School of Pharmacy, Fudan University, Shanghai, China.
Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China.
Phytother Res. 2023 Feb;37(2):592-610. doi: 10.1002/ptr.7637. Epub 2022 Sep 30.
Sorafenib (SF), a multi-kinase inhibitor, is the first FDA-approved systemic chemotherapy drug for advanced hepatocellular carcinoma (HCC). However, its clinical application is limited by severe toxicity and side effects associated with high applied doses. Sophora alopecuroides L. is traditionally used as Chinese herbal medicine for treating gastrointestinal diseases, bacillary dysentery, viral hepatitis, and other diseases, and exerts an important role in anti-tumor. Hence, we investigated the synergistic actions of seventeen flavonoids from this herb combined with SF against HCC cell lines and their primary mechanism. In the experiment, most compounds were found to prominently enhance the inhibitory effects of SF on HCC cells than their alone treatment. Among them, three compounds leachianone A (1), sophoraflavanone G (3), and trifolirhizin (17) exhibited significantly synergistic anticancer activities against MHCC97H cells at low concentration with IC of SF reduced by 5.8-fold, 3.6-fold, and 3.5-fold corresponding their CI values of 0.49, 0.66, and 0.46 respectively. Importantly, compounds 3 or 17 combined with SF could synergistically induce MHCC97H cells apoptosis via the endogenously mitochondrial-mediated apoptotic pathway, involving higher Bax/Bcl-2 expressions with the activation of caspase-9 and -3, and arrest the cell cycle in G1 phases. Strikingly, this synergistic effect was also closely related to the co-suppression of ERK and AKT signaling pathways. Furthermore, compound 3 significantly enhanced the suppression of SF on tumor growth in the HepG2 xenograft model, with a 79.3% inhibition ratio at high concentration, without systemic toxicity, compared to either agent alone. These results demonstrate that the combination treatment of flavonoid 3 and SF at low doses exert synergistic anticancer effects on HCC cells in vitro and in vivo.
索拉非尼（SF）是一种多激酶抑制剂，是首个被美国食品药品监督管理局批准用于治疗晚期肝细胞癌（HCC）的系统化疗药物。然而，由于高剂量应用相关的严重毒性和副作用，其临床应用受到限制。苦参是传统的中草药，用于治疗胃肠道疾病、细菌性痢疾、病毒性肝炎等疾病，并在抗肿瘤方面发挥重要作用。因此，我们研究了该草药中的 17 种黄酮类化合物与 SF 联合应用对 HCC 细胞系的协同作用及其主要机制。在实验中，大多数化合物被发现比单独用药更显著地增强 SF 对 HCC 细胞的抑制作用。其中，三种化合物 leachianone A（1）、苦参黄酮 G（3）和三叶豆紫檀苷（17）在低浓度下对 MHCC97H 细胞表现出显著的协同抗癌活性，相应的 SF 抑制作用降低 5.8 倍、3.6 倍和 3.5 倍，CI 值分别为 0.49、0.66 和 0.46。重要的是，化合物 3 或 17 与 SF 联合应用可通过内源性线粒体介导的凋亡途径协同诱导 MHCC97H 细胞凋亡，涉及 Bax/Bcl-2 表达升高，caspase-9 和 -3 的激活，以及细胞周期在 G1 期停滞。引人注目的是，这种协同作用还与 ERK 和 AKT 信号通路的共同抑制密切相关。此外，化合物 3 可显著增强 SF 对 HepG2 异种移植模型中肿瘤生长的抑制作用，高浓度时抑制率为 79.3%，与单独使用任一药物相比，无全身毒性。这些结果表明，低剂量的黄酮类化合物 3 与 SF 联合治疗在体外和体内对 HCC 细胞具有协同抗癌作用。
