Sun Peiyuan, Wang Zhuoyi, Zhang Ruohan, Li Xuanyou, Xu Boxing, Shen Rui, Sheng Jun, Wang Jing
Key Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, 650201, China.
College of Science, Yunnan Agricultural University, Kunming, 650201, China.
Sci Rep. 2025 Aug 11;15(1):29425. doi: 10.1038/s41598-025-14889-x.
Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases and has gained considerable global attention. Epidermal growth factor receptor (EGFR) plays a key role in NSCLC treatment. NSCLC with wild-type EGFR (WT-EGFR) is not responsive to EGFR tyrosine kinase inhibitors (TKIs), and chemotherapy, such as cisplatin (cDDP), continues to be utilized as a primary clinical treatment. However, the therapeutic efficacy of cDDP remains limited. Therefore, there exists an urgent need for the development of novel therapeutic strategies. Cudratricusxanthone A (CTXA) as a natural bioactive xanthone exhibits potential antitumor activity, but the mechanism has been unknown. In this study, we aimed to evaluate the potential antitumor effect and mechanism of CTXA against NSCLC with WT-EGFR by cell experiments, molecular dynamics simulation and surface plasmon resonance (SPR) technology. Our results showed that CTXA inhibited cell proliferation in NSCLC cells by suppressing the EGFR/Erk/AKT pathway. Additionally, CTXA exhibited antitumor effects by inhibiting the migration of A549 cells, causing G1 phase arrest, and inducing cell apoptosis. Further investigation revealed that these effects were mediated by the binding of CTXA to EGFR, with a K value of 6.302 × 10 M. This interaction may lead to the suppression of EGFR phosphorylation and its downstream signaling. Moreover, the synergistic inhibition of CTXA in combination with cDDP was also found to be mediated by the suppression of the EGFR pathway and its downstream signaling. We demonstrated that CTXA exhibited antitumor activity and enhanced chemosensitivity to cDDP against NSCLC via the EGFR signaling. Our findings indicate that the utilization of CTXA alone or in combination with cDDP represents a potential novel candidate against NSCLC harboring WT-EGFR.
非小细胞肺癌（NSCLC）约占所有肺癌病例的85%，已引起全球广泛关注。表皮生长因子受体（EGFR）在NSCLC治疗中起关键作用。具有野生型EGFR（WT-EGFR）的NSCLC对EGFR酪氨酸激酶抑制剂（TKIs）无反应，顺铂（cDDP）等化疗仍作为主要临床治疗方法。然而，cDDP的治疗效果仍然有限。因此，迫切需要开发新的治疗策略。蛇葡萄素A（CTXA）作为一种天然生物活性氧杂蒽酮具有潜在的抗肿瘤活性，但其机制尚不清楚。在本研究中，我们旨在通过细胞实验、分子动力学模拟和表面等离子体共振（SPR）技术评估CTXA对具有WT-EGFR的NSCLC的潜在抗肿瘤作用及其机制。我们的结果表明，CTXA通过抑制EGFR/Erk/AKT通路抑制NSCLC细胞的增殖。此外，CTXA通过抑制A549细胞的迁移、导致G1期阻滞和诱导细胞凋亡发挥抗肿瘤作用。进一步研究发现，这些作用是由CTXA与EGFR结合介导的，K值为6.302×10⁻⁹ M。这种相互作用可能导致EGFR磷酸化及其下游信号传导的抑制。此外，还发现CTXA与cDDP联合使用的协同抑制作用也是由EGFR通路及其下游信号传导的抑制介导的。我们证明，CTXA通过EGFR信号通路对NSCLC表现出抗肿瘤活性并增强对cDDP的化疗敏感性。我们的研究结果表明，单独使用CTXA或与cDDP联合使用代表了一种针对携带WT-EGFR的NSCLC的潜在新候选药物。
