Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, 266021, China.
Acta Pharmacol Sin. 2020 Dec;41(12):1609-1620. doi: 10.1038/s41401-020-0395-5. Epub 2020 Apr 16.
Sorafenib is currently the standard chemotherapy drug for treatment of advanced hepatocellular carcinoma (HCC). But its efficacy requires improvement, it is imperative to seek therapeutic strategies that combine sorafenib with other anticancer agents. In this study we investigated the synergistic anticancer effect of combining sorafenib and artesunate, an anti-malaria drug derivative, against HCC in vitro and in vivo. We first showed that artesunate (1-100 μM) alone dose-dependently inhibited the proliferation of five HCC cell lines tested with IC values of around 100 μM. Artesunate treatment dose-dependently increased the ROS level in both HuH7 and Hep3B cells; addition of NAC significantly ameliorated the antiproliferation effect of artesunate against HuH7 and Hep3B cells. Then we demonstrated that combination of sorafenib and artesunate exerted synergistic antiproliferation effect and induced synergistic apoptosis in HCC cell lines. In nude mice bearing Hep3B xenografts, combined administration of sorafenib and artesunate significantly enhanced the suppression on tumor growth. We further revealed that sorafenib dose-dependently decreased the levels of p-ERK and p-STAT3, whereas artesunate markedly increased the levels of p-ERK and p-STAT3 in HuH7 and Hep3B cells. When used in combination, sorafenib abolished artesunate-elevated levels of p-STAT3 and p-ERK. Moreover, pharmacological inhibition of ERK by inhibitor PD0325901 or STAT3 by inhibitor Stattic markedly enhanced the anticancer activity of artesunate, suggesting that suppression of ERK and STAT3 signaling by sorafenib contributes to the synergistic anticancer activity against HCC caused by combination of sorafenib and artesunate. Taken together, our results provide an evidence for possible use of sorafenib plus artesunate or artemisinin analogs for treatment of HCC in the future.
索拉非尼目前是治疗晚期肝细胞癌（HCC）的标准化疗药物。但其疗效有待提高，因此迫切需要寻求将索拉非尼与其他抗癌药物联合治疗的策略。在这项研究中，我们研究了索拉非尼和青蒿琥酯（一种抗疟药物衍生物）联合治疗体外和体内 HCC 的协同抗癌作用。我们首先表明，青蒿琥酯（1-100μM）单独作用时，浓度依赖性地抑制了所测试的五种 HCC 细胞系的增殖，IC 值约为 100μM。青蒿琥酯处理剂量依赖性地增加了 HuH7 和 Hep3B 细胞中的 ROS 水平；添加 NAC 可显著改善青蒿琥酯对 HuH7 和 Hep3B 细胞的增殖抑制作用。然后，我们证明索拉非尼和青蒿琥酯联合使用可发挥协同的抗增殖作用，并诱导 HCC 细胞系协同凋亡。在荷瘤裸鼠中，索拉非尼和青蒿琥酯联合给药显著增强了对肿瘤生长的抑制作用。我们进一步揭示，索拉非尼剂量依赖性地降低了 p-ERK 和 p-STAT3 的水平，而青蒿琥酯则显著增加了 HuH7 和 Hep3B 细胞中 p-ERK 和 p-STAT3 的水平。联合使用时，索拉非尼消除了青蒿琥酯升高的 p-STAT3 和 p-ERK 水平。此外，ERK 抑制剂 PD0325901 或 STAT3 抑制剂 Stattic 对 ERK 和 STAT3 信号通路的药理抑制显著增强了青蒿琥酯的抗癌活性，表明索拉非尼对 ERK 和 STAT3 信号通路的抑制作用有助于索拉非尼与青蒿琥酯联合治疗 HCC 的协同抗癌活性。总之，我们的研究结果为未来索拉非尼联合青蒿琥酯或青蒿素类似物治疗 HCC 提供了依据。
