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.