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Network Pharmacology Approach and Experimental Verification to Explore the Anti-NSCLC Mechanism of Grifolic Acid
Xiangdan Cuan1, Jinxian Wang1,2, Yue Zhao1,2
1Key Laboratory of Pu-Er Tea Science, Ministry of Education, Yunnan Agricultural University, Heilongtan, North of Kunming, Kunming 650201, China.
Abstract:
Lung cancer is the leading cause of cancer-related death. Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers and over 60% express wild-type EGFR (WT-EGFR); however, EGFR tyrosine kinase inhibitors (TKIs) have limited effect in most patients with WT-EGFR tumors. In this study, we applied network pharmacology screening and MTT screening of bioactive compounds to obtain one novel grifolic acid that may inhibit NSCLC through the EGFR-ERK1/2 pathway. Through the PPI network and machine learning, we identified two hub genes, EGFR and AKT1, as potential therapeutic targets. Molecular docking confirmed that the grifolic acid could effectively bind to the key target, EGFR. Using the NSCLC cell line NCI-H1781 as an in vitro model, we evaluated the effect of the drugs' combination on viability, apoptosis, and clonogenicity capacity. In vitro studies showed that combined treatment decreased cell viability, increased activation PARP, and caused cell cycle redistribution and significantly greater inhibition of pEGFR and pAKT. This study not only provides new insights into the mechanism of grifolic acid against NSCLC but also important information and new research ideas for the discovery of anti-NSCLC compounds from natural products.
Insights
A novel compound, grifolic acid, shows potential in inhibiting non-small cell lung cancer (NSCLC) by targeting the EGFR-ERK1/2 pathway. This natural product may offer new therapeutic strategies for NSCLC treatment.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality.
- Wild-type EGFR (WT-EGFR) is present in over 60% of NSCLC cases, but EGFR tyrosine kinase inhibitors (TKIs) show limited efficacy.
- Novel therapeutic targets and natural compounds are needed for effective NSCLC treatment.
Purpose of the Study:
- To identify novel compounds and therapeutic targets for NSCLC.
- To investigate the potential of grifolic acid in inhibiting NSCLC via the EGFR-ERK1/2 pathway.
- To explore EGFR and AKT1 as key therapeutic targets.
Main Methods:
- Network pharmacology and MTT screening were used to identify grifolic acid.
- Protein-protein interaction (PPI) network and machine learning identified hub genes (EGFR, AKT1).
- Molecular docking validated grifolic acid's binding to EGFR. In vitro studies used NSCLC cell line NCI-H1781.
Main Results:
- Grifolic acid demonstrated potential inhibition of NSCLC through the EGFR-ERK1/2 pathway.
- EGFR and AKT1 were identified as key therapeutic targets.
- In vitro studies showed combined treatment reduced cell viability, increased PARP activation, altered cell cycle, and inhibited pEGFR and pAKT.
Conclusions:
- Grifolic acid shows promise as an anti-NSCLC agent targeting the EGFR-ERK1/2 pathway.
- EGFR and AKT1 are validated as crucial targets for NSCLC therapy.
- This study provides insights into natural products for NSCLC drug discovery.
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