Water-Soluble Total Flavonoids Isolated from Isodon Lophanthoides Var.Gerardianus (Benth.) H.Hara Promotes Hepatocellular Carcinoma Sensitivity to 5-Fluorouracil

Background: Isodon lophanthoides var. gerardianus (Benth.) H. Hara is an autochthonous plant produced chiefly in South China, and as one of mainstream varieties of Xihuangcao, which has been applied for prevention and treatment of common diseases of liver and gall for several hundred years. The water-soluble total flavonoids (WSTF) from the folk herbal medicine has many pharmacological effects. This study investigate whether WSTF has a synergistic effect of combination treatment with 5-fluorouracil (5-FU) on HCC. Methods: Cells were treated with WSTF alone or combination treatment with 5-FU and we implied cell viability, colony formation assay and cell cycle, reactive oxygen species (ROS), apoptosis analysis and western blot, immunohistochemistry and xenograft tumorigenicity assay for investigating the roles of WSTF on HCC in vitro and in vivo. Results: WSTF caused G0/G1-phase arrest, and increased ROS levels. The generation of ROS levels could cause cell apoptosis and inhibite colony formation. WSTF decreased the expression of bcl-2, but promoted the expression of bax. These showed that WSTF-mediated apoptosis is associated with mitochondria-dependent. WSTF combined with 5-Fu has a synergistic effect to significantly suppress tumorigenicity both in vitro and in vivo. Reduction of ROS changed the synergistic effect of WSTF and 5-FU Conclusions: WSTF inhibits the growth of HCC and enhances chemosensitivity to 5-FU in HCC. WSTF combined with 5-FU in HCC can play synergistic effect when applied in the clinical setting.