Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao, Inner Mongolia, China.
Inner Mongolia University for the Nationalities, Tongliao, Inner Mongolia, China.
PLoS One. 2020 Apr 16;15(4):e0231466. doi: 10.1371/journal.pone.0231466. eCollection 2020.
DaHuangWan (DHW) is a traditional herbal medicine used by Mongolian to treat liver cancer for many years. Clinical application of the drug has been shown to help control tumor progression, prolong survival and improve quality of life. However, the underlying mechanisms and side effects of this drug remain unclear, which greatly limits the clinical application and further optimization of DHW. In this study, we found that DHW inhibits the proliferation of hepatoma cells by modulating the epithelial growth factor (EGF) signaling pathway. Berberine and Costunolide are the main active ingredients in DHW. Interestingly, the combination of Berberine and Costunolide has a dramatic synergistic effect on inhibiting the proliferation of hepatoma cells. Neither Berberine nor Costunolide directly block EGFR phosphorylation. Berberine promotes endocytosis of activated EGFR, while as Costunolide increases ubiquitination of EGFR and reduces EGFR recycling to cell membrane distribution, thereby inhibiting EGF signaling. Berberine and Costunolide target two different steps in regulating the EGF signaling, which explains the synergistic anti-cancer effect of DHW. Since Berberine and Costunolide do not directly target EGFR phosphorylation, DHW could be a supplementary medicine to tyrosine kinase inhibitors in cancer therapy.
大黄丸（DHW）是一种传统的草药药物，多年来一直被蒙古人用于治疗肝癌。临床应用表明，该药物有助于控制肿瘤进展、延长生存期并提高生活质量。然而，该药物的潜在机制和副作用仍不清楚，这极大地限制了 DHW 的临床应用和进一步优化。在这项研究中，我们发现 DHW 通过调节表皮生长因子（EGF）信号通路来抑制肝癌细胞的增殖。小檗碱和木香烃内酯是 DHW 的主要活性成分。有趣的是，小檗碱和木香烃内酯的组合对抑制肝癌细胞的增殖具有显著的协同作用。小檗碱和木香烃内酯都不会直接阻断 EGFR 的磷酸化。小檗碱促进激活的 EGFR 内吞，而木香烃内酯增加 EGFR 的泛素化并减少 EGFR 向细胞膜分布的再循环，从而抑制 EGF 信号。小檗碱和木香烃内酯针对调节 EGF 信号的两个不同步骤，这解释了 DHW 的协同抗癌作用。由于小檗碱和木香烃内酯并不直接靶向 EGFR 的磷酸化，DHW 可以作为癌症治疗中酪氨酸激酶抑制剂的辅助药物。
