Artemisinin inhibits tumor lymphangiogenesis by suppression of vascular endothelial growth factor C

We have previously reported that dihydroartemisinin is found to have a potent ability in influencing lymphatic endothelial cell migration and tube formation. In this study, we investigated the effect of artemisinin on tumor growth, lymphangiogenesis, metastasis and survival in mouse Lewis lung carcinoma (LLC) models. We found that orally administered artemisinin inhibited lymph node and lung metastasis and prolonged survival without retarding tumor growth. Consistent with the decrease in lymph node metastasis, tumor lymphangiogenesis and expression of vascular endothelial growth factor C (VEGF-C) was significantly decreased in artemisinin-treated mice, as compared to control mice. Furthermore, IL-1beta-induced p38 mitogen-activated protein kinase (MAPK) activation and upregulation of VEGF-C mRNA and protein in LLC cells was also suppressed by artemisinin or by the p38 MAPK inhibitor SB-203580, suggesting that p38 MAPK could serve as a mediator of proinflammatory cytokine-induced VEGF-C expression. These data indicate that artemisinin may be useful for the prevention of lymph node metastasis by downregulating VEGF-C and reducing tumor lymphangiogenesis.