Synergistic antitumor activity of oridonin and arsenic trioxide on hepatocellular carcinoma cells

Abstract

Although arsenic trioxide (As 2O 3) has been successfully employed in treatment of patients with APL (acute promyelocytic leukemia), the sensitivity of solid tumor cells to this treatment was much lower than APL cells. The single agent of As 2O 3 was inefficient for treatment of hepatocellular carcinoma (HCC) in phase II trial demonstrating that new modalities of treatment with enhanced therapeutic effect are needed. In this study, we showed that oridonin, a diterpenoid isolated from traditional Chinese medicine Rabdosia rubescences, greatly potentiated apoptosis induced by As 2O 3 in hepatocellular carcinoma cells. The synergistic pro-apoptosis effect of combination of these two drugs led to increase in intracellular reactive oxygen species (ROS) level and N-acetyl-L-cysteine (NAC), a thiol-containing anti-oxidant, was able to completely block the effect. The combination treatment induced ROS-dependent decrease in mitochondrial membrane potential (MMP) decrease, and relocation of Bax and cytochrome C. Besides, oridonin dramatically increased the intracellular Ca 2+ overload triggered by As 2O 3. Furthermore, the co-treatment of oridonin and As 2O 3 induced ROS-mediated down-regulation of Akt and XIAP, and inhibition of NF-κB activation. The two drug combination enhanced tumor suppression activity in murine HCC model compared with single agent treatment in vivo. These findings demonstrate that oridonin can sensitize hepatocellular carcinoma cells to As 2O 3 treatment and will facilitate the optimization of As 2O 3 therapy for HCC patients.