoneal injections of 3 g/kg ethanol at 4 h intervals 8.75 days post coitum (dpc). The fetal head, trunk, yolk sac and placenta were collected at 9.5 and 12.5 dpc and polyamine concentrations were determined. RESULTS: No measurable quantity of polyamines could be detected in the embryo head at 9.5 dpc, 12 h after ethanol exposure. Putrescine was not detectable in the trunk of the embryo at that time, whereas polyamines in yolk sac and placenta were at control level. Polyamine deficiency was associated with slow cell growth, reduction in endothelial cell sprouting, an altered pattern of blood vessel network formation and consequently retarded migration of neural crest cells and growth restriction. DISCUSSION: Our results indicate that the polyamine pools in embryonic and extraembryonic tissues are developmentally regulated. Alcohol administration, at the critical stage, perturbs polyamine levels with various patterns, depending on the tissue and its developmental stage. The total absence of polyamines in the embryo head at 9.5 dpc may explain why this stage is so vulnerable to the development of neural tube defect, and growth restriction, the findings previously observed in fetal alcohol syndrome.