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

Int J Cancer. 2000 May 15;86(4):570-6. doi: 10.1002/(sici)1097-0215(20000515)86:4<570::aid-ijc20>3.0.co;2-t.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Carcinoma, Small Cell / drug therapy*
  • Carcinoma, Small Cell / pathology
  • Caspase 3
  • Caspases / metabolism
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / pathology
  • Oligonucleotides, Antisense / pharmacology*
  • Proto-Oncogene Proteins c-bcl-2 / analysis
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / physiology
  • Tumor Cells, Cultured
  • bcl-X Protein

Substances

  • BCL2L1 protein, human
  • Oligonucleotides, Antisense
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-X Protein
  • CASP3 protein, human
  • Caspase 3
  • Caspases