Ascorbyl Stearate Inhibits Cell Proliferation and Tumor

Ascorbyl stearate is a lipophilic, vitamin C derivative with antitumorigenic properties. The molecular mechanism(s) underlying the anticarcinogenic effect of this compound have not been well documented. The effect of ascorbyl stearate was studied in a panel of human ovarian epithelial cancer cells. Treatment with ascorbyl stearate caused a dose-dependent inhibition of the cell proliferation. The antiproliferative effect was due to the arrest of cells in the S/G2-M-phase of the cell cycle. Treatment of OVCAR-3 cells with ascorbyl stearate also inhibited PI3K/AKT activity. The presence of a constitutively active AKT protected OVCAR-3 cells from the effects of ascorbyl stearate, suggesting that this nutraceutical targets the PI3K/AKT pathway. The administration of ascorbyl stearate by gavage induced involution of human ovarian carcinoma xenografts in nude mice. These studies indicate that the antiproliferative effect of ascorbyl stearate on ovarian epithelial cancer cells is associated with decreased PI3K/AKT activity, and point toward the PI3K/AKT signaling pathway as a target for this drug. Ovarian cancer represents the most lethal gynecological malignancy in the United States with an annual incidence of approximately 23,300 new cases and 13,900 deaths (1). The pathobiology of ovarian epithelial cancer, accounting for about 90% of all ovarian malignant tumors, is unknown. The rate of ovulation, hormonal imbalance and persistent inflammatory conditions are considered to be predisposing factors for the development of this malignancy (2). Ovarian epithelial cancer remains asymptomatic for a long time and is usually detected late in its course, accounting for the high stage and poor survival rate (3, 4). This problem is compounded by the lack of efficient preventive and screening strategies, as well as the frequent development of chemotherapy and radiation resistance. Hence, development of alternative strategies is essential for the management of this disease. The effects of ascorbyl stearate (Asc-S), an ester of vitamin C, were investigated on a panel of human ovarian carcinoma cells including PA-1, OVCAR-3, A-2780, ES-2, Caov3 and SW626. This compound was chosen because of the considerable epidemiological evidence pointing to the benefits of vitamin C, and of its derivatives, in the prevention and treatment of several types of cancer. Ascorbyl esters are non-toxic, synthetic compounds derived from the esterification of ascorbic acid with a fatty acid (palmitic acid or stearic acid). This reaction confers lipophilic properties to the ascorbate, allowing its passage across biological membranes (5). Ascorbic acid and ascorbyl esters have shown antineoplastic properties against several malignant cell lines (6-10), and have been effective in reducing the incidence of estradioland diethylstilbestrol-induced renal tumors in hamster (9). Vitamin C was able to mitigate the mutagenic effects of 203 *Both authors contributed equally to this work. Abbreviations: Asc-S, Ascorbyl stearate; MTT, 3-(4,5dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide; PI3K, phosphotidylinositol 3-kinase; Myr-AKT, myristoylated AKT. Correspondence to: Dr. Domenico Coppola, Department of Interdisciplinary Oncology, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, U.S.A. Tel: 813-745-3275, Fax: 813-632-1708, e-mail: [email protected]