Inhibition of tumor metastasis in vivo by combination of paclitaxel and hyaluronic acid

There is little information about the inhibitory effects of hyaluronic acid with paclitaxel on tumor metastasis and ascites formation. The aim of present study is to determine whether the combined administration of hyaluronic acid (HA) with paclitaxel can produce additional or synergistic therapeutic effects in the control of Lewis lung carcinoma (LLC) migration and ascites formation of U14 cervical tumor. The anti-metastasis effect of hyaluronic acid alone, paclitaxel alone and paclitaxel–hyaluronic acid combination were examined in a mouse model bearing LLC cells. i.v. Paclitaxel–hyaluronic acid, in the ratio of 1:3 (w/w), significantly reduced the migration of LLC cells in a synergistic fashion. In the experiment with mice bearing U14 tumor cells, i.p. paclitaxel–hyaluronic acid markedly improved the life span of mice and significantly decreased ascites formation when compared to paclitaxel alone or hyalunonan alone. We also analyzed the serum proteome of mice with lung neoplasm before and after treatment with paclitaxel–hyaluronic acid. Proteomic analysis on LLC mice was studied using two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and mass spectrometry. The results showed that i.v. administration of hyaluronic acid in combination with paclitaxel had significantly up-regulated the expression of vitamin D3 binding proteins (DBP), which is a macrophage-stimulating activator. In conclusion, the in vivo anti-metastasis effect was associated with the synergistic therapeutic effects of hyaluronic acid–paclitaxel combination and a significant promotion of immune proteins expression. These results demonstrated that the combination of paclitaxel and hyaluronic acid may be an effective way to inhibit tumor migration.