Institute of Immunology, School of Medicine, Shanxi Datong University, Datong Shanxi 037009.
School of Pharmaceutical Sciences, Guangzhou Medical University, Key Laboratory of Molecular Target & Clinical Pharmacology, State Key Laboratory of Respiratory Disease, Guangzhou 511436, China.
Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2022 Feb 28;47(2):143-152. doi: 10.11817/j.issn.1672-7347.2022.210104.
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.
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.
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 <0.05), indicating that the in vitro cell proliferation, migration and invasion ability were decreased. The mRNA levels of , , , , , and were decreased, while the expression of was increased (all <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 <0.05).
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.
非小细胞肺癌（NSCLC）占所有肺癌的 85%，具有高发病率和死亡率。迫切需要开发新的 NSCLC 药物。本研究旨在探讨拉蒂醇衍生物的活性及其抑制 NSCLC 细胞生长的作用机制。
从拉蒂醇合成了 3 种拉蒂醇衍生物，并通过核磁共振对其结构进行了验证。MTT 法检测拉蒂醇衍生物对 NSCLC 细胞（A549 和 H1299 细胞）增殖活性的影响，选择活性最佳的化合物进行后续实验。平板克隆形成实验、划痕愈合实验和 Transwell 实验分别用于检测 A549 和 H1299 细胞的体外细胞增殖、迁移和侵袭能力。实时定量 RT-PCR 和 Western blot 分别用于检测 A549 细胞中 E-钙黏蛋白、N-钙黏蛋白、β-连环蛋白和 MMP2 的 mRNA 和蛋白水平。
3 种拉蒂醇衍生物均能剂量依赖性地抑制 A549 和 H1299 细胞的生长，对正常细胞 Beas-2B 和 16HBE 表现出较弱的抑制作用，提示其具有一定的选择性毒性作用。因此，活性最佳的 C-5 苯甲酰化拉蒂醇被选为后续实验的理想药物。与对照组相比，A549 和 H1299 细胞处理组的细胞集落数量和大小明显减少，相对迁移率明显降低，侵袭细胞数量明显减少（均<0.05），提示体外细胞增殖、迁移和侵袭能力降低。mRNA 水平降低，而 表达增加（均<0.05）。N-钙黏蛋白、β-连环蛋白、MMP2 和整合素αV 的蛋白水平降低，而 E-钙黏蛋白的表达增加（均<0.05）。
本研究合成的拉蒂醇衍生物对 NSCLC 具有良好的抑制活性。其中，C-5 苯甲酰化拉蒂醇通过调节上皮-间充质转化过程，显著抑制 NSCLC 细胞的体外增殖、迁移和侵袭能力。
