Antiproliferative activity of sulforaphane in Akt-overexpressing ovarian cancer cells

Abstract

Epidemiologic studies show a correlation between increased consumption of fruits and vegetables with reduced risk of ovarian cancer. One major bioactive compound found in cruciferous vegetables, particularly broccoli, is sulforaphane, derived from the breakdown of glucoraphanin. We observed potent antiproliferative effects of sulforaphane on human ovarian cancer cell line SKOV3 (IC 50 40 Mmol/L) and mouse ovarian cancer cell lines C3 and T3 (IC 50 25 Mmol/L each) by cell viability assays. The loss of viability is reflected by a downregulation of cell cycle transition regulators cyclin D1, cyclin-dependent kinase 4 (cdk4), and cdk6. The upstream mediators of sulforaphane effects on the cell cycle in ovarian cancer are still unknown. However, because the Akt signal transduction pathway is overactivated in ovarian cancer, we investigated the effects of sulforaphane on this prosurvival pathway. Both total Akt protein and active phosphorylated levels of Akt (Ser 473 ) and phosphoinositide 3-kinase were significantly decreased in sulforaphane-treated SKOV3, C3, and T3 cells with a concomitant inhibition of Akt kinase activity by sulforaphane in SKOV3 and C3 cells. This inhibitory effect of sulforaphane leads to a potent induction of apoptosis in all three cell lines, along with the cleavage of poly(ADP)-ribose polymerase. Our study is the first to report the antiproliferative effects of sulforaphane in ovarian cancer and identifying the Akt pathway as a target of sulforaphane, with implications for the inhibition of carcinogenesis by diet-based chemoprevention. [Mol Cancer Ther 2007;6(1):334 -45]

Anti-angiogenic activity of cranberry proanthocyanidins and cytotoxic properties in ovarian cancer cells

“…This pathway is particularly important in the drug response of tumor cells, such as ovarian cancer, that display activation of AKT and other components or low expression of tumor suppressors (e.g. PTEN, a Pi3K/AKT cascade regulator) (31,42). AKT activity has been shown to correlate with poor prognosis in patients suffering ovarian cancer (43).…”

Thiol-reducing agents prevent sulforaphane-induced growth inhibition in ovarian cancer cells

“…In addition, treatment with 8 μM sulforaphane for 72 h effectively reduced growth (by 50%) of the ovarian cancer cell lines MDAH 2774 and SKOV3 [19]. A previous study demonstrated that sulforaphane effectively suppresses the growth of human and mouse ovarian cancer cells that overexpress AKT [12]. In our study, the growth-inhibitory effect of sulforaphane was also observed in OVCAR4 and OVCAR5 cells that express low levels of AKT, in addition to OVCAR3 and SKOV3 cells that express high levels of AKT [14].…”

“…Administration of sulforaphane inhibits and/or retards tumorigenesis induced by carcinogens in animal models [10,11]. In addition to its preventive effect on cancer, sulforaphane has recently been shown to inhibit the growth of various types of cancer cells by modulating multiple pathways related to cancer progression [7,12]. …”

“…Sulforaphane effectively reduces activation of the AKT signaling pathway in ovarian cancer cells that constitutively overexpress AKT [12]. Sulforaphane also induces cell-cycle arrest in PA-1 cells [18] and in MDAH 2774 and SKOV3 cells [19].…”

Sulforaphane inhibits angiogenesis through activation of FOXO transcription factors

“…Consequently, activation of the PI3K pathway serves to repress FOXO-mediated growth arrest and apoptosis. SFN has been shown to downregulate PI3K/ AKT (26,27) pathways in vitro. Furthermore, we have recently demonstrated that SFN can inhibit the phosphorylation (activation) of AKT in human prostate cancer cells orthotopically implanted in nude mice (9).…”