Abstract
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 TOP2α 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 TOP2α 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 TOP2α being significantly suppressed, which increased by 5-FU. Consistently, miR-494, which reportedly regulates TOP2α, 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.
Highlights
Colorectal cancer (CRC, known as colon cancer) is one of the most commonly diagnosed cancers. e GLOBOCAN 2018 data estimates of cancer incidence and mortality showed that colorectal cancer (CRC) is the third most commonly diagnosed cancer, with an incidence of 10.2% and a mortality of 9.2% [1]
The results suggested that ethanol extract of Spica Prunellae (EESP) suppressed TOP2α expression and promoted the levels of miR-494, which could partially reverse 5-FU resistance in HCT-8/5-FU cells
A recent study demonstrated that genes in drug metabolism-cytochrome P450 and pyrimidine metabolic pathways with promoter hypermethylation and concordant expression were silenced in HCT-8/5-FU cells [37]
Summary
Colorectal cancer (CRC, known as colon cancer) is one of the most commonly diagnosed cancers. e GLOBOCAN 2018 data estimates of cancer incidence and mortality showed that CRC is the third most commonly diagnosed cancer, with an incidence of 10.2% and a mortality of 9.2% [1]. Colorectal cancer (CRC, known as colon cancer) is one of the most commonly diagnosed cancers. Chemotherapy drugs for the treatment of CRC include capecitabine, oxaliplatin, fluorouracil (5-FU), leucovorin (folinic acid), and irinotecan. Among these chemotherapy agents, 5-FU is most commonly used for CRC [3]. Erefore, combination chemotherapy has become widely used in chemotherapeutic regimens [8]. This therapeutic strategy might be partly beneficial; problems, such as new chemotherapeutic resistance or unacceptable side effects, can still occur. This therapeutic strategy might be partly beneficial; problems, such as new chemotherapeutic resistance or unacceptable side effects, can still occur. erefore, explored of the resistance mechanism for 5-FU would benefit for searching the new safe and acceptable resistance-reversal medications
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