Bcl-x(L) antisense oligonucleotides radiosensitise colon cancer cells.
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-x(L) gene product. Since approximately 60% of human colon cancers express Bcl-x(L), it was the aim of this study to explore the potential of Bcl-x(L) antisense oligonucleotides as a novel radiosensitisation strategy. Caco-2 colon cancer cells were treated with Bcl-x(L) antisense oligonucleotides in combination with IR or cisplatin, and Bcl-x(L) 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-x(L) is an important factor contributing to the treatment resistance of human colon cancer. Specific reduction of Bcl-x(L) 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.
Wacheck
V
V
Department of Clinical Pharmacology, Section of Experimental Oncology/Molecular Pharmacology, University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
Selzer
E
E
Günsberg
P
P
Lucas
T
T
Meyer
H
H
Thallinger
C
C
Monia
B P
BP
Jansen
B
B
D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000528:radiation effects*; D015153:Blotting, Western; D018938:Caco-2 Cells / Q000528:radiation effects; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D015536:Down-Regulation; D005434:Flow Cytometry; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D014162:Transfection; D014410:Tumor Stem Cell Assay; D051020:bcl-X Protein
D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D011838:Radiation-Sensitizing Agents; D051020:bcl-X Protein; D002945:Cisplatin