Background: Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. The inhibition of epidermal growth factor receptor (EGFR) signaling by tyrosine kinase inhibitors or monoclonal antibodies plays a key role in NSCLC treatment. Unfortunately, these treatment strategies are limited by eventual resistance and cell lines with differential EGFR status. Therefore, new therapeutic strategies for NSCLC are urgently required. Methods: To improve the stability and absorption of (−)-epigallocatechin-3-gallate (EGCG), we synthesized a series of EGCG derivatives. The antitumor activities of EGCG derivatives with or without cisplatin were investigated in vitro and vivo. Cell proliferation, cell cycle distribution and apoptosis were measured in NSCLC cell lines and in vivo in a NCI-H441 xenograft model. Results: We found that the EGCG derivatives inhibited cell viability and colony formation, caused cell cycle redistribution, and induced apoptosis. More importantly, the combination of the EGCG derivative and cisplatin led to increased growth inhibition, caused cell cycle redistribution, and enhanced the apoptosis rate compared to either compound alone. Consistent with the experiments in vitro, EGCG derivatives plus cisplatin significantly reduced tumor growth. Conclusions: The combination treatment was found to inhibit the EGFR signaling pathway and decrease the expression of p-EGFR, p-AKT, and p-ERK in vitro and vivo. Our results suggest that compound 3 is a novel potential compound for NSCLC patients.

Background: Alpiniae oxyphyllae Fructus (AOF) is a medicinal and edible resource that holds potential to ameliorate hyperuricemia (HUA), yet its mechanism of action warrants further investigation. Methods: We performed network pharmacology, molecular docking, molecular dynamics simulation, and in vitro experiments to investigate the potential action and mechanism of AOF against HUA. Results: The results indicate that 48 potential anti-HUA targets for 4 components derived from AOF were excavated and predicted through public databases. Gene Ontology (GO) enrichment analysis indicated that there are 190 entries related to biological process, 24 entries related to cellular component, 42 entries related to molecular function, and 44 entries related to Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways. The results of molecular docking showed that the main active ingredients of AOF may have potential therapeutic effects on immune system disorders and inflammation caused by HUA by binding to targets including peroxisome-proliferator-activated receptor gamma (PPARG), estrogen receptor 1 (ESR1), prostaglandin G/H synthase 2 (PTGS2), and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). Subsequently, we further determined the stability of the complex between the core active ingredient and the core target proteins by molecular dynamics simulation. The results of cell experiments demonstrated that stigmasterol as the core active ingredient derived from AOF significantly upregulated the expression levels of ESR1 and PPARG (p < 0.001) to exert an anti-HUA effect. Conclusions: In summary, we have systematically elucidated that the mechanism of main active ingredients derived from AOF mainly exert their pharmacological effects by acting on multiple targets in this study. Our studies will provide a scientific basis for the precise development and utilization of AOF.

As one of the medicinal and edible resources, Gastrodia elata (GE) is considered to hold potential in alleviating alcoholic liver injury, yet its mechanism needs further elucidation. To explore the molecular mechanisms of GE against alcoholic liver injury, network pharmacology, molecular docking, molecular dynamics simulations, and cell experiments were employed. Thirty-two active components of GE may exert efficacy against alcohol-induced liver injury via regulating 207 targets. Among them, the main functional components might be 4-hydroxybenzyl methyl ether, 4-ethoxytolyl-4′-hydroxybenzyl ether, pseudolaric acid B, palmitic acid, and myricetin. Analyses of Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment showed that a total of 322 GO items and 154 KEGG pathways are related to the effects of GE against alcoholic liver injury. The results of molecular docking show that the main active components of GE might interact with the key target proteins of GAPDH, PPARG, EGFR, STAT3, and AKT1. Molecular dynamics simulation further determined that pseudolaric acid B, as the core component, stably binds to these key target proteins. Cell experiments demonstrate that pseudolaric acid B exhibits a protective effect on ethanol-induced HepG2 cell injury by down-regulating the protein expression levels of GAPDH, STAT3, PPARG, and EGFR. Furthermore, the agent also suppresses IL-6 and inhibits the abnormal absorption of total cholesterol in HepG2 cells. Our findings suggest the efficacy and mechanism of GE in combating alcoholic liver injury and lay the groundwork for the precise development and utilization of GE.

Epidermal growth factor receptor (EGFR)-activating mutations are critical factors in the development of EGFR-driven non-small-cell lung cancer (NSCLC), and molecular targeted therapies have focused on inhibiting these mutations. EGFR tyrosine kinase inhibitors (TKIs) have remarkable inhibitory effects on NSCLC with EGFR mutations. However, acquired resistance limits the clinical application of EGFR-TKIs, highlighting the need for discovery of novel therapeutic strategies. 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone is a natural product derived from Garcinia xanthochymus, has shown potential anti-tumor activity, but the underlying mechanism needs further elucidation. In this study, we developed Ba/F3 and NIH/3T3 cells harboring EGFR L858R/T790M/C797S mutation, and then found that 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone exerted inhibitory effects against cells with EGFR L858R/T790M/C797S mutation. Additionally, 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone exhibited potent anti-tumor activity against cells harboring the triple-mutant EGFR by promoting apoptosis and inducing changes in cell cycle distribution. Furthermore, 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone was found to significantly reduce tumor growth via suppressing the phosphorylation of EGFR in tumor tissues. These effects are associated with binding of 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone to EGFR resulting in the suppression of extracellular signal-regulated kinase (Erk) phosphorylation. In conclusion, our results suggest that 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone may be a potential novel candidate for further investigation and treatment of NSCLC with the triple-mutant EGFR.

Non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations have brought great challenges to the medical treatment in the world. Current treatment strategies, such as EGFR tyrosine kinase inhibitors (TKIs), have reached certain achievements, however, patients inevitably experienced resistance after undergoing a period of treatment with these drugs. Hence, more novel therapy strategies need to be urgently developed. Natural compounds have become popular topics in drug development. α-Mangostin, which is derived from mangosteen, possesses multiple biological properties, yet the antitumor mechanism against NSCLC has not been further elucidated. In this study, an MTT assay, Western blotting, a colony formation assay, and flow cytometry were performed to detect the antitumor activity of α-Mangostin on NSCLC cell NCI-H1975. Molecular docking and molecular dynamics simulations were performed to analyze the interactions between α-Mangostin and the core target proteins. The results indicated that α-Mangostin exerts its antitumor activity by inhibiting cell proliferation and migration, reducing cell cycle arrest, promoting cell apoptosis, and regulating the phosphorylation expression levels of EGFR and signal transducer and activator of transcription 3 (STAT3). Moreover, the results of the molecular simulation study revealed the potential binding mode of α-Mangostin to EGFR and STAT3. In summary, we characterized that α-Mangostin may be used as a potent pro-drug against NSCLC via the EGFR/STAT3 pathway.