Han Yi, Shi Jianquan, Xu Ziwei, Zhang Yushan, Cao Xiaoqing, Yu Jianhua, Li Jie, Xu Shaofa
Department of Thoracic Surgery, Beijing Chest Hospital, Capital Medical University and Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China.
Department of Critical Care Medicine, Beijing Chest Hospital, Capital Medical University and Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China.
Front Pharmacol. 2022 Aug 10;13:802168. doi: 10.3389/fphar.2022.802168. eCollection 2022.
Although Cisplatin (DDP) is a widely used first-line chemotherapy medication, DDP resistance is one of the main causes of treatment failure in advanced lung cancer. Therefore, it is urgent to identify DDP sensitizers and investigate the underlying molecular mechanisms. Here we utilized DDP-resistant organoids established from tumor biopsies of patients with relapsed lung cancers. In this study, we identified Solamargine as a potential DDP sensitizer through screening a natural product library. Mechanically, Solamargine induced G0/G1-phase arrest and apoptosis in DDP-resistant lung cancer cell lines. Gene expression analysis and KEGG pathway analysis indicated that the hedgehog pathway was suppressed by Solamargine. Moreover, Gli responsive element (GRE) reporter gene assay and BODIPY-cyclopamine binding assay showed that Solamargine inhibited the hedgehog pathway via direct binding to SMO protein. Interestingly, Solamargine and DDP showed a synergetic effect in inhibiting DDP-resistant lung cancer cell lines. Taken together, our work herein revealed Solamargine as a hedgehog pathway inhibitor and DDP-sensitizer, which might provide a new direction for further treatment of advanced DDP-resistant lung cancer patients.
尽管顺铂（DDP）是一种广泛使用的一线化疗药物，但顺铂耐药是晚期肺癌治疗失败的主要原因之一。因此，迫切需要鉴定顺铂增敏剂并研究其潜在的分子机制。在此，我们利用从复发性肺癌患者的肿瘤活检中建立的顺铂耐药类器官。在本研究中，我们通过筛选天然产物文库鉴定了澳洲茄碱作为一种潜在的顺铂增敏剂。机制上，澳洲茄碱在顺铂耐药肺癌细胞系中诱导G0/G1期阻滞和凋亡。基因表达分析和KEGG通路分析表明，刺猬信号通路被澳洲茄碱抑制。此外，Gli反应元件（GRE）报告基因测定和硼二吡咯-环杷明结合测定表明，澳洲茄碱通过直接结合SMO蛋白抑制刺猬信号通路。有趣的是，澳洲茄碱和顺铂在抑制顺铂耐药肺癌细胞系方面显示出协同作用。综上所述，我们的工作揭示了澳洲茄碱作为一种刺猬信号通路抑制剂和顺铂增敏剂，这可能为进一步治疗晚期顺铂耐药肺癌患者提供新的方向。
