title: Bcl-x(L) antisense oligonucleotides induce apoptosis and increase sensitivity of pancreatic cancer cells to gemcitabine.
abstract: 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.
authors.affiliation: Department of Visceral and Transplantation Surgery, University of Berne, Inselspital, Berne, Switzerland.
authors.forename: Z
authors.initials: Z
authors.lastname: Xu
authors.forename: H
authors.initials: H
authors.lastname: Friess
authors.forename: M
authors.initials: M
authors.lastname: Solioz
authors.forename: S
authors.initials: S
authors.lastname: Aebi
authors.forename: M
authors.initials: M
authors.lastname: Korc
authors.forename: J
authors.initials: J
authors.lastname: Kleeff
authors.forename: M W
authors.initials: MW
authors.lastname: Büchler
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015152:Blotting, Northern; D015153:Blotting, Western; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; C494811:BCL2L1 protein, human; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051020:bcl-X Protein; D003841:Deoxycytidine; D000093542:Gemcitabine