Liver cancer is one of the most lethal malignancies and sorafenib resistance is the main treatment obstacle for patients with advanced liver cancer. Developing drugs that sensitize liver cancer patients to sorafenib is of great importance. Lianhua Qingwen (LHQW), a sort of Traditional Chinese Medicine (TCM) approved by the Chinese Food and Drug Administration (CFDA), is reported to exert synergistic effects with oseltamivir against Influenza virus. However, whether LHQW could exhibit anti-liver cancer effects and enhance the efficacy of sorafenib against liver cancer have not been reported. In the present study, the potential anti-liver cancer effects of LHQW and its synergistic effects with sorafenib were investigated via applying network pharmacology, molecular docking, and in vitro experiments. An “ingredient-compound- target-liver cancer” network was constructed which included 12 ingredients, 164 compounds, and 402 targets. AKT1 was identified as the most hub gene and the PI3K/AKT pathway was revealed as the most enriched pathway. Subsequently, the molecular docking results showed that kaempferol, luteolin, and quercetin were screened as the top 3 compounds which showed the tightest binding to AKT1. Further, the in vitro experiments verified that LHQW significantly inhibited liver cancer cell proliferation and induced apoptosis. Western blot assays confirmed that LHQW could attenuate the PI3K/AKT pathway. Interestingly, LHQW showed a synergistic effect with sorafenib against liver cancer via reducing cell viability, inducing apoptosis, and down- regulating PI3K/AKT pathway. This study broadens the potential application of LHQW and provides insights for liver cancer treatment.

中文翻译：

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连花清瘟通过PI3K/AKT通路发挥抗肝癌作用并与索拉非尼协同作用：整合网络药理学、分子对接和实验验证

肝癌是最致命的恶性肿瘤之一，索拉非尼耐药是晚期肝癌患者的主要治疗障碍。开发使肝癌患者对索拉非尼敏感的药物非常重要。连花清瘟（LHQW）是经国家食品药品监督管理总局（CFDA）批准的一种中药，据报道与奥司他韦对流感病毒具有协同作用。然而，LHQW是否能够发挥抗肝癌作用并增强索拉非尼抗肝癌的疗效尚未见报道。本研究通过应用网络药理学、分子对接和体外实验研究了LHQW潜在的抗肝癌作用及其与索拉非尼的协同作用。构建了“成分-化合物-靶点-肝癌”网络，其中包括12种成分、164种化合物和402个靶点。 AKT1 被确定为最中心基因，PI3K/AKT 通路被揭示为最富集的通路。随后，分子对接结果显示山奈酚、木犀草素和槲皮素被筛选为与 AKT1 结合最紧密的前 3 个化合物。此外，体外实验证实LHQW显着抑制肝癌细胞增殖并诱导细胞凋亡。 Western blot 检测证实 LHQW 可以减弱 PI3K/AKT 通路。有趣的是，LHQW 通过降低细胞活力、诱导细胞凋亡和下调 PI3K/AKT 通路，与索拉非尼发挥协同抗肝癌作用。这项研究拓宽了 LHQW 的潜在应用，并为肝癌治疗提供了见解。