Ras antagonist inhibits growth and chemosensitizes human epithelial ovarian cancer cells.
The objective of this article was to determine whether human ovarian carcinoma cells (OVCAR-3) express significant amounts of Ras oncogene and active Ras-guanosine triphosphate (GTP) and, if so, whether the Ras inhibitor farnesyl thiosalicylic acid (FTS) inhibits their growth and chemosensitizes them to cisplatin. We assayed Ras and Ras-GTP in OVCAR-3 cells before and after FTS treatment. The effect of FTS on OVCAR-3 cell growth was assessed in terms of cell number. Because the OVCAR-3 cell line was derived from a patient who was refractory to cisplatin, we examined whether FTS enables cisplatin to induce death of these cells. Significant amounts of Ras and active Ras-GTP were expressed by OVCAR-3 cells and were reduced by 40% by FTS. FTS inhibited OVCAR-3 cell growth in a dose-dependent manner. When combined with cisplatin, FTS reduced the number of OVCAR-3 cells by 80%, demonstrating synergism between FTS and cisplatin. FTS, at a concentration range that allows downregulation of Ras and Ras-GTP in OVCAR-3 cells, also chemosensitizes these cells and inhibits their growth. These results suggest that ovarian carcinomas might respond well to Ras inhibition, both alone and when combined with cisplatin. The combined treatment would allow the use of smaller doses of chemotherapy, resulting in decreased cytotoxicity.
Beiner
M E
ME
Department of Gynecologic Oncology, Sheba Medical Center, Tel-Hashomer, Israel. lmbeiner@zahav.net.il
Niv
H
H
Haklai
R
R
Elad-Sfadia
G
G
Kloog
Y
Y
Ben-Baruch
G
G
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005204:Farnesol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D011905:Genes, ras; D006160:Guanosine Triphosphate; D006801:Humans; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D018631:ras Proteins / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; C112353:farnesylthioacetic acid; D005204:Farnesol; D006160:Guanosine Triphosphate; D018631:ras Proteins; D002945:Cisplatin