Arsenic trioxide inhibits angiogenesis of hepatocellular carcinoma after insufficient radiofrequency ablation via blocking paracrine angiopoietin-1 and angiopoietin-2

Angiogenesis occurs during tumor progression of hepatocellular carcinoma (HCC) after insufficient radiofrequency ablation (RFA). Arsenic trioxide (ATO) shows promising therapeutic potential in advanced HCC. Whether ATO regulates angiogenesis and can be used to prevent tumor progression in HCC after insufficient RFA is still unknown.Insufficient RFA was simulated using a water bath. MTT assay and tube formation assay were used to evaluate the effects of ATO on viability and proangiogenic abilities of SMMC7721 and HepG2 cells after insufficient RFA in vitro. The molecular changes with the treatment of ATO were evaluated through Western blot. An ectopic nude mice model was used to evaluate the effect of ATO on the tumor of SMMC7721 cells in vivo after insufficient RFA.In this study, HepG2 and SMMC7721 cells after insufficient RFA (named HepG2-H and SMMC7721-H, respectively) showed higher proliferation than the untreated cells and promoted tube formation of endothelial cells in a paracrine manner. ATO eliminated the difference in proliferation between untreated and RFA-treated cells and suppressed angiogenesis induced by HCC cells after insufficient RFA through the Ang-1 (angiopoietin-1)/Ang-2 (angiopoietin-2)/Tie2 pathway. Hif-1α overexpression abolished the inhibitory effect of ATO on angiogenesis in HCC after insufficient RFA. ATO inhibited tumor growth and angiogenesis in HCC after insufficient RFA.Our results demonstrate that ATO blocks the paracrine signaling of Ang-1 and Ang-2 by inhibiting p-Akt/Hif-1α and further suppresses the angiogenesis of HCC after insufficient RFA.