Inhibition of lymphangiogenesis, nodal and lung metastasis by dihy-droartemisinin in mice bearing Lewis lung carcinoma

ObjectiveTo investigate the activity of anti-malarial dihydroartemisinin (DHA) on tumor growth, lymphangiogenesis, nodal and lung metastasis and survival in mice bearing Lewis lung carcimoma (LLC).MethodsThe models of C57BL/6 mice transplantation tumors were established via subcutaneous injection of LLC cells and divided into 4 groups; control group, DHA group, DHA + ferrous sulfate (FS) group and FS group, with 25 mice in each group. Tumor volumes and weights, nodal and lung metastasis, and survival were monitored. Tumor lymphatic microvessel density (LMVD) was determined by lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) immnohistochemistry. After LLC cells were treated with DHA or DHA + FS, protein and mRNA levels of vascular endothelial growth factor (VEGF) -C were evaluated by Western blotting and real time quantitative RT-PCR, respectively.ResultsOral administration of DHA or DHA + FS inhibited lymph node and lung metastasis, and prolonged survival. However, no significant tumor growth retardation effect was observed when mice were treated with DHA alone. The inhibited tumor metastasis was related to the decreased LMVD in the peritumoral regions, but not in the in-tratumoral regions. DHA significantly down-regulated the expression of VEGF-C protein and mRNA in LLC cells.ConclusionDHA effectively inhibits LLC transplantation tumor lymphangiogenesis, nodal and lung metastasis, and may be a promising chemotherapeutic agent for controlling lung cancer metastasis by decreasing VEGF-C expression.