ReferenceID 2664
Targeted inhibition of c-MET by podophyllotoxin promotes caspase-dependent apoptosis and suppresses cell growth in gefitinib-resistant non-small cell lung cancer cells
Phytomedicine
BACKGROUND: Lung cancer has the highest incidence and cancer-related mortality of all cancers worldwide. Its treatment is focused on molecular targeted therapy. c-MET plays an important role in the development and metast
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- Reference Id
- 2664
- Evidence Id
- 19254
- Core Evidence Id
- 19254
- Source Reference Id
- 5326
- Herb2 Reference Id
- HBREF006123
- Subject Paper Key
- HBIN040358_33039730
- Pubmed Id
- 33039730
- Doi
- 10.1016/j.phymed.2020.153355
- Paper Title
- Targeted inhibition of c-MET by podophyllotoxin promotes caspase-dependent apoptosis and suppresses cell growth in gefitinib-resistant non-small cell lung cancer cells
- Paper Abstract
- BACKGROUND: Lung cancer has the highest incidence and cancer-related mortality of all cancers worldwide. Its treatment is focused on molecular targeted therapy. c-MET plays an important role in the development and metastasis of various human cancers and has been identified as an attractive potential anti-cancer target. Podophyllotoxin (PPT), an aryltetralin lignan isolated from the rhizomes of Podophyllum species, has several pharmacological activities that include anti-viral and anti-cancer effects. However, the mechanism of the anti-cancer effects of PPT on gefitinib-sensitive (HCC827) or -resistant (MET-amplified HCC827GR) non-small cell lung cancer (NSCLC) cells remains unexplored. PURPOSE: In the present study, we investigated the underlying mechanisms of PPT-induced apoptosis in NSCLC cells and found that the inhibition of c-MET kinase activity contributed to PPT-induced cell death. METHODS: The regulation of c-MET by PPT was examined by pull-down assay, ATP-competitive binding assay, kinase activity assay, molecular docking simulation, and Western blot analysis. The cell growth inhibitory effects of PPT on NSCLC cells were assessed using the MTT assay, soft agar assay, and flow cytometry analysis. RESULTS: PPT could directly interact with c-MET and inhibit kinase activity, which further induced the apoptosis of HCC827GR cells. In contrast, PPT did not significantly affect EGFR kinase activity. PPT significantly inhibited the cell viability of HCC827GR cells, whereas the PPT-treated HCC827 cells showed a cell viability of more than 80%. PPT dose-dependently induced G2/M cell cycle arrest, as shown by the downregulation of cyclin B1 and cdc2, and upregulation of p27 expression in HCC827GR cells. Furthermore, PPT treatment induced Bad expression and downregulation of Mcl-1, survivin, and Bcl-xl expression, subsequently activating multi-caspases. PPT thereby induced caspase-dependent apoptosis in HCC827GR cells. CONCLUSION: These results suggest the potential of PPT as a c-MET inhibitor to overcome tyrosine kinase inhibitor resistance in lung cancer.
- Journal
- Phytomedicine
- Publish Year
- 2021
- Experiment Subject
- human; gefitinib-sensitive (hcc827) or -resistant (met-amplified hcc827gr; hcc827 cells; hcc827gr cells; nsclc cells
- Experiment Type
- Cell Experiment
- Phenotype Related
- Lung Cancer; Cancers; Non-small Cell Lung Cancer
- Paper Title Cn
- Paper Title En
- Targeted inhibition of c-MET by podophyllotoxin promotes caspase-dependent apoptosis and suppresses cell growth in gefitinib-resistant non-small cell lung cancer cells
- Bilingual Status
- semi_complete