Cell Cycle Perturbation and Acquired 5-Fluorouracil Chemoresistance

• Published in: Anticancer research 2008-01, Vol.28 (1A), p.9-14
• Main Authors: XIAOXIA GUO, GOESSL, Elisabeth, COLLIE-DUGUID, Elaina S. R, CASSIDY, James, WEIGUANG WANG, O'BRIEN, Vincent
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Cycle - physiology; Cell Cycle Proteins - biosynthesis; Cell Cycle Proteins - genetics; Cell Growth Processes - physiology; Cell Line, Tumor; Colonic Neoplasms - drug therapy; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; DNA, Neoplasm - biosynthesis; Down-Regulation; Drug Resistance, Neoplasm; Fluorouracil - pharmacology; Humans; Medical sciences; Tumors
• ISSN: 0250-7005; 1791-7530

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 (H630 R10 ) and breast (T47D FU2.5 ) cancer cell lines was compared with their parental cell lines using flow cytometric analysis. The resistant cell lines showed significantly lower labelling index (T47D FU2.5 ) and cell cycle delay in G1 and G1/S boundary and prolonged DNA synthesis time (H630 R10 ). Both resistant cell lines demonstrated significantly prolonged potential doubling time (T pot ). 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.