title: Dual inhibition of phosphatidylinositol 3'-kinase and mammalian target of rapamycin using NVP-BEZ235 as a novel therapeutic approach for mucinous adenocarcinoma of the ovary.
abstract: Ovarian mucinous adenocarcinoma (MAC) resists standard chemotherapy and is associated with poor prognosis. A more effective treatment is needed urgently. The present study assessed the possibility of molecular-targeted therapy with a novel dual inhibitor of phosphatidylinositol 3'-kinase (PI3K) and mammalian target of rapamycin (mTOR), NVP-BEZ235 (BEZ235) to treat of MAC. Seven human MAC cell lines were used in this study. The sensitivity of the cells to BEZ235, temsirolimus, and anticancer agents was determined with the WST-8 assay. Cell cycle distribution was assessed by flow cytometry, and the expression of proteins in apoptotic pathways and molecules of the PI3K/Akt/mTOR signaling pathways was determined by Western blot analysis. We also examined the effects of BEZ235 on tumor growth in nude mice xenograft models. The cell lines showed half-maximal inhibitory concentration values of BEZ235 from 13 to 328 nmol/L. Low half-maximal inhibitory concentration values to BEZ235 were observed in MCAS and OMC-1 cells; these 2 lines have an activating mutation in the PIK3CA gene. NVP-BEZ235 down-regulated the protein expression of phosphorylated (p-) Akt, p-p70S6K, and p-4E-BP1, suppressed cell cycle progression, up-regulated the expression of cleaved PARP and cleaved caspase 9, and increased apoptotic cells. Synergistic effects were observed on more than 5 cell lines when BEZ235 was combined with paclitaxel or cisplatin. The treatment of mice bearing OMC-1 or RMUG-S with BEZ235 significantly suppressed tumor growth in MAC xenograft models without severe weight loss. We conclude that the PI3K/Akt/mTOR pathway is a potential therapeutic target and that BEZ235 should be explored as a therapeutic agent for MAC.
authors.affiliation: *Department of Obstetrics and Gynecology, Tottori University School of Medicine; and †Tottori University Hospital Cancer Center, Yonago, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Kudoh
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Oishi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Itamochi
authors.forename: Seiya
authors.initials: S
authors.lastname: Sato
authors.forename: Jun
authors.initials: J
authors.lastname: Naniwa
authors.forename: Shinya
authors.initials: S
authors.lastname: Sato
authors.forename: Muneaki
authors.initials: M
authors.lastname: Shimada
authors.forename: Junzo
authors.initials: J
authors.lastname: Kigawa
authors.forename: Tasuku
authors.initials: T
authors.lastname: Harada
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000188:drug therapy*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib