ABSTRACT
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.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Endometrial Neoplasms/drug therapy , ras Proteins/antagonists & inhibitors , Cell Differentiation/drug effects , Cell Growth Processes/drug effects , Cell Line, Tumor , Down-Regulation/drug effects , Endometrial Neoplasms/genetics , Endometrial Neoplasms/pathology , Estrogen Receptor alpha/genetics , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/genetics , Estrogen Receptor beta/metabolism , Farnesol/administration & dosage , Farnesol/analogs & derivatives , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Medroxyprogesterone Acetate/administration & dosage , Phosphorylation , RNA, Messenger/genetics , RNA, Messenger/metabolism , Salicylates/administration & dosage , Transcription, Genetic/drug effectsABSTRACT
Five new natural products, aeruginosins GE686 (1), GE766 (2), GE730 (3), GE810 (4), and GE642 (5), were isolated along with four known aeruginosins, 98C, 101, KY642, and DA688, from bloom material of the cyanobacterium Microcystis aeruginosa collected from a fish pond in Kibbutz Geva, Israel, in August 2007. Their structures were elucidated by a combination of various spectroscopic techniques, primarily NMR and MS, while the absolute configurations of the stereogenic centers were determined by Marfey's and chiral-phase HPLC methods. Two of the new aeruginosins, aeruginosins GE686 (1) and GE766 (2), contain the unprecedented d-m-Br-m'-Cl-p-hydroxyphenyllactic acid derivative. The structures and biological activities of the five new metabolites are described.
