RRC ID 44901
Author Kashiyama T, Oda K, Ikeda Y, Shiose Y, Hirota Y, Inaba K, Makii C, Kurikawa R, Miyasaka A, Koso T, Fukuda T, Tanikawa M, Shoji K, Sone K, Arimoto T, Wada-Hiraike O, Kawana K, Nakagawa S, Matsuda K, McCormick F, Aburatani H, Yano T, Osuga Y, Fujii T.
Title Antitumor activity and induction of TP53-dependent apoptosis toward ovarian clear cell adenocarcinoma by the dual PI3K/mTOR inhibitor DS-7423.
Journal PLoS ONE
Abstract DS-7423, a novel, small-molecule dual inhibitor of phosphatidylinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR), is currently in phase I clinical trials for solid tumors. Although DS-7423 potently inhibits PI3Kα (IC50 = 15.6 nM) and mTOR (IC50 = 34.9 nM), it also inhibits other isoforms of class I PI3K (IC50 values: PI3Kβ = 1,143 nM; PI3Kγ = 249 nM; PI3Kδ = 262 nM). The PI3K/mTOR pathway is frequently activated in ovarian clear cell adenocarcinomas (OCCA) through various mutations that activate PI3K-AKT signaling. Here, we describe the anti-tumor effect of DS-7423 on a panel of nine OCCA cell lines. IC50 values for DS-7423 were <75 nM in all the lines, regardless of the mutational status of PIK3CA. In mouse xenograft models, DS-7423 suppressed the tumor growth of OCCA in a dose-dependent manner. Flow cytometry analysis revealed a decrease in S-phase cell populations in all the cell lines and an increase in sub-G1 cell populations following treatment with DS-7423 in six of the nine OCCA cell lines tested. DS-7423-mediated apoptosis was induced more effectively in the six cell lines without TP53 mutations than in the three cell lines with TP53 mutations. Concomitantly with the decreased phosphorylation level of MDM2 (mouse double minute 2 homolog), the level of phosphorylation of TP53 at Ser46 was increased by DS-7423 in the six cell lines with wild-type TP53, with induction of genes that mediate TP53-dependent apoptosis, including p53AIP1 and PUMA at 39 nM or higher doses. Our data suggest that the dual PI3K/mTOR inhibitor DS-7423 may constitute a promising molecular targeted therapy for OCCA, and that its antitumor effect might be partly obtained by induction of TP53-dependent apoptosis in TP53 wild-type OCCAs.
Volume 9(2)
Pages e87220
Published 2014
DOI 10.1371/journal.pone.0087220
PII PONE-D-13-40048
PMID 24504419
PMC PMC3913610
MeSH Adenocarcinoma, Clear Cell / drug therapy Adenocarcinoma, Clear Cell / enzymology Adenocarcinoma, Clear Cell / genetics Adenocarcinoma, Clear Cell / pathology* Animals Antineoplastic Agents / pharmacology* Antineoplastic Agents / therapeutic use Apoptosis / drug effects* Apoptosis Regulatory Proteins / metabolism Cell Line, Tumor Cell Proliferation / drug effects Class I Phosphatidylinositol 3-Kinases DNA Mutational Analysis Female Flow Cytometry Gene Expression Regulation, Neoplastic / drug effects Humans Mice, Nude Ovarian Neoplasms / drug therapy Ovarian Neoplasms / enzymology Ovarian Neoplasms / genetics Ovarian Neoplasms / pathology* Phosphatidylinositol 3-Kinases / antagonists & inhibitors* Phosphatidylinositol 3-Kinases / metabolism Phosphorylation / drug effects Phosphoserine / metabolism Protein Kinase Inhibitors / pharmacology* Protein Kinase Inhibitors / therapeutic use RNA, Messenger / genetics RNA, Messenger / metabolism Signal Transduction / drug effects Signal Transduction / genetics Sirolimus / pharmacology TOR Serine-Threonine Kinases / antagonists & inhibitors* TOR Serine-Threonine Kinases / metabolism Tumor Suppressor Protein p53 / metabolism Xenograft Model Antitumor Assays
IF 2.776
Times Cited 16
Human and Animal Cells