The discovery of more active therapeutic compounds is essential if the outcome for patients with advanced-stage epithelial ovarian cancer is to be improved. Gedunin, an extract of the neem tree, has been used as a natural remedy for centuries in Asia. Recently, gedunin has been shown to have potential in vitro antineoplastic properties; however, its effect on ovarian cancer cells is unknown. We evaluated the in vitro effect of gedunin on SKOV3, OVCAR4, and OVCAR8 ovarian cancer cell lines proliferation, alone and in the presence of cisplatin. Furthermore, we analyzed in vitro gedunin sensitivity data, integrated with genome-wide expression data from 54 cancer cell lines in an effort to identify genes and molecular pathways that underlie the mechanism of gedunin action. In vitro treatment of ovarian cancer cell lines with gedunin alone produced up to an 80% decrease in cell proliferation (P < 0.01) and, combining gedunin with cisplatin, demonstrated up to a 47% (P < 0.01) decrease in cell proliferation compared with cisplatin treatment alone. Bioinformatic analysis of integrated gedunin sensitivity and gene expression data identified 52 genes to be associated with gedunin sensitivity. These genes are involved in molecular functions related to cell cycle control, carcinogenesis, lipid metabolism, and molecular transportation. We conclude that gedunin has in vitro activity against ovarian cancer cells and, further, may enhance the antiproliferative effect of cisplatin. The molecular determinants of in vitro gedunin response are complex and may include modulation of cell survival and apoptosis pathways.
Divisions of *Gynecologic Surgical Oncology, †Cancer Prevention & Control, and ‡Experimental Therapeutics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL.
Address correspondence and reprint requests to Johnathan M. Lancaster, MD, PhD, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL. E-mail: Johnathan.Lancaster@Moffitt.org.
This study was supported by Ovarian Cancer Research Fund, Liz Tilberis Scholars Program for Excellence in Ovarian Cancer Research, Hearing the Ovarian Cancer Whisper, Jacquie Liggett Ovarian Cancer Fellowship, and The Ocala Royal Dames Cancer Research Award.