title: Growth of poorly differentiated endometrial carcinoma is inhibited by combined action of medroxyprogesterone acetate and the Ras inhibitor Salirasib.
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.
authors.affiliation: Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Raya
authors.initials: R
authors.lastname: Faigenbaum
authors.forename: Roni
authors.initials: R
authors.lastname: Haklai
authors.forename: Gilad
authors.initials: G
authors.lastname: Ben-Baruch
authors.forename: Yoel
authors.initials: Y
authors.lastname: Kloog
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism; D005204:Farnesol / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000008:administration & dosage; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012459:Salicylates / Q000008:administration & dosage; D014158:Transcription, Genetic / Q000187:drug effects; D018631:ras Proteins / Q000037:antagonists & inhibitors*
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D012333:RNA, Messenger; D012459:Salicylates; C093323:farnesylthiosalicylic acid; D005204:Farnesol; D017258:Medroxyprogesterone Acetate; D018631:ras Proteins