title: Cell cycle perturbation and acquired 5-fluorouracil chemoresistance.
abstract: Acquired chemoresistance is one of the obstacles for success of 5-fluorouracil (5-FU)-based cancer chemotherapy. Some molecular mechanisms of acquired 5-FU resistance are still unknown. We have recently demonstrated down-regulation of a group of cell cycle related genes in acquired 5-FU resistant human cancer cell lines. In this study, the bivariate distribution of propidium iodide versus BrdU in acquired 5-FU resistant colon (H630R10) and breast (T47DFU2.5) cancer cell lines was compared with their parental cell lines using flow cytometric analysis. The resistant cell lines showed significantly lower labelling index (T47DFU2.5) and cell cycle delay in G1 and G1/S boundary and prolonged DNA synthesis time (H630R10). Both resistant cell lines demonstrated significantly prolonged potential doubling time (Tpot). The protein expression levels of some G1 and S phase transition-related genes were also analysed by Western blot. CDK2 protein and Thr-160 phosphorylated CDK2 were remarkably reduced in the resistant cell lines. Cyclin D3 and cyclin A were also decreased in the resistant cells. Total pRB expression was unaltered but hypophosphorylation of pRB (Ser780, Ser795 and Ser807/811) was detected in the resistant cancer cells. Our data suggest that there may be a slow down in cell cycle traverse preventing incorporation of 5-FU metabolites into DNA and also providing cancer cells with sufficient time to correct the mis-incorporated nucleotides. The cell cycle perturbation may be involved in acquired 5-FU resistance.
authors.affiliation: Research Institute in Healthcare Science, University of Wolverhampton, Wolverhampton, UK.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Guo
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Goessl
authors.forename: Gang
authors.initials: G
authors.lastname: Jin
authors.forename: Elaina S R
authors.initials: ES
authors.lastname: Collie-Duguid
authors.forename: James
authors.initials: J
authors.lastname: Cassidy
authors.forename: Weiguang
authors.initials: W
authors.lastname: Wang
authors.forename: Vincent
authors.initials: V
authors.lastname: O'Brien
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans
chemical_list: D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D005472:Fluorouracil