Identification of solamargine as a cisplatin sensitizer through phenotypical screening in cisplatin-resistant NSCLC organoids
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Published on: November 22, 2021
Yi Han1, Jianquan Shi2, Ziwei Xu1
1Department of Thoracic Surgery, Beijing Chest Hospital, Capital Medical University and Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China.
Abstract:
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.
Insights
Solamargine, a natural compound, sensitizes cisplatin-resistant lung cancer by inhibiting the hedgehog pathway. This finding offers a potential new therapeutic strategy for advanced lung cancer patients who do not respond to chemotherapy.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Cisplatin (DDP) resistance is a major challenge in treating advanced lung cancer, leading to treatment failure.
- Identifying novel DDP sensitizers and understanding their mechanisms is crucial for improving patient outcomes.
Purpose of the Study:
- To identify natural compounds that can sensitize cisplatin-resistant lung cancer.
- To elucidate the molecular mechanisms by which these compounds exert their effects.
- To evaluate the synergistic potential of identified sensitizers with DDP.
Main Methods:
- Screening of a natural product library using cisplatin-resistant organoids derived from patient biopsies.
- Cell cycle analysis (G0/G1 arrest) and apoptosis assays in DDP-resistant lung cancer cell lines.
- Gene expression analysis, KEGG pathway analysis, Gli responsive element (GRE) reporter gene assay, and BODIPY-cyclopamine binding assay to investigate pathway inhibition.
Main Results:
- Solamargine was identified as a potent DDP sensitizer.
- Solamargine induced G0/G1 cell cycle arrest and apoptosis in DDP-resistant lung cancer cells.
- Solamargine suppressed the hedgehog signaling pathway by directly binding to the SMO protein.
- Solamargine and DDP exhibited a synergistic effect in inhibiting DDP-resistant lung cancer cell lines.
Conclusions:
- Solamargine acts as a hedgehog pathway inhibitor and a DDP sensitizer.
- Solamargine represents a promising therapeutic agent for overcoming DDP resistance in advanced lung cancer.
- This study provides a novel therapeutic direction for treating DDP-resistant lung cancer.
