Gedunin, a Novel Natural Substance, Inhibits Ovarian Cancer Cell Proliferation

Abstract

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.

Revisiting Amazonian Plants for Skin Care and Disease

“…Other studies have shown toxic properties of limonoids on insect larvae [30,31]. More specifically, gedunin and some of its derivatives have been investigated for antimalarial, hepatoprotective, and antitumor properties [32][33][34]. Anti-inflammatory, analgesic, and antiallergic virtues of the oil have led to the development of pharmaceutical products [35].…”

Gedunin Inactivates the Co-chaperone p23 Protein Causing Cancer Cell Death by Apoptosis

“…Caspase-dependent Cleavage of p23-Gedunin has been reported to induce cancer cell death in prostate, ovarian, and colon cancer cell lines (21)(22)(23). Data in Fig.…”

“…3A) that is isolated from the Meliacae family of medicinal plants and has been used for the treatment of malaria and other infectious diseases in traditional Indian medicine. Recent reports have shown that gedunin exhibits anti-proliferative activity against tumor cells from prostate, ovarian, and colon origins (21)(22)(23). Connectivity map analysis established that gedunin is an inhibitor of the Hsp90 machine (24) via a yet unknown mechanism, which is distinct from that of ansamycin analogues (23).…”

Gedunin Binds to Myeloid Differentiation Protein 2 and Impairs Lipopolysaccharide-Induced Toll-Like Receptor 4 Signaling in Macrophages

“…Gedunin and its analogs are an important bioactive limonoid-type tetranortriterpene isolated from the Meliaceae family and are reported to display a wide range of biologic activities, including antitumor, antimalarial, antiallergic, and anti-inflammatory activity in different experimental models (Brandt et al, 2008;Kamath et al, 2009;Ferraris et al, 2011Ferraris et al, , 2012Miranda Júnior et al, 2012;Henriques and Penido, 2014;Conte et al, 2015). The molecular mechanism of action related to the biologic effects of gedunin relies on the inhibition of Hsp90 activity via specific binding to the cochaperone p23 and by disrupting the cochaperone Cdc37-Hsp90 interaction (Matts et al, 2011;Patwardhan et al, 2013).…”