Department of Hematologic Oncology, State Key Laboratory of Oncology in South China/Cancer Center, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China; Department of Medical Oncology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
TUM School of Medicine, Technical University Munich, 81675, Munich, Germany.
Biochem Biophys Res Commun. 2021 Jun 18;558:14-21. doi: 10.1016/j.bbrc.2021.04.047. Epub 2021 Apr 22.
Sorafenib remains the standard first-line treatment for advanced hepatocellular carcinoma (HCC), although other clinical trials are currently underway for treatments that show better curative effects. However, some patients are not sensitive to sorafenib. α-Mangostin, extracted from the pericarp of the mangosteen, which is widely used as a traditional medicine, has anticancer and anti-proliferative properties in various types of cancers, including HCC. In the present study, we found that combining sorafenib and α-Mangostin could be synergistically toxic to HCC both in vitro and in vivo. We then demonstrated that the combination of sorafenib and α-Mangostin enhances the inhibition of cell proliferation in HCC cell lines. Combination therapy leads directly to apoptosis. In xenograft mouse models, the in vivo safety and effectivity was confirmed by a reduction in tumor size after combination treatment. RNA sequencing and protein testing showed that the expression of LRRC8A and RNF181 genes and mTOR and MAPK pathways may be associated with the synergistic effect of the two drugs. In conclusion, our results highlight the synergistic effect of the combination of sorafenib and α-Mangostin, which indicates a potential treatment for advanced HCC for patients that are not sensitive to sorafenib therapy.
索拉非尼仍然是晚期肝细胞癌 (HCC) 的标准一线治疗药物，尽管目前正在进行其他临床试验以寻找疗效更好的治疗方法。然而，有些患者对索拉非尼不敏感。从山竹果皮中提取的 α-倒捻子素有抗癌和抗增殖作用，在包括 HCC 在内的各种类型的癌症中均有作用。在本研究中，我们发现索拉非尼和 α-倒捻子素联合使用对 HCC 细胞系具有协同毒性作用。我们进一步证明，索拉非尼和 α-倒捻子素联合抑制 HCC 细胞系的增殖。联合治疗直接导致细胞凋亡。在异种移植小鼠模型中，通过联合治疗后肿瘤体积缩小证实了体内安全性和有效性。RNA 测序和蛋白质检测表明，LRRC8A 和 RNF181 基因的表达以及 mTOR 和 MAPK 通路可能与两种药物的协同作用有关。总之，我们的结果强调了索拉非尼和 α-倒捻子素联合使用的协同作用，这为对索拉非尼治疗不敏感的晚期 HCC 患者提供了一种潜在的治疗方法。
