Induction of apoptosis in lung-cancer cells followingbcl-xL anti-sense treatment

Autor: A. Paula Simões-Wüst, Uwe Zangemeister-Wittke, Jonathan Hall, Siân H. Leech, Robert A. Olie, Stefan Tschopp, Oliver Gautschi, Rolf A. Stahel, Robert Häner
Rok vydání: 2000
Předmět:
Zdroj: International Journal of Cancer. 86:570-576
ISSN: 1097-0215
0020-7136
DOI: 10.1002/(sici)1097-0215(20000515)86:4<570::aid-ijc20>3.0.co;2-t
Popis: 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.
Databáze: OpenAIRE
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