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Effect of lathyrol derivatives on non-small cell lung cancer and the possible mechanism
Yanyan Yan1,2, Wenmin Zhou3, Qiaoru Guo3
1Institute of Immunology, School of Medicine, Shanxi Datong University, Datong Shanxi 037009. zwsanyan@163.com.
Objectives:
Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancer, with highmorbidity and mortality rate. Nove drug development for NSCLC is urgently needed.This study aims to investigate the activity of lathyrol derivatives and the mechanism for its inhibitory effect on the growth of NSCLC cells.
Methods:
Three lathyrol derivatives were synthesized from lathyrol and their structures were verified by nuclear magnetic resonance. MTT assay was used to detect the effects of the lathyrol derivatives on the proliferation activity of NSCLC cells (A549 and H1299 cells), and the compound with the best activity was selected for subsequent experiments. Colony forming assay, wound-healing assay, and transwell assay were applied to detect in vitro cell proliferation, migration and invasion ability in A549 and H1299 cells, respectively. Quantitative real-time RT-PCR and Western blotting were performed to detect mRNA and protein levels of E-cadherin, N-cadherin, β-catenin, and MMP2 in A549 cells, respectively.
Results:
Three lathyrol derivatives inhibited the growth of A549 and H1299 cells in a dose-dependent manner, and they showed a weak inhibitory effect on normal cells Beas-2B and 16HBE, indicating that they possessed certain selective toxic effects. Therefore, C-5 benzoylated lathyrol with the best activity was selected as the ideal drug for the subsequent experiments. Compared with the control group, the number and size of cell clusters in the treatment group of A549 and H1299 cells were significantly decreased, the relative mobility were significantly decreased, and the number of invaded cells were significantly decreased (all P<0.05), indicating that the in vitro cell proliferation, migration and invasion ability were decreased. The mRNA levels of integrin α2, integrin β1, MMP2, MMP9, β-catenin, and N-cadherin were decreased, while the expression of E-cadherin was increased (all P<0.05). The protein levels of N-cadherin, β-catenin, MMP2, and integrin αV were decreased, while the expression of E-cadherin was increased (all P<0.05).
Conclusions:
The lathyrol derivatives synthesized in this study possess good inhibitory activity against NSCLC. Among them, C-5 benzoylated lathyrol significantly inhibits the proliferation, migration, and invasion ability of NSCLC cells in vitro through regulating the process of epithelial-mesenchymal transition.
Insights
New lathyrol derivatives show potent inhibitory effects against non-small cell lung cancer (NSCLC) by reducing cancer cell proliferation, migration, and invasion. C-5 benzoylated lathyrol effectively targets NSCLC, offering a promising avenue for novel cancer therapies.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths, necessitating the development of novel therapeutic agents.
- Current treatment options for NSCLC have limitations, highlighting the urgent need for innovative drug discovery.
Purpose of the Study:
- To synthesize and evaluate the anti-cancer activity of novel lathyrol derivatives against NSCLC cells.
- To elucidate the mechanism underlying the inhibitory effects of these derivatives on NSCLC cell growth, migration, and invasion.
Main Methods:
- Synthesis and structural verification of three lathyrol derivatives using nuclear magnetic resonance.
- Assessment of cytotoxicity and anti-proliferative effects using MTT assays on NSCLC cell lines (A549, H1299) and normal cells.
- In vitro evaluation of cell proliferation, migration, and invasion using colony formation, wound-healing, and Transwell assays.
- Analysis of epithelial-mesenchymal transition (EMT) markers (E-cadherin, N-cadherin, β-catenin, MMP2) at mRNA and protein levels via qRT-PCR and Western blotting.
Main Results:
- Lathyrol derivatives exhibited dose-dependent inhibition of NSCLC cell growth with selective toxicity towards cancer cells.
- C-5 benzoylated lathyrol demonstrated significant suppression of NSCLC cell proliferation, migration, and invasion in vitro.
- Treatment with C-5 benzoylated lathyrol led to decreased expression of EMT markers (N-cadherin, β-catenin, MMP2) and increased E-cadherin expression at both mRNA and protein levels.
Conclusions:
- Synthesized lathyrol derivatives possess significant inhibitory activity against non-small cell lung cancer.
- C-5 benzoylated lathyrol effectively inhibits NSCLC cell proliferation, migration, and invasion by modulating the epithelial-mesenchymal transition process.
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