{"title":"Resistance to 5-fluorouracil: The molecular mechanisms of development in colon cancer cells","authors":"","doi":"10.1016/j.ejphar.2024.176979","DOIUrl":null,"url":null,"abstract":"<div><p>Colon cancer is a significant health problem worldwide as it is one of the most common and deadliest cancers. The standard approach for the treatment of colon cancer is 5-fluorouracil (5-FU) based chemotherapy, which is limited by the development of resistance to this drug. Therefore, our study aimed to establish 5-FU resistance in SW-480 and HT-29 colon cancer cells and to precisely determine the molecular mechanisms and biomarkers that contribute to its development, both after short-term exposure and in cells with already developed resistance (SW-480-5FUR and HT-29-5FUR). The expression of various molecules involved in the different mechanisms of resistance development was monitored at the gene (qPCR) and protein (immunocytochemistry) levels. Based on the obtained results, alterations in the 5-FU anabolic pathway, biotransformation, drug efflux, mismatch repair, and apoptosis process together contributed to the development of 5-FU resistance in SW-480 and HT-29 colon cancer cells. In addition, <em>UMPS</em>, <em>ABCC1</em>, <em>ABCC5</em>, and <em>MLH1</em>, as well as the disturbed ratio of pro-apoptotic <em>BAX</em> and anti-apoptotic <em>BCL2</em>, should be taken into consideration as potential targets for the discovery of 5-FU resistance-related biomarkers in colon cancer cells. We suggest that future investigations focus on further validation of these findings by additional <em>in vitro</em> and <em>in vivo</em> testing, which is a limitation of our study.</p></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":null,"pages":null},"PeriodicalIF":4.2000,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"European journal of pharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S001429992400668X","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
Abstract
Colon cancer is a significant health problem worldwide as it is one of the most common and deadliest cancers. The standard approach for the treatment of colon cancer is 5-fluorouracil (5-FU) based chemotherapy, which is limited by the development of resistance to this drug. Therefore, our study aimed to establish 5-FU resistance in SW-480 and HT-29 colon cancer cells and to precisely determine the molecular mechanisms and biomarkers that contribute to its development, both after short-term exposure and in cells with already developed resistance (SW-480-5FUR and HT-29-5FUR). The expression of various molecules involved in the different mechanisms of resistance development was monitored at the gene (qPCR) and protein (immunocytochemistry) levels. Based on the obtained results, alterations in the 5-FU anabolic pathway, biotransformation, drug efflux, mismatch repair, and apoptosis process together contributed to the development of 5-FU resistance in SW-480 and HT-29 colon cancer cells. In addition, UMPS, ABCC1, ABCC5, and MLH1, as well as the disturbed ratio of pro-apoptotic BAX and anti-apoptotic BCL2, should be taken into consideration as potential targets for the discovery of 5-FU resistance-related biomarkers in colon cancer cells. We suggest that future investigations focus on further validation of these findings by additional in vitro and in vivo testing, which is a limitation of our study.
期刊介绍:
The European Journal of Pharmacology publishes research papers covering all aspects of experimental pharmacology with focus on the mechanism of action of structurally identified compounds affecting biological systems.
The scope includes:
Behavioural pharmacology
Neuropharmacology and analgesia
Cardiovascular pharmacology
Pulmonary, gastrointestinal and urogenital pharmacology
Endocrine pharmacology
Immunopharmacology and inflammation
Molecular and cellular pharmacology
Regenerative pharmacology
Biologicals and biotherapeutics
Translational pharmacology
Nutriceutical pharmacology.