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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<jats:italic>\u03b1<\/jats:italic> showed a decrease in HCT-8\u2009cells but an increase in 5-FU-resistant HCT-8\/5-FU cells with 5-FU exposure. Downregulation of TOP2<jats:italic>\u03b1<\/jats:italic> 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<jats:italic>\u03b1<\/jats:italic> being significantly suppressed, which increased by 5-FU. Consistently, miR-494, which reportedly regulates TOP2<jats:italic>\u03b1<\/jats:italic>, 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.<\/jats:p>","DOI":"10.1155\/2019\/5953619","type":"journal-article","created":{"date-parts":[[2019,9,30]],"date-time":"2019-09-30T21:49:49Z","timestamp":1569880189000},"page":"1-12","source":"Crossref","is-referenced-by-count":14,"title":["Spica Prunellae Extract Enhances Fluorouracil Sensitivity of 5-Fluorouracil-Resistant Human Colon Carcinoma HCT-8\/5-FU Cells via TOP2<i>\u03b1<\/i> and miR-494"],"prefix":"10.1155","volume":"2019","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3001-7028","authenticated-orcid":true,"given":"Yi","family":"Fang","sequence":"first","affiliation":[{"name":"Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China"},{"name":"Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, 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