Synergistic anticancer effects of ginsenoside CK and gefitinib against gefitinib-resistant NSCLC by regulating the balance of angiogenic factors through HIF-1α/VEGF

Xiaoping Song; Lina Wang; Panpan Cai; Ying Xu; Qingchao Liu; Daidi Fan

doi:10.1016/j.taap.2024.116938

Synergistic anticancer effects of ginsenoside CK and gefitinib against gefitinib-resistant NSCLC by regulating the balance of angiogenic factors through HIF-1α/VEGF

Toxicol Appl Pharmacol. 2024 Apr 19:486:116938. doi: 10.1016/j.taap.2024.116938. Online ahead of print.

Authors

Xiaoping Song¹, Lina Wang², Panpan Cai², Ying Xu², Qingchao Liu³, Daidi Fan⁴

Affiliations

¹ 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.
² Department of Pharmaceutical Engineering, School of Chemical Engineering, Northwest University, 229 Taibai North Road, Xi'an 710069, China.
³ 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. Electronic address: liuqc21@nwu.edu.cn.
⁴ 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. Electronic address: fandaidi@nwu.edu.cn.

PMID: 38642809
DOI: 10.1016/j.taap.2024.116938

Abstract

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.

Keywords: Drug Resistance; Gefitinib; Ginsenoside CK; HIF-1α/VEGF.