Low-dose 5-fluorouracil induces cell cycle G2 arrest and apoptosis in keloid fibroblasts.

Abstract

Intralesional injection of low-dose 5-fluorouracil (5-FU) has recently been used as an experimental modality for treating keloid scarring and has shown promising efficacy in improving scar appearance and preventing recurrence of the keloid. We sought to explore the cellular- and molecular-based evidence for the observed clinical benefits. Primary cell lines of keloid fibroblasts were treated with 5-FU at a range of lower doses (∼10 mg mL(-1) ) in monolayer culture and subjected to examination for cell viability, proliferative potential, apoptosis, cell cycle and associated proteins involved in cell cycle control. 5-FU significantly inhibited cell proliferation of keloid fibroblasts in the full dose range used in this study. The DNA synthesis was completely inhibited by 5-FU at 72 h, and significant cell apoptosis was observed at concentrations ≥ 1 mg mL(-1) for a period over 72 h. 5-FU caused a significant delay in cell cycle progression and the G2/M phase arrest. 5-FU induced p53 and p21 accumulation together with a decrease in cyclin B1 and Bcl-2 levels in treated keloid fibroblasts. Our data indicate that low-dose 5-FU (as low as 1 mg mL(-1) ) induces significant inhibition of proliferation, G2/M cell cycle arrest and apoptosis but not immediate cell death of keloid fibroblasts. The lack of tissue necrosis is a particular benefit as further scarring is likely to be prevented. These results support the use of low-dose 5-FU as a potential modality for treating keloid scars.