Cytotoxic effects of 15-deoxy-Δ12,14-prostaglandin J2 alone and in combination with dasatinib against uterine sarcoma in vitro

• Material Type: 博士論文
• Title: Cytotoxic effects of 15-deoxy-Δ12,14-prostaglandin J2 alone and in combination with dasatinib against uterine sarcoma in vitro
• Author/Editor: Kawakita, Takako; Nisimura, Masato; Takiguchi, Eri; Abe, Akiko; Irahara, Minoru
• Author Heading: Kawakita, Takako; Nisimura, Masato; Takiguchi, Eri; Abe, Akiko; Irahara, Minoru
• Publication, Distribution, etc.: Spandidos publications
• Publication Date: 2017-04-18
• Publication Date (W3CDTF): 2017-04-18
• Alternative Title: 15-deoxy-Δ12,14-prostaglandin J2の単剤とダサチニブの併用療法は子宮肉腫の増殖を抑制する; CYTOTOXIC EFFECT OF 15d-PGJ2 AGAINST UTERINE SALCOMA
• Periodical title: Experimental and Therapeutic Medicine
• No. or year of volume/issue: 13 6
• Volume: 13
• Issue: 6
• Pages: 2939-2945
• ISSN (Periodical Title): ISSN : 1792-0981; ISSN : 1792-1015
• Degree grantor/type: 徳島大学
• Date Granted: 2017-03-06
• Dissertation Number: 甲第3021号
• Degree Type: 博士（医学）
• Text Language Code: eng
• Subject Heading: 15‑deoxy‑Δ12,14‑prostaglandin J2; uterine sarcoma; dasatinib; MAPK; ERK; AKT
• Target Audience: 一般
• Note (General): Effective chemotherapeutic strategies for uterine sarcoma are lacking; existing therapies achieve poor response rates. Previous studies have identified the prostaglandin 15-deoxy- Δ12,14-prostaglandin J2 (15d-PGJ2) as a potential anticancer treatment; however, its effectiveness in uterine sarcoma has not been examined. Furthermore, the molecular mechanisms underlying the cytotoxic mechanism of 15d-PGJ2 remain unclear. Here, we evaluated the effects of 15d-PGJ2 alone and in combination with the tyrosine kinas inhibitor (TKI) dasatinib in uterine sarcoma cell lines (MES-SA, MES-SA/DX5 and SKN). 15d-PGJ2 inhibited cell growth and increased apoptosis. Western blotting demonstrated that 15d-PGJ2 treatment increased MEK and ERK phosphorylation, and decreased levels of phosphorylated AKT. Dasatinib in combination with 15d-PGJ2 significantly reduced cell proliferation compared with 15d-PGJ2 alone, and repressed both the AKT and MAPK pathways. The cell growth inhibition rate in the PGJ2 was 21.5±12.0, 35.3±5.4 and 28.3±4.2%, respectively (MES-SA, MES-SA/DX5 and SKN cell lines) and the cell growth inhibition rate in the combination therapy was significantly higher compared with 15d-PGJ2 alone (MES-SA; 64.2±0.8, MES-SA/DX5;23.9±8.2 and SKN; 41.4±17.6%). The PGJ2 IC50 determined by MTT assay was 27.41,10.46 and 17.38 μmol/l, respectively (MES-SA, MES-SA/DX5 and SKN cell lines) and the dasatinib IC50 was 6.68,17.30 and 6.25 μmol/l, respectively. Our findings demonstrate that 15d-PGJ2 suppresses proliferation by inactivating the AKT pathway in uterine sarcoma. Furthermore, combining 15d-PGJ2 with dasatinib produced a synergistic effect on cancer cell inhibition by repressing 15d-PGJ2-mediated activation of MAPK signaling, and further repressing AKT signaling. These results suggest that 15d-PGJ2 could be used in combination with dasatinib as a potential therapeutic approach for uterine sarcoma.
• Format (IMT): application/pdf
• Access Restrictions: インターネット公開
• Rights (production): © Kawakita et al. This is an open access article distributed under the terms of Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc-nd/4.0/).
• Related Material (DOI): 10.3892/etm.2017.4346
• Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）; https://irdb.nii.ac.jp
• Original Data Provider (Database): 徳島大学 : 徳島大学機関リポジトリ

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