Department of Pharmaceutical Engineering, School of Chemical Engineering, Northwest University, 229 Taibai North Road, Xi'an 710069, China; Engineering Research Center of Western Resource Innovation Medicine Green Manufacturing, Ministry of Education, School of Chemical Engineering, Northwest University, Xi'an 710069, China; Biotech. & Biomed. Research Institute, Northwest University, 229 Taibai North Road, Xi'an 710069, China.
Department of Pharmaceutical Engineering, School of Chemical Engineering, Northwest University, 229 Taibai North Road, Xi'an 710069, China.
Toxicol Appl Pharmacol. 2024 May;486:116938. doi: 10.1016/j.taap.2024.116938. Epub 2024 Apr 19.
Drug resistance is a serious problem for gefitinib in the treatment of lung cancer. Ginsenoside CK, a metabolite of diol ginsenosides, have many excellent pharmacological activities, but whether ginsenoside CK can overcome gefitinib resistance remains unclear. In our study, the sensitizing activity of ginsenoside CK on gefitinib-resistant non-small cell lung cancer (NSCLC) in vitro and in vivo was investigated. Ginsenoside CK was confirmed to enhance the anti-proliferation, pro-apoptotic and anti-migration effects of gefitinib in primary and acquired resistant NSCLC. Furthermore, the combined administration of CK and gefitinib effectively promoted the sensitivity of lung cancer xenograft to gefitinib in vivo, and the tumor inhibition rate reached 70.97% (vs. gefitinib monotherapy 32.65%). Subsequently, tubule formation experiment and western blot results showed that co-treatment of ginsenoside CK inhibited the angiogenesis ability of HUVEC cells, and inhibited the expression of HIF-1α, VEGF, FGF and MMP2/9. More interestingly, ginsenoside CK co-treatment enhanced the expression of anti-angiogenic factor PF4, increased pericellular envelope, and promoted the normalization of vascular structure. In conclusion, ginsenoside CK improved the resistance of gefitinib by regulating the balance of angiogenic factors through down-regulating the HIF-1α/VEGF signaling pathway, providing a theoretical basis for improving the clinical efficacy of gefitinib and applying combined strategies to overcome drug resistance.
药物耐药性是吉非替尼治疗肺癌的一个严重问题。二醇型人参皂苷的代谢产物人参皂苷 CK 具有许多优异的药理活性，但人参皂苷 CK 是否能克服吉非替尼耐药性尚不清楚。在我们的研究中，研究了人参皂苷 CK 对体外和体内吉非替尼耐药性非小细胞肺癌（NSCLC）的增敏活性。证实人参皂苷 CK 增强了原发性和获得性耐药 NSCLC 中吉非替尼的抗增殖、促凋亡和抗迁移作用。此外，CK 和吉非替尼联合给药有效地促进了肺癌异种移植对吉非替尼的敏感性，肿瘤抑制率达到 70.97%（vs. 吉非替尼单药治疗 32.65%）。随后，管腔形成实验和 Western blot 结果表明，人参皂苷 CK 联合治疗抑制了 HUVEC 细胞的血管生成能力，并抑制了 HIF-1α、VEGF、FGF 和 MMP2/9 的表达。更有趣的是，人参皂苷 CK 联合治疗通过下调 HIF-1α/VEGF 信号通路增强了抗血管生成因子 PF4 的表达，增加了细胞周包被，促进了血管结构的正常化。总之，人参皂苷 CK 通过调节血管生成因子的平衡来改善吉非替尼的耐药性，为提高吉非替尼的临床疗效和应用联合策略克服耐药性提供了理论依据。
