Zhao Weijia, Bai Binglong, Hong Zhong, Zhang Xuming, Zhou Bin
Department of Hepatobiliary Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, People's Republic of China.
ACS Omega. 2020 Sep 18;5(38):24838-24847. doi: 10.1021/acsomega.0c03527. eCollection 2020 Sep 29.
Sorafenib (SORA), a multi kinase inhibitor, is the standard first-line targeted therapy approved by the Food and Drug Administration for advanced hepatocellular carcinoma (HCC). However, emerging evidence from clinical practice indicates that SORA alone has only moderate antitumor effects and could not completely inhibit the progression of the disease. Therefore, it is very necessary and urgent to develop novel combination therapy to improve the clinical outcomes of SORA. The pharmacological study on the chemosensitizing effects of natural products has become a hotspot in recent years, which is commonly thought to be a potential way to improve the effectiveness of drugs in clinical use. Berbamine (BBM) has potential sensitizing effects in multiple chemotherapies and target therapy. However, it remains unclarified whether the combination of BBM and SORA as a treatment could exert a synergistic effect on HCC cell lines. In this study, we first investigated whether BBM can increase the sensitivity of HCC cell lines to SORA. The results revealed that the combination of BBM and SORA could synergistically inhibit the growth of two HCC cell lines and promoted their apoptosis. Mechanistically, our results showed that BBM exerted a dose-dependent inhibitory effect on the basal and IL-6-induced STAT3 activation of HCC cell lines. In addition, the combined treatment of BBM and SORA synergistically suppressed STAT3 phosphorylation at Tyr705 and knockdown of STAT3 abolished the sensitization effect of BBM, indicating that BBM's sensitization effect is mainly mediated by its inhibition of STAT3. These findings identify a new type of natural STAT3 inhibitor and provide a novel approach to the enhancement of SORA efficacy by blocking the activation of STAT3.
索拉非尼（SORA）是一种多激酶抑制剂，是美国食品药品监督管理局批准用于晚期肝细胞癌（HCC）的标准一线靶向治疗药物。然而，临床实践中不断出现的证据表明，单独使用索拉非尼仅具有中等抗肿瘤作用，无法完全抑制疾病进展。因此，开发新型联合治疗方案以改善索拉非尼的临床疗效非常必要且迫切。近年来，关于天然产物化学增敏作用的药理学研究已成为热点，人们普遍认为这是提高临床用药有效性的一种潜在途径。小檗胺（BBM）在多种化疗和靶向治疗中具有潜在的增敏作用。然而，BBM与索拉非尼联合治疗对肝癌细胞系是否能发挥协同作用仍不明确。在本研究中，我们首先探究了BBM是否能增加肝癌细胞系对索拉非尼的敏感性。结果显示，BBM与索拉非尼联合可协同抑制两种肝癌细胞系的生长并促进其凋亡。机制上，我们的结果表明，BBM对肝癌细胞系的基础及IL-6诱导的STAT3激活具有剂量依赖性抑制作用。此外，BBM与索拉非尼联合治疗可协同抑制Tyr705位点的STAT3磷酸化，敲低STAT3可消除BBM的增敏作用，表明BBM的增敏作用主要通过抑制STAT3介导。这些发现鉴定出一种新型天然STAT3抑制剂，并提供了一种通过阻断STAT3激活来增强索拉非尼疗效的新方法。
