Bcl-x(L) antisense oligonucleotides induce apoptosis and increase sensitivity of pancreatic cancer cells to gemcitabine.

Pancreatic cancer is one of the leading causes of cancer-related death in Western countries. Bcl-x(L) is an anti-apoptotic factor of the Bcl-2 family, which is overexpressed in pancreatic cancer and its presence correlates with shorter patient survival. In this study, sequence-specific antisense oligonucleotides targeting the coding region of Bcl-x(L) were designed to examine whether apoptosis could be induced and chemosensitivity could be increased in pancreatic cancer cells. Five pancreatic cancer cell lines, Panc-1, MIA-PaCa-2, Capan-1, ASPC-1 and T3M4, were treated with Bcl-x(L) sense or antisense oligonucleotides and gemcitabine and the cell viability was examined by the SRB method. Apoptosis was determined using DAPI staining. In all examined pancreatic cancer cells, Bcl-x(L) expression was reduced after transfection of the antisense oligonucleotides. Cell death analysis using DAPI staining revealed that antisense, but not sense oligonucleotides caused apoptotic cell death. Furthermore, Bcl-x(L) antisense oligonucleotides enhanced the cytotoxic effects of gemcitabine in pancreatic cancer cells. Our results indicate that Bcl-x(L) antisense oligonucleotides effectively inhibited pancreatic cancer cell growth and caused apoptosis by reducing Bcl-x(L) protein levels. Bcl-x(L) antisense oligonucleotides also increased the chemosensitivity of pancreatic cancer cells, suggesting that Bcl-x(L) antisense therapy might be a potential future approach in this disease. Copyright 2001 Wiley-Liss, Inc.