Bcl‐XL Antisense Sensitizes Human Colon Cancer Cell Line to 5‐Fluorouracil

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Abstract
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‐XL, might be associated with resistance to 5‐FU in colorectal cancer. The aim of this study is to analyze the role of Bcl‐XL in 5‐FU resistance and to explore a new therapeutic strategy using Bcl‐XL antisense. First, western blot analysis shows that Bcl‐XL rather than Bcl‐2 is overexpressed in primary adenocarcinoma of colon. Second, when Colo320 cells, with undetectable endogenous Bcl‐XL expression, were transfected with Bcl‐XL gene, they acquired high resistance to 5‐FU. Finally, antisense oligodeoxynucleotides (ODNs) that targeted the start codon of Bcl‐XL mRNA (ASI) prove to be the most effective in DLD1 cells with high endogenous Bcl‐XL expression. Bcl‐XL protein expression was decreased in a dose‐dependent manner when the cells were treated with AS1 ODNs, while non‐sense and sense controls and 5‐FU had no effect on Bcl‐XL 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‐XL 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‐XL is an important factor for 5‐FU resistance and the suppression of Bcl‐XL expression by the specific antisense ODNs can increase the sensitivity of colon cancer cells to 5‐FU.