State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, SAR, PR China.
State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, SAR, PR China; Department of Chemistry, Southern University of Science and Technology, Shenzhen, Guangdong, PR China.
Pharmacol Res. 2020 Sep;159:104934. doi: 10.1016/j.phrs.2020.104934. Epub 2020 May 25.
Tyrosine kinase inhibitors (TKIs) have been widely used for the clinical treatment of patients with non-small cell lung cancer (NSCLC) harboring mutations in the EGFR. Unfortunately, due to the secondary mutation in EGFR, eventual drug-resistance is inevitable. Therefore, to overcome the resistance, new agent is urgently required. Chelidonine, extracted from the roots of Chelidonium majus, was proved to effectively suppress the growth of NSCLC cells with EGFR double mutation. Proteomics analysis indicated that mitochondrial respiratory chain was significantly inhibited by chelidonine, and inhibitor of AMPK effectively blocked the apoptosis induced by chelidonine. Molecular dynamics simulations indicated that chelidonine could directly bind to EGFR and showed a much higher binding affinity to EGFR than EGFR, which demonstrated that chelidonine could selectively inhibit the phosphorylation of EGFR in cells with EGFR double-mutation. In vivo study revealed that chelidonine has a similar inhibitory effect like second generation TKI Afatinib. In conclusion, targeting EGFR and inhibition of mitochondrial function is a promising anti-cancer therapeutic strategy for inhibiting NSCLC with EGFR mutation and TKI resistance.
酪氨酸激酶抑制剂 (TKIs) 已广泛用于治疗携带 EGFR 突变的非小细胞肺癌 (NSCLC) 患者。不幸的是，由于 EGFR 的继发突变，最终不可避免地会产生耐药性。因此，迫切需要新的药物来克服耐药性。从Chelidonium majus 的根中提取的白屈菜碱已被证明可有效抑制具有 EGFR 双重突变的 NSCLC 细胞的生长。蛋白质组学分析表明，白屈菜碱可显著抑制线粒体呼吸链，而 AMPK 抑制剂可有效阻断白屈菜碱诱导的细胞凋亡。分子动力学模拟表明，白屈菜碱可以直接与 EGFR 结合，并且与 EGFR 的结合亲和力比 EGFR 高得多，这表明白屈菜碱可以选择性地抑制具有 EGFR 双重突变的细胞中 EGFR 的磷酸化。体内研究表明，白屈菜碱具有与第二代 TKI 阿法替尼相似的抑制作用。总之，靶向 EGFR 和抑制线粒体功能是抑制具有 EGFR 突变和 TKI 耐药性的 NSCLC 的一种有前途的抗癌治疗策略。
