A novel bispecific antisense oligonucleotide inhibiting both bcl-2 and bcl-xL expression efficiently induces apoptosis in tumor cells

Citation
U. Zangemeister-wittke et al., A novel bispecific antisense oligonucleotide inhibiting both bcl-2 and bcl-xL expression efficiently induces apoptosis in tumor cells, CLIN CANC R, 6(6), 2000, pp. 2547-2555
Citations number
30
Categorie Soggetti
Oncology
Journal title
CLINICAL CANCER RESEARCH
ISSN journal
10780432 → ACNP
Volume
6
Issue
6
Year of publication
2000
Pages
2547 - 2555
Database
ISI
SICI code
1078-0432(200006)6:6<2547:ANBAOI>2.0.ZU;2-Q
Abstract
Bcl-2 and Bcl-xL are inhibitors of apoptosis frequently overexpressed in so lid tumors, The bcl-2 and bcl-xL mRNAs share a region of homology comprisin g nucleotides 605-624 and 687-706, respectively, which differs by only thre e nucleotides. This sequence does not occur in the proapoptotic splice vari ant bcl-xS, To test the possibility that oligonucleotides targeting this re gion have the potential to down-regulate bcl-2 and bcl-xL expression simult aneously, three 2'-O-methoxy-ethoxy-modified phosphorothioate oligonucleoti des were designed. These oligonucleotides differed in the number of mismatc hes to bcl-2 and bcl-xL and in the number of nucleotides to which the modif ications were made. The effects of these oligonucleotides on bcl-2 and bcl- xL expression, as well as their abilities to induce apoptosis, were assesse d in small cell and non-small cell lung cancer cell lines expressing differ ent basal levels of bcl-2 acid bcl-xL, Although all oligonucleotides down-r egulated bcl-2 and bcl-xL expression, oligonucleotide 4625, which has no mi smatching nucleotides to bcl-2 but three to bcl-xL, two of which were modif ied by 2'-O-methoxy-ethoxy residues, showed the strongest bispecific activi ty on the transcript and protein level, In all cell lines this bispecific a ctivity induced apoptotic cell death, as demonstrated by increased uptake o f propidium iodide, a 10-100-fold increase in caspase-3-like protease activ ity, and nuclear condensation and fragmentation, This is the first report o f a bcl-2/bcl-xL bispecific antisense oligonucleotide that deserves attenti on as a therapeutic compound in lung cancer and other malignancies in which bcl-2 and/or bcl-xL are overexpressed.