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

✍ Scribed by Siân H. Leech; Robert A. Olie; Oliver Gautschi; A. Paula Simões-Wüst; Stefan Tschopp; Robert Häner; Jonathan Hall; Rolf A. Stahel; Uwe Zangemeister-Wittke

• Publisher: John Wiley and Sons
• Year: 2000
• Tongue: French
• Weight: 239 KB
• Volume: 86
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/(sici)1097-0215(20000515)86:4<570::aid-ijc20>3.0.co;2-t

✦ Synopsis

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 antisense 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. Int.