title: The PI3K/mTOR dual inhibitor NVP-BEZ235 reduces the growth of ovarian clear cell carcinoma.
abstract: Patients with clear cell carcinoma of the ovary (OCCC) have poor survival due to resistance to standard chemotherapy. OCCC has frequent activating mutations of the PIK3CA gene. The present study was conducted to clarify the efficacy of the inhibition of the PI3K-AKT-mTOR pathway in OCCC. We used 8 OCCC cell lines and 5 ovarian serous adenocarcinoma (OSAC) cell lines. The mutation status of the PIK3CA and KRAS genes was examined by direct sequencing. The IC50 values of NVP-BEZ235 (BEZ235) and temsirolimus were determined by WST-8 assay. Protein expression levels of PI3K-AKT-mTOR pathway molecules were examined by western blotting. Cell cycle distribution was analyzed by flow cytometry. Annexin V staining was used for detecting apoptosis. We also investigated the effects of BEZ235 on OCCC tumor growth in a nude mouse xenograft model. Four of the 8 OCCC cell lines showed a PIK3CA mutation while none of the 5 OSAC cell lines showed a mutation. The IC50 values of BEZ235 for the OCCC cell lines were lower than these values for the OSAC cell lines. The IC50 value of temsirolimus was higher than BEZ235 in the OCCC cell lines. The PIK3CA mutation was more frequently noted in OCCC than OSAC cells, but the sensitivity of these cell lines to BEZ235 or temsirolimus was not related to the mutation status. pHER3 and pAkt proteins were expressed more frequently in OCCC compared with OSAC. However, protein expression levels were distributed widely, and were not related to the sensitivity. Treatment with BEZ235 suppressed expression of pAkt, although treatment with temsirolimus did not. OCCC cells exhibited G1 phase arrest after treatment with BEZ235 and apoptosis with a higher concentration of the agent. BEZ235 significantly inhibited tumor growth in mice bearing OVISE and TU-OC-1 cell tumors. The present study indicated that the PI3K-AKT-mTOR pathway is a potential target for OCCC, and that BEZ235 warrants investigation as a therapeutic agent.
authors.affiliation: Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago, Tottori 683-8504, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Oishi
authors.affiliation: Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago, Tottori 683-8504, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Itamochi
authors.affiliation: Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago, Tottori 683-8504, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Kudoh
authors.affiliation: Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago, Tottori 683-8504, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Nonaka
authors.affiliation: Tottori University Hospital Cancer Center, Yonago, Tottori 683-8504, Japan.
authors.forename: Misaki
authors.initials: M
authors.lastname: Kato
authors.affiliation: Tottori University Hospital Cancer Center, Yonago, Tottori 683-8504, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Nishimura
authors.affiliation: Tottori University Hospital Cancer Center, Yonago, Tottori 683-8504, Japan.
authors.forename: Nao
authors.initials: N
authors.lastname: Oumi
authors.affiliation: Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago, Tottori 683-8504, Japan.
authors.forename: Seiya
authors.initials: S
authors.lastname: Sato
authors.affiliation: Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago, Tottori 683-8504, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Naniwa
authors.affiliation: Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago, Tottori 683-8504, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Sato
authors.affiliation: Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago, Tottori 683-8504, Japan.
authors.forename: Muneaki
authors.initials: M
authors.lastname: Shimada
authors.affiliation: Tottori University Hospital Cancer Center, Yonago, Tottori 683-8504, Japan.
authors.forename: Junzo
authors.initials: J
authors.lastname: Kigawa
authors.affiliation: Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago, Tottori 683-8504, Japan.
authors.forename: Tasuku
authors.initials: T
authors.lastname: Harada
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000188:drug therapy / Q000473:pathology*; D000818:Animals; D045744:Cell Line, Tumor; D018293:Cystadenoma, Serous / Q000188:drug therapy / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; C401859:temsirolimus; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib; D020123:Sirolimus