Zhao Qi, Zhang Yan, Liu Jieyu, Chen Peipei, Onga Annabeth, Cho Namki, Cui Ri, Zheng Chenguo
The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Front Pharmacol. 2025 Jan 9;15:1532695. doi: 10.3389/fphar.2024.1532695. eCollection 2024.
Polydatin (3,4',5-trihydroxy-3-β-d-glucopyranoside, PD) is known for its antioxidant and anti-inflammatory properties. Oxaliplatin (OXA)-based chemotherapy is the first-line treatment for metastatic and recurrent colorectal cancer (CRC). However, the lack of selectivity for normal cells often results in side effects. Consequently, the search for anti-cancer components with high efficacy and low cytotoxicity has become a significant focus in recent years.
The anti-tumor effects of PD, OXA or their combination were assessed by cell viability, colony formation, and wound-healing assays. Reactive oxygen species (ROS) generation was measured by flow cytometry and DNA damage was assessed by immunofluorescence assay. The relative gene and protein expressions were analyzed by quantitative real time-PCR (qRT-PCR) and Western blot assays. Molecular docking analysis predicted the interaction between PD and potential targets.
We found that PD exerted anti-CRC activity by promoting Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase 5 (NOX5)-mediated ROS production, activating the endoplasmic reticulum (ER) stress, and inducing DNA damage. Knocking down NOX5 attenuated the inhibition of proliferation and colony forming ability induced by PD in colon cancer cells and reversed the expression of C/EBP-homologous protein (CHOP) and activating transcription factor 4 (ATF4) proteins. In addition, combination of PD and OXA synergistically exerted anti-CRC activities by promoting DNA damage and activating ER stress signaling pathway.
The combination of PD and OXA could be an effective treatment strategy for certain patients with CRC.
白藜芦醇苷（3,4',5-三羟基-3-β-D-吡喃葡萄糖苷，PD）以其抗氧化和抗炎特性而闻名。基于奥沙利铂（OXA）的化疗是转移性和复发性结直肠癌（CRC）的一线治疗方法。然而，对正常细胞缺乏选择性常常导致副作用。因此，近年来寻找高效低细胞毒性的抗癌成分已成为一个重要的研究重点。
通过细胞活力、集落形成和伤口愈合试验评估PD、OXA或它们的组合的抗肿瘤作用。通过流式细胞术测量活性氧（ROS）的产生，并通过免疫荧光试验评估DNA损伤。通过定量实时PCR（qRT-PCR）和蛋白质免疫印迹试验分析相关基因和蛋白质的表达。分子对接分析预测了PD与潜在靶点之间的相互作用。
我们发现，PD通过促进烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶5（NOX5）介导的ROS产生、激活内质网（ER）应激和诱导DNA损伤来发挥抗CRC活性。敲低NOX5可减弱PD对结肠癌细胞增殖和集落形成能力的抑制作用，并逆转C/EBP同源蛋白（CHOP）和激活转录因子4（ATF4）蛋白的表达。此外，PD和OXA的组合通过促进DNA损伤和激活ER应激信号通路协同发挥抗CRC活性。
PD和OXA的组合可能是某些CRC患者的有效治疗策略。
