Bcl-xL antisense oligonucleotides radiosensitise colon cancer cells

Abstract

Advanced colon cancer is a malignancy with poor response to various treatment modalities including ionising radiation (IR) and chemotherapy. Both IR and chemotherapeutic agents have been shown to act by inducing apoptosis, a type of cell death antagonised by the Bcl-xL gene product. Since approximately 60% of human colon cancers express Bcl-xL, it was the aim of this study to explore the potential of Bcl-xL antisense oligonucleotides as a novel radiosensitisation strategy. Caco-2 colon cancer cells were treated with Bcl-xL antisense oligonucleotides in combination with IR or cisplatin, and Bcl-xL protein expression, apoptosis, cell viability and clonogenic survival were examined. Bcl-x L antisense oligonucleotide specifically reduced the Bcl-x L protein level by almost 50% in Caco-2 cells. The decreased threshold for the induction of apoptosis resulted in a 300% increase of apoptosis after IR or cisplatin treatment and led to a 60% reduction of cell proliferation beyond response rates achieved with IR. These data suggest that Bcl-xL is an important factor contributing to the treatment resistance of human colon cancer. Specific reduction of Bcl-xL protein levels by antisense oligonucleotides qualifies as a promising therapeutic strategy for colon cancer that may help overcome resistance and improve clinical outcome in this malignancy. © 2003 Cancer Research UK.