Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology, Rourkela, Odisha,, 769008, India.
Mol Biol Rep. 2024 Apr 17;51(1):523. doi: 10.1007/s11033-024-09477-7.
In recent decades, phytotherapy has remained as a key therapeutic option for the treatment of various cancers. Evodiamine, an excellent phytocompound from Evodia fructus, exerts anticancer activity in several cancers by modulating drug resistance. However, the role of evodiamine in cisplatin-resistant NSCLC cells is not clear till now. Therefore, we have used evodiamine as a chemosensitizer to overcome cisplatin resistance in NSCLC.
Here, we looked into SOX9 expression and how it affects the cisplatin sensitivity of cisplatin-resistant NSCLC cells. MTT and clonogenic assays were performed to check the cell proliferation. AO/EtBr and DAPI staining, ROS measurement assay, transfection, Western blot analysis, RT-PCR, Scratch & invasion, and comet assay were done to check the role of evodiamine in cisplatin-resistant NSCLC cells.
SOX9 levels were observed to be higher in cisplatin-resistant A549 (A549CR) and NCI-H522 (NCI-H522CR) compared to parental A549 and NCI-H522. It was found that SOX9 promotes cisplatin resistance by regulating β-catenin. Depletion of SOX9 restores cisplatin sensitivity by decreasing cell proliferation and cell migration and inducing apoptosis in A549CR and NCI-H522CR. After evodiamine treatment, it was revealed that evodiamine increases cisplatin-induced cytotoxicity in A549CR and NCI-H522CR cells through increasing intracellular ROS generation. The combination of both drugs also significantly inhibited cell migration by inhibiting epithelial to mesenchymal transition (EMT). Mechanistic investigation revealed that evodiamine resensitizes cisplatin-resistant cells toward cisplatin by decreasing the expression of SOX9 and β-catenin.
The combination of evodiamine and cisplatin may be a novel strategy for combating cisplatin resistance in NSCLC.
近几十年来，植物疗法一直是治疗各种癌症的重要治疗选择。吴茱萸碱是吴茱萸中的一种优秀植物化合物，通过调节耐药性在多种癌症中发挥抗癌活性。然而，吴茱萸碱在顺铂耐药非小细胞肺癌（NSCLC）细胞中的作用至今尚不清楚。因此，我们使用吴茱萸碱作为化学增敏剂来克服 NSCLC 中的顺铂耐药性。
在这里，我们研究了 SOX9 的表达及其如何影响顺铂耐药 NSCLC 细胞对顺铂的敏感性。通过 MTT 和集落形成实验检测细胞增殖。通过 AO/EtBr 和 DAPI 染色、ROS 测量实验、转染、Western blot 分析、RT-PCR、划痕和侵袭实验以及彗星实验检测吴茱萸碱在顺铂耐药 NSCLC 细胞中的作用。
与亲本 A549 和 NCI-H522 相比，顺铂耐药的 A549（A549CR）和 NCI-H522（NCI-H522CR）中 SOX9 水平更高。研究发现，SOX9 通过调节β-catenin 促进顺铂耐药。SOX9 耗竭通过降低细胞增殖和细胞迁移并诱导 A549CR 和 NCI-H522CR 中的细胞凋亡来恢复顺铂敏感性。用吴茱萸碱处理后，结果表明吴茱萸碱通过增加细胞内 ROS 生成来增加 A549CR 和 NCI-H522CR 细胞中顺铂诱导的细胞毒性。两种药物的联合也通过抑制上皮间质转化（EMT）显著抑制细胞迁移。机制研究表明，吴茱萸碱通过降低 SOX9 和β-catenin 的表达使顺铂耐药细胞对顺铂重新敏感。
吴茱萸碱和顺铂的联合应用可能是克服 NSCLC 中顺铂耐药的一种新策略。
