Luteolin overcomes acquired resistance to osimertinib in non-small cell lung cancer cells by targeting the HGF-MET-Akt pathway.

Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has overcome the acquired resistance of first- and second-generation EGFR-TKIs due to the EGFR T790M mutation in non-small cell lung cancer (NSCLC). However, acquired resistance to osimertinib remains a significant clinical challenge. Luteolin, a natural flavonoid from traditional Chinese medicine, has exerted antitumor effects in various tumors. In this study, we investigated whether the natural flavonoid luteolin can enhance the antitumor effects of osimertinib in NSCLC cells. We established an acquired osimertinib-resistant cell line, H1975/OR, and evaluated the effects of luteolin and osimertinib alone and in combination on proliferation, migration, invasion, and apoptosis of H1975/OR cells. The potential mechanisms by which the combination of luteolin and osimertinib exert their effects were investigated by PCR, western blot, gene silencing, molecular docking, SPR and kinase activity analysis. The combination of luteolin and osimertinib inhibited the proliferation, migration, and invasion of H1975/OR cells and promoted apoptosis. We identified mesenchymal-epithelial transition factor (MET) amplification and overactivation as important resistance mechanisms of H1975/OR cells. The combination downregulated the gene and protein expression of MET and inhibited its protein phosphorylation, thereby blocking the activation of the downstream Akt pathway. Additionally, the mediated effects of MET on the synergistic effect of luteolin and osimertinib were confirmed by silencing of MET. Luteolin strongly bound with nonphosphorylated MET by occupying the active pocket of MET and inhibiting its activation. Notably, the combination also downregulated the expression of autocrine hepatocyte growth factor (HGF), the sole ligand of MET. In conclusion, luteolin can synergize with osimertinib to overcome MET amplification and overactivation-induced acquired resistance to osimertinib by suppressing the HGF-MET-Akt pathway, suggesting the clinical potential of combining luteolin with osimertinib in NSCLC patients with acquired resistance.

Integration analysis using bioinformatics and experimental validation on the clinical and biological significance of TSLP in cancers.

Thymic stromal lymphopoietin (TSLP) has significantly impacted the development and progression of various neoplastic disorders. To comprehensively evaluate the diverse significance of TSLP in malignant tumors, we first integrative analyze the TSLP expression level in paired and unpaired pan-cancer tissue and cell line, compared against the normal tissue. The correlation between TSLP expression, molecular subtypes, immune subtypes, diagnostic value, and prognostic value in pan-cancer was also investigated. We then explored the impact of TSLP expression on multifaced immune cell infiltration and subsequent clinical outcomes in lung adenocarcinoma (LUAD) patients. and conducted cellular experiments to functionally examine the effect of TSLP on cell proliferation, apoptosis, cell cycle, migration, and invasion in LUAD. The anti-neoplastic mechanism of TSLP was further investigated by qRT-PCR and western blotting. Our findings reveal that TSLP expression is abnormally low in various cancers compared to normal tissue and is associated with different molecular and immune subtypes of cancers. Moreover, ROC and survival analysis results suggest that TSLP expression is correlated with the diagnostic, prognostic, clinical features, and immune cells of LUAD patients. Cell experiments showed that overexpression of TSLP elicited a significant reduction in LUAD cell viability, promoted cell apoptosis, impeded cell cycle progression in the G2/M phase, and inhibited cell migration and invasion. In addition, TSLP inhibited LUAD progression through the JAK1/STAT3 signaling pathway. Therefore, targeting TSLP shows potential as a therapeutic strategy for pan-cancer, particularly for LUAD, and as a biomarker for predicting the prognosis of this malignancy.

Efficacy of astragalus in the treatment of radiation-induced lung injury based on traditional Chinese medicine: A systematic review and meta-analysis of 25 RCTs.

BACKGROUND: Astragalus (Hedysarum Multijugum Maxim., Huangqi) is a Chinese herbal medicine, and according to the theory of traditional Chinese medicine (TCM), Chinese medicinal preparations containing astragalus can be used clinically to treat radiation-induced lung injury (RILI). To systematically review the efficacy and safety of Chinese medicinal preparations containing astragalus in the prevention and treatment of RILI by means of meta-analysis. METHODS: A systematic literature on randomized controlled trials (RCTs) of prescriptions containing astragalus in the treatment of RILI by Pubmed, Embase, Web of Science, Cochrane Library, China Biomedical Literature Database, China National Knowledge Infrastructure, China Science and Technology Journal Database, WANFANG Database. The retrieval time is from the establishment of the database to January 18, 2022. Meta-analysis, heterogeneity test and sensitivity analysis were performed on eligible RCTs using Revman 5.4 software and STATA 17.0 software, and a "funnel plot" was used to analyze potential publication bias. RESULTS: A total of 25 RCTs were included, including 1762 patients, and the most widely used drugs were heat-clearing and detoxifying, yin-nourishing and qi-nourishing. The prescriptions containing astragalus can significantly reduce the total incidence of RILI (P < .01), improve the total effective rate and cure rate of RILI (P < .01), improve the quality of life of patients, alleviate breathing difficulties and reduce the expression of inflammatory factors (P < .01), and no adverse reactions related to TCM treatment were reported. CONCLUSION: The traditional Chinese medicinal preparation containing astragalus can effectively alleviate the clinical symptoms of RILI, reduce the toxic side effects, and is safe to use in clinic.