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Activation of the Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase Pathway Overcomes Cisplatin Resistance in Ovarian Carcinoma Cells

Nonaka, Michiko MD; Itamochi, Hiroaki MD, PhD; Kawaguchi, Wakae MD, PhD; Kudoh, Akiko MD; Sato, Seiya MD, PhD; Uegaki, Kazunori MD, PhD; Naniwa, Jun MD, PhD; Sato, Shinya MD, PhD; Shimada, Muneaki MD, PhD; Oishi, Tetsuro MD, PhD; Terakawa, Naoki MD, PhD; Kigawa, Junzo MD, PhD; Harada, Tasuku MD, PhD

International Journal of Gynecological Cancer: July 2012 - Volume 22 - Issue 6 - p 922–929
doi: 10.1097/IGC.0b013e31824f0b13
Basic Science

Objective This study was aimed to elucidate the roles of the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3′-kinase (PI3K)/Akt pathways in regulating cytotoxicity induced by cisplatin (CDDP) in ovarian carcinoma cells.

Methods We treated 7 ovarian cancer cell lines with CDDP alone or with CDDP and either a PI3K inhibitor (LY294002), a MEK inhibitor (PD98059), or a MEK/ERK activator (phorbol 12-myristate 13-acetate [PMA]) and assessed cell viability, expression of MEK/ERK and PI3K/Akt, cell cycle distribution, and apoptosis. We also investigated the effect of combination treatment on survival in a xenograft model.

Results The cell lines showed half-maximal inhibitory concentrations (IC50) of CDDP from 2.4 to 26.9 μmol/L. KFr, a CDDP-resistant cell line developed from KF cells, showed an IC50 of CDDP of 9.6 μmol/L. Five of the cell lines with IC50 values of 9.6 μmol/L or greater were defined as CDDP-resistant. Cisplatin and LY294002 had an additive effect on inhibiting cell growth, and CDDP and PD98059 had and antagonistic effect on cell growth in all cell lines. In CDDP-resistant cells, CDDP and PMA dramatically suppressed the cell growth, up-regulated the expression of phosphorylated ERK and cleaved caspase-9, down-regulated the expression of checkpoint kinases, and increased the proportion of cells in the synthesis-phase fraction and apoptotic cells. The treatment of nude mice with CDDP and PMA prolonged survival in an ovarian cancer xenograft model.

Conclusions The present study indicates that further study is warranted to determine the effectiveness of combination treatment with CDDP and PMA for platinum-resistant ovarian carcinoma.

Department of Obstetrics and Gynecology, Tottori University Faculty of Medicine, Yonago, Japan.

Address correspondence and reprint requests to Hiroaki Itamochi, MD, PhD, Department of Obstetrics and Gynecology, Tottori University Faculty of Medicine, 36-1 Nishicho, Yonago 683-8504, Japan. E-mail:

This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (17244120 to H. Itamochi and 20249066 to N. Terakawa).

The authors declare that there are no conflicts of interest.

Received January 12, 2012

Accepted February 7, 2012

Copyright © 2012 by IGCS and ESGO