Bcl-XL antisense sensitizes human colon cancer cell line to 5-fluorouracil

Resistance to 5-fluorouracil (5-FU) has been frequently found in the treatment of digestive tract cancer patients. Our previous study suggested that high expression of endogenous Bcl-X-L, might be associated with resistance to 5-FU in colorectal cancer. The aim of this study is to analyze the role of Bcl-X-L in 5-FU resistance and to explore a new therapeutic strategy using Bcl-X-L antisense, First, western blot analysis shows that Bcl-X-L rather than Bcl-2 is overexpressed in primary adenocarcinoma of colon. Second, when Colo320 cells, with undetectable endogenous Bcl-X-L expression, were transfected with Bcl-X-L gene, they acquired high resistance to 5-FU, Finally, antisense oligodeoxynucleotides (ODNs) that targeted the start codon of Bcl-X-L mRNA (AS1) prove to be the most effective in DLD1 cells with high endogenous Bcl-X-L expression, Bcl-X-L protein expression was decreased in a dose-dependent manner when the cells mere treated with AS1 ODNs, while non sense and sense controls and 5-FU had no effect on Bcl-X-L protein. 5-FU treatment induced a level of apoptosis 10-fold higher in DLD1 cells than in untreated control cells, while the same dose of 5-FU induced a 55-fold higher level of apoptosis in DLD1 cells treated with Bcl-X-L antisense oligodeoxynucleotides (P=0.0003). Moreover, AS1 ODNs coupled with 5-FU decreased viable colon cancer cells 40% more than did 5-FU alone (P<0.05). These results suggest that Bcl-X-L is an important factor for 5-FU resistance and the suppression of Bcl-X-L expression by the specific antisense ODNs can increase the sensitivity of colon canter cells to 5-FU.