Growth of poorly differentiated endometrial carcinoma is inhibited by combined action of medroxyprogesterone acetate and the Ras inhibitor Salirasib
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Raya Faigenbaum1, Roni Haklai1, Gilad Ben-Baruch2 and Yoel Kloog1
1 Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
2 Department of Obstetrics and Gynecology, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine,Tel Aviv University, Tel Aviv, Israel
Yoel Kloog, email:
Keywords: Endometrial cancer, medroxyprogesterone acetate, FTS, Ras, ERα, ERβ
Received: February 11, 2013 Accepted: February 26, 2013 Published: February 27, 2013
Type 2 endometrial carcinoma (EC) is a poorly differentiated EC. Unlike type 1 EC, which responds to hormonal treatment (progestins), type 2 EC is refractory to hormonal treatment because of its low expression of active estrogen and progesterone receptors (ER, PR). The aim of this study was to develop a novel drug combination designed to treat these aggressive type 2 EC tumors without surgery and with fertility potential preserved. We examined the effects of combined treatment with the progestin medroxyprogesterone acetate (MPA) and the Ras inhibitor S-farnesylthiosalicylic acid (FTS; Salirasib). Because FTS can induce cell differentiation in tumor cells, we examined whether FTS could induce re-differentiation of type 2 EC cells, thereby sensitizing them to MPA. We found that FTS reduced Ras-GTP, phospho-Akt, and phospho-ERK, and that these reductions all correlated with a decrease in ERα phosphorylation. Combined treatment with FTS and MPA induced stronger reduction in USPC1 type 2 EC cell numbers than the reduction induced by either drug alone. MPA caused ERα degradation. Death of the cells was caused by MPA but not by FTS. The phosphorylated ERα induces gene transcription manifested by enhanced cell proliferation and survival. The combination of FTS and MPA, by reducing the mRNA expression of ERα-mediated genes (i.e. PR, c-fos and ps2/TFF1), inhibited tumor growth and enhanced the death of type 2 EC cells. These promising results might herald a novel treatment for the highly aggressive, incurable type 2 endometrial carcinoma.
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