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Antitumor activity and induction of TP53-dependent apoptosis toward ovarian clear cell adenocarcinoma by the dual PI3K/mTOR inhibitor DS-7423.
Kashiyama, Tomoko; Oda, Katsutoshi; Ikeda, Yuji; Shiose, Yoshinobu; Hirota, Yasuhide; Inaba, Kanako; Makii, Chinami; Kurikawa, Reiko; Miyasaka, Aki; Koso, Takahiro; Fukuda, Tomohiko; Tanikawa, Michihiro; Shoji, Keiko; Sone, Kenbun; Arimoto, Takahide; Wada-Hiraike, Osamu; Kawana, Kei; Nakagawa, Shunsuke; Matsuda, Koichi; McCormick, Frank; Aburatani, Hiroyuki; Yano, Tetsu; Osuga, Yutaka; Fujii, Tomoyuki.
Afiliación
  • Kashiyama T; Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
  • Oda K; Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
  • Ikeda Y; Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
  • Shiose Y; Oncology Research Laboratories, Daiichi Sankyo Co. Ltd., Tokyo, Japan.
  • Hirota Y; Oncology Research Laboratories, Daiichi Sankyo Co. Ltd., Tokyo, Japan.
  • Inaba K; Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
  • Makii C; Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
  • Kurikawa R; Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
  • Miyasaka A; Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
  • Koso T; Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
  • Fukuda T; Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
  • Tanikawa M; Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
  • Shoji K; Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
  • Sone K; Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
  • Arimoto T; Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
  • Wada-Hiraike O; Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
  • Kawana K; Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
  • Nakagawa S; Department of Obstetrics and Gynecology, Faculty of Medicine, Teikyo University, Tokyo, Japan.
  • Matsuda K; Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • McCormick F; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, United States of America.
  • Aburatani H; Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
  • Yano T; Department of Obstetrics and Gynecology, National Center for Global Health and Medicine, Tokyo, Japan.
  • Osuga Y; Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
  • Fujii T; Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
PLoS One ; 9(2): e87220, 2014.
Article en En | MEDLINE | ID: mdl-24504419
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: PI3Kß = 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Apoptosis / Adenocarcinoma de Células Claras / Inhibidores de Proteínas Quinasas / Serina-Treonina Quinasas TOR / Inhibidores de las Quinasa Fosfoinosítidos-3 / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2014 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Apoptosis / Adenocarcinoma de Células Claras / Inhibidores de Proteínas Quinasas / Serina-Treonina Quinasas TOR / Inhibidores de las Quinasa Fosfoinosítidos-3 / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2014 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Estados Unidos