Innets Bhurichaya, Racha Satapat, Ei Zin Zin, Sriratanasak Nicharat, Chanvorachote Pithi
Center of Excellence in Cancer Cell and Molecular Biology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.
Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.
Anticancer Res. 2025 Jul;45(7):3021-3029. doi: 10.21873/anticanres.17667.
BACKGROUND/AIM: Akt signaling promotes cancer survival and therapy resistance. This study aimed to modify and improve resveratrol's efficacy by enhancing apoptosis induction in non-small cell lung cancer.
Molecular docking analysis was used to investigate the binding between resveratrol derivatives and the Akt protein. Western blot analysis evaluated the levels of apoptosis markers and signaling proteins.
Resveratrol derivative, RD4 (4-(3-hydroxy-4-methoxyphenethyl)-2,6-dimethoxyphenol), shows binding potential to the allosteric site of Akt. After treatment of H460 cells with RD4 for 24 h, increased apoptosis and decreased levels of phosphorylated-Akt (p-Akt) protein were observed. Moreover, the levels of pro-apoptotic protein Bax and cleaved PARP were elevated, while those of the anti-apoptotic protein Bcl-2 were decreased. However, RD2 exhibited moderate effects at high concentrations and RD3 elevated p-Akt expression while exhibiting no apoptotic activity.
RD4 suppresses Akt pathways by binding at the allosteric site of Akt. These findings provide a rationale for the design and optimization of novel Akt targeting agents for non-small cell lung cancer treatment.
背景/目的：Akt信号传导促进癌症存活和治疗抗性。本研究旨在通过增强非小细胞肺癌中的细胞凋亡诱导来改善和提高白藜芦醇的疗效。
采用分子对接分析研究白藜芦醇衍生物与Akt蛋白之间的结合。蛋白质免疫印迹分析评估细胞凋亡标志物和信号蛋白的水平。
白藜芦醇衍生物RD4（4-(3-羟基-4-甲氧基苯乙基)-2,6-二甲氧基苯酚）显示出与Akt变构位点的结合潜力。用RD4处理H460细胞24小时后，观察到细胞凋亡增加，磷酸化Akt（p-Akt）蛋白水平降低。此外，促凋亡蛋白Bax和裂解的PARP水平升高，而抗凋亡蛋白Bcl-2水平降低。然而，RD2在高浓度下表现出中等效果，RD3提高了p-Akt表达，同时没有表现出凋亡活性。
RD4通过结合Akt的变构位点抑制Akt途径。这些发现为设计和优化用于非小细胞肺癌治疗的新型Akt靶向药物提供了理论依据。
