Dihydroartemisinin enhances the inhibitory effect of sorafenib on HepG2 cells by inducing ferroptosis and inhibiting energy metabolism

作者：Zhao Cui, Huajing Wang, Shuo Li, Tingting Qin, Hang Shi, Ji Ma, Lanfang Li, Guihua Yu, Tingliang Jiang, Canghai Li · 发表于：Journal of Pharmacological Sciences · 年份：2021 · DOI：10.1016/j.jphs.2021.09.008 · 被引用次数：53 · 研究领域：Ferroptosis and cancer prognosis、Cancer, Lipids, and Metabolism、Drug Transport and Resistance Mechanisms

Although sorafenib (Sora) shows improved efficacy in clinical liver cancer therapy, its therapeutic efficacy is still greatly limited due to side effects as well as drug resistance. Thus new drug intervention strategies are imperative. Our research showed the combined application of Dihydroartemisinin (DHA) and Sora had a synergistic inhibitory effect on HepG2 and SW480 cells, and DHA enhanced Sora efficacy on xenograft tumor in nude mice. DHA and Sora significantly inhibited the cell energy metabolism by decreasing the ATP synthesis rate of oxidative phosphorylation and glycolysis rate, and induced ferroptosis by increasing the level of lipid reactive oxygen species (L-ROS), labile iron pool (LIP) as well as malondialdehyde (MDA) and decreasing the level of glutathione (GSH) in HepG2 cells. In addition, DHA and Sora significantly decreased the levels of SLC7A11 (xCT), GCLC, GPX4, and HO-1 protein in HepG2 cells. Importantly, the above-mentioned indicators changed more significantly after the combined application of DHA and Sora as compared with Sora. In conclusion, DHA and Sora had the same mechanism, and the combined application of them could have a synergistic anti-tumor effect by inducing ferroptosis and inhibiting energy metabolism in HepG2 cells.