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Inhibitory effect of gefitinib derivative LPY‑9 on human glioma
Yuchen Sun1, Liangzhao Chu1, Huijuan Wang2
1Department of Neurosurgery, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550000, P.R. China.
Abstract:
The present study aimed to investigate the effects of a gefitinib derivative, LPY‑9, on the proliferation, apoptosis and migration of human glioma cell line U251‑MG by CCK8, Transwell or flow cytometry, and the effect of LPY‑9 on the activity of caspase‑3 enzyme and related proteins in the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) pathways by western blot and ELISA. It was found that LPY‑9 exhibited higher a inhibitory effect on the proliferation of U251‑MG cell lines compared with gefitinib and it also exhibited a certain dose‑dependence. Following LPY‑9 treatment, typical apoptotic morphology was observed under the microscope after Giemsa staining. LPY‑9 induced apoptosis at low concentration, and the activity of caspase‑3 enzyme increased with the increase in drug concentration, significantly inhibiting the secretion of VEGF in a dose‑dependent manner. The effect was notably more evident compared with gefitinib at the same concentration. The expression level of caspase‑3 and cleaved caspase‑3 increased with the increase in LPY‑9 concentration; however, expression levels of VEGF, EGFR, phosphorylated AKT and PI3K decreased with the increase of LPY‑9 concentration and no change was observed in the expression level of AKT. LPY‑9 inhibited the proliferation of the human glioma cell line U251‑MG, promoted apoptosis and effectively inhibited the migration of U251‑MG cells. The effect of LPY‑9 was more noticeable compared with gefitinib. The results of the present study may provide a foundation for further study and clinical research of this as an anti‑tumor drug in animal models.
Insights
LPY-9, a gefitinib derivative, effectively inhibits human glioma cell proliferation and migration while promoting apoptosis. This novel compound shows greater anti-tumor potential than gefitinib, warranting further investigation for clinical applications.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Glioblastoma multiforme (GBM) is an aggressive brain tumor with limited treatment options.
- Targeted therapies, such as EGFR inhibitors, have shown promise but face challenges.
- Novel drug derivatives are needed to overcome resistance and improve efficacy.
Purpose of the Study:
- To evaluate the anti-cancer effects of LPY-9, a gefitinib derivative, on the U251-MG human glioma cell line.
- To investigate LPY-9's impact on cell proliferation, apoptosis, and migration.
- To elucidate the molecular mechanisms underlying LPY-9's action, focusing on caspase-3, VEGF, and EGFR pathways.
Main Methods:
- Cell proliferation was assessed using CCK8 assays.
- Cell migration was evaluated using Transwell assays.
- Apoptosis, caspase-3 activity, and protein expression (VEGF, EGFR, p-AKT, PI3K) were analyzed by flow cytometry, Western blot, and ELISA.
Main Results:
- LPY-9 demonstrated superior inhibition of U251-MG cell proliferation compared to gefitinib in a dose-dependent manner.
- LPY-9 induced significant apoptosis and inhibited cell migration.
- LPY-9 increased caspase-3 activity and expression while decreasing VEGF, EGFR, p-AKT, and PI3K levels.
Conclusions:
- LPY-9 exhibits potent anti-glioma activity by inhibiting proliferation, promoting apoptosis, and reducing migration.
- LPY-9's mechanism involves modulation of the caspase-3, VEGF, and EGFR signaling pathways.
- LPY-9 represents a promising candidate for further preclinical and clinical development as an anti-cancer therapeutic.
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