c-erbB-2 anti-sense phosphorothioate oligodeoxynucleotides inhibit growth and serum-induced cell spreading of P185c-erbB-2-overexpressing ovarian carcinoma cells.
Overexpression of the c-erbB-2 proto-oncogene product (p185c-erbB-2) occurs frequently in different types of human cancer and is correlated with a significantly decreased survival in ovarian cancer patients. The effect of c-erbB-2 anti-sense phosphorothioate oligodeoxynucleotides (S-ODNs) was examined on the ovarian cancer cell line SK-OV-3. p185c-erbB-2 levels were specifically reduced by a single-dose application of 5 microM c-erbB-2 anti-sense S-ODNs. This was accompanied by a 60% inhibition of anchorage-dependent cell growth. More strikingly, c-erbB-2 anti-sense S-ODNs almost completely abrogated serum-induced cell spreading. A control of complementary sense oligodeoxynucleotides did not show significant inhibitory effects on cell growth or on cell spreading. The inhibition of cell spreading was imitated by a monoclonal antibody (9G6) targeting the extracellular domain of p185c-erbB-2 and by the tyrosine kinase inhibitor erbstatin. The inhibitory activity of these 2 compounds was lost after a few hours, while the inhibition of serum-induced cell spreading by anti-sense S-ODNs was still present after 24 hr. Our results show that c-erbB-2 anti-sense S-ODNs effectively inhibit the mitogenic and spreading activity of p185c-erbB-2 in ovarian cancer cells. Thus, anti-sense strategies have the potential of providing new strategies for the therapy of ovarian cancer.
Wiechen
K
K
Institute of Pathology, Universitätsklinikum Charité, Medizinische Fakultät der Humboldt-Universität Berlin, Germany.
Dietel
M
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics*; D013873:Thionucleotides / Q000494:pharmacology*
D000970:Antineoplastic Agents; D016376:Oligonucleotides, Antisense; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases; D013873:Thionucleotides; C000715470:MAS1 protein, human