Suppression of Vascular Endothelial Growth Factor (VEGF) Induced Angiogenic Responses by Phlorotannin Compounds

Abstract

Marine algae are rich source of new secondary metabolites with wide variety of biological activities. Anticancer activity is one of the potential bio-activity of marine natural products. Cancer is a serious disease with a complex pathogenesis, which threats human life greatly. And angiogenesis is directly involved in invasion and metastasis of cancer. This study reveals the effect of fucodiphloroethol G and dieckol isolated from Ecklonia cava on angiogenesis through inhibiting protinase enzymes; AP-N, MMP-2,-9 and transcriptional factor; c-fos, together with underling molecular mechanisms. The results show that fucodiphloroethol G and dieckol inhibited the activity AP-N dose dependently. And also expression of MMP-2,-9 were significantly inhibited at both protein and gene levels. The responsible transcriptional factor for the activation of AP-N and MMPs, c-fos protein was significantly inhibited by the treatment of fucodiphloroethol G and dieckol. We have found the effects fucodiphloroethol G and dieckol on the signaling pathways; MAPK and Akt, related to activation of transcription of AP-N, MMPs and c-fos. Fucodiphloroethol G and dieckol showed a significant inhibition on molecules of MAPK pathway; MEK, ERK, and p38, and Akt, but not JNK. Finally these results demonstrate the potential anti-angiogenic effect of fucodiphloroethol G on VEGF induced ECV-304 and EA.hy926 through inhibition of AP-N, MMP-2,-9, c-fos via blocking of the signal transduction of MAPK and Akt pathways. Due to the shown ability to inhibit angiogenesis, both fucodiphloroethol G and dieckol could be used as potential therapeutic targets in the treatment of angiogenesis.