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Gynecol Oncol. 2019 Sep 4. pii: S0090-8258(19)31480-5. doi: 10.1016/j.ygyno.2019.08.028. [Epub ahead of print]

Anti-tumor activity of dual inhibition of phosphatidylinositol 3-kinase and MDM2 against clear cell ovarian carcinoma.

Author information

1
Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan.
2
Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan; Current address; Department of Obstetrics and Gynecology, Nihon University, Tokyo, Japan.
3
Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan. Electronic address: katsutoshi-tky@umin.ac.jp.
4
Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan; Division of Genome Science, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
5
Department of Obstetrics and Gynecology, Nihon University, Tokyo, Japan.
6
Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Saitama, Japan.
7
Division of Genome Science, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.

Abstract

INTRODUCTION:

PI3K pathway signaling has received attention as a molecular target in clear cell ovarian carcinoma (CCOC). MDM2 is one of the AKT effectors in the PI3K pathway, which binds to and degrades p53. In this study, we aimed to clarify the prognostic significance of PIK3CA and MDM2 expression, and potential therapeutic effect of a dual inhibition of the PI3K pathway and MDM2.

MATERIALS AND METHODS:

cDNA expression was evaluated by using microarray data using 75 samples of CCOC. DS-7423 (dual inhibitor of pan-PI3K and mTOR) and RG7112 (MDM2 inhibitor) were used on CCOC cell lines to evaluate cell proliferation, expression level of MDM2 related proteins, and apoptosis by MTT assay, western blotting, and flow cytometry. DS-7423 (3 mg/kg) and/or RG7112 (50 mg/kg) were orally administrated every day for three weeks, and the anti-tumor effect was evaluated using tumor xenografts, along with immunohistochemistry.

RESULTS:

Tumors with high expression of both PIK3CA and MDM2 showed significantly worse prognosis in expression array of 71 CCOCs (P = 0.013). Dual inhibition of the PI3K pathway by DS-7423 and MDM2 by RG7112 showed synergistic anti-proliferative effect in 4 CCOC cell lines without TP53 mutations. The combination therapy more robustly induced pro-apoptotic proteins (PUMA and cleaved PARP) with increase of sub G1 population and apoptotic cells, compared with either single agent alone. The combination therapy significantly reduced tumor volume in mice (P < 0.001 in OVISE, and P = 0.038 in RMG-I) without severe body weight loss. Immunohistochemistry from the xenograft tumors showed that the combination treatment significantly reduced vascularity and cell proliferation, with an increase of apoptotic cell death.

CONCLUSION:

A combination therapy targeting the PI3K pathway and MDM2 might be a promising therapeutic strategy in CCOC.

KEYWORDS:

Clear cell ovarian carcinoma; MDM2; Molecular targeted therapy; Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway; Prognosis

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