Induction of apoptosis in lung-cancer cells following bcl-xL anti-sense treatment.
Over-expression of the anti-apoptotic protein bcl-xL is frequently found in lung cancer where it potentially contributes to tumor development, progression and drug resistance. To override the apoptotic block in lung-adenocarcinoma and small-cell-lung-cancer (SCLC) cells caused by over-expression of bcl-xL, an anti-sense oligodeoxynucleotide was designed targeting a sequence unique to the bcl-xL coding region and not shared by the pro-apoptotic splice variant bcl-xS. Moreover, to improve the biophysical properties of the anti-sense compound, 2;-methoxy-ethoxy modifications were made to selected deoxy-ribose residues. The resulting gapmer oligonucleotide 4259 was tested on lung-adenocarcinoma and SCLC cell lines in vitro. Treatment of the adenocarcinoma cell lines A549 and NCI-H125 and the SCLC cell lines SW2 and NCI-H69 with 600 nM 4259 reduced bcl-xL levels by 70 to 90%. In the lung-adenocarcinoma cell lines, apoptosis was induced, as indicated by caspase-3-like protease activation and nuclear condensation and fragmentation. In contrast, in the SCLC cell lines, no induction of apoptosis could be demonstrated. These findings imply that bcl-xL is a more critical survival factor for lung adenocarcinomas than for SCLC, and suggest the use of oligonucleotide 4259 for therapy of this major sub-type of lung cancer.
Leech
S H
SH
Division of Oncology, Department of Internal Medicine, University Hospital Zurich, Switzerland.
Olie
R A
RA
Gautschi
O
O
Simões-Wüst
A P
AP
Tschopp
S
S
Häner
R
R
Hall
J
J
Stahel
R A
RA
Zangemeister-Wittke
U
U
D017209:Apoptosis / Q000187:drug effects*; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000502:physiology; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases