Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China.
Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China.
Biomed Res Int. 2019 Sep 30;2019:5953619. doi: 10.1155/2019/5953619. eCollection 2019.
The use of 5-fluorouracil (5-FU) has been proven benefits, but it also has adverse events in colorectal cancer (CRC) chemotherapy. In this study, we explored the mechanism of 5-FU resistance by bioinformatics analysis of the NCBI public dataset series GSE81005. Fifteen hub genes were screened out of 582 different expressed genes. Modules of the hub genes in protein-protein interaction networks gathered to TOP2 showed a decrease in HCT-8 cells but an increase in 5-FU-resistant HCT-8/5-FU cells with 5-FU exposure. Downregulation of TOP2 with siRNA or miR-494 transfection resulted in an increase of cytotoxicity and decrease of cell colonies to 5-FU for HCT-8/5-FU cells. Moreover, we found that an ethanol extract of Spica Prunellae (EESP), which is a traditional Chinese medicine with clinically beneficial effects in various cancers, was able to enhance the sensitivity of 5-FU in HCT-8/5-FU cells and partly reverse the 5-FU resistance effect. It significantly helped suppress cell growth and induced cell apoptosis in HCT-8/5-FU cells with the expression of TOP2 being significantly suppressed, which increased by 5-FU. Consistently, miR-494, which reportedly regulates TOP2, exhibited reverse trends in EESP/5-FU combination treatment. These results suggested that Spica Prunellae may be beneficial in the treatment of 5-FU-resistant CRC patients.
5-氟尿嘧啶（5-FU）的应用已被证明具有益处，但它也会在结直肠癌（CRC）的化疗中产生不良反应。在这项研究中，我们通过对 NCBI 公共数据集系列 GSE81005 的生物信息学分析来探索 5-FU 耐药的机制。从 582 个差异表达基因中筛选出 15 个枢纽基因。在蛋白-蛋白相互作用网络中，TOP2 基因模块的枢纽基因聚集，HCT-8 细胞中 TOP2 基因表达减少，但 5-FU 耐药 HCT-8/5-FU 细胞中 TOP2 基因表达增加，与 5-FU 暴露有关。用 siRNA 或 miR-494 转染下调 TOP2 后，HCT-8/5-FU 细胞对 5-FU 的细胞毒性增加，细胞集落减少。此外，我们发现夏枯草（Spica Prunellae）的乙醇提取物（EESP）是一种中药，在多种癌症中具有临床获益，能够增强 HCT-8/5-FU 细胞对 5-FU 的敏感性，并部分逆转 5-FU 的耐药作用。它显著有助于抑制 HCT-8/5-FU 细胞的生长并诱导细胞凋亡，同时显著抑制 TOP2 的表达，而 TOP2 的表达因 5-FU 的增加而增加。同样，据报道 miR-494 可调节 TOP2，在 EESP/5-FU 联合治疗中表现出相反的趋势。这些结果表明，夏枯草可能有助于治疗 5-FU 耐药的 CRC 患者。
