Bcl-xL antisense oligonucleotides chemosensitize human glioblastoma cells.
BACKGROUND
Resistance to chemotherapy in glioblastoma has been linked to the expression of antiapoptotic Bcl-2 family members including Bcl-xL.


METHODS
Bcl-xL expression was specifically reduced in M059K glioblastoma cells with antisense oligonucleotides (ISIS 16009, ISIS 16967) as assessed by Western blotting. Induction of apoptosis by treatment with antisense oligonucleotides in combination with paclitaxel in cell culture was monitored by WST-1 assays and flow cytometric analysis.


RESULTS
Antisense oligonucleotide-mediated reduction of Bcl-xL levels led to enhanced cytotoxicity in M059K cells when compared to the use of a mismatch control oligonucleotide (p < 0.001). A decreased threshold for the induction of apoptosis led to significantly enhanced cytotoxic responses to paclitaxel treatment in WST-1 assays (p < 0.001) and flow cytometric analyses.


CONCLUSIONS
Combination treatment using Bcl-xL antisense oligonucleotides and paclitaxel may qualify as a promising strategy to ultimately improve the clinical outcome of glioblastoma.
Guensberg
Patrick
P
Department of Clinical Pharmacology, Section of Experimental Oncology/Molecular Pharmacology, University of Vienna, Vienna, Austria.
Wacheck
Volker
V
Lucas
Trevor
T
Monia
Brett
B
Pehamberger
Hubert
H
Eichler
Hans-Georg
HG
Jansen
Burkhard
B
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000473:pathology*; D019008:Drug Resistance, Neoplasm; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
D000972:Antineoplastic Agents, Phytogenic; C494811:BCL2L1 protein, human; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D017239:Paclitaxel