Tranilastは 骨肉腫の抗がん剤の効果を増強する

• Material Type: 博士論文
• Title: Tranilastは 骨肉腫の抗がん剤の効果を増強する
• Author/Editor: 中島, 隆之
• Author Heading: 中島, 隆之 ナカシマ, タカユキ
• Publication, Distribution, etc.: Spandidos Publications
• Alternative Title: Tranilast enhances the effect of anticancer agents in osteosarcoma
• Degree grantor/type: 鹿児島大学
• Date Granted: 2020-03-12
• Dissertation Number: 甲総研第541号
• Degree Type: 博士(医学); Doctor of Philosophy in Medical Science
• Text Language Code: eng
• Subject Heading: tranilast; osteosarcoma; cisplatin; G2/M arrest; apoptosis
• Target Audience: 一般
• Note (General): 博士論文全文, 博士論文要旨, 最終試験結果の要旨, 論文審査の要旨; Tranilast [N‑(3',4'‑dimethoxycinnamoyl)‑anthranilic acid], initially developed as an antiallergic drug, also exhibits a growth inhibitory effect on various types of cancer. Osteosarcoma is treated mainly with high‑dose methotrexate, doxorubicin, cisplatin and ifosfamide; however, 20‑30% of patients cannot be cured of metastatic disease. We investigated whether tranilast enhances the anticancer effects of chemotherapeutic drugs and analyzed its mechanism of action in osteosarcomas. Tranilast inhibited proliferation of HOS, 143B, U2OS and MG‑63 osteosarcoma cells in a dose‑dependent manner, as well as enhancing the effects of cisplatin and doxorubicin. The average combination index at effect levels for tranilast in combination with cisplatin was 0.57 in HOS, 0.4 in 143B, 0.39 in U2OS and 0.51 in MG‑63 cells. Tranilast and cisplatin synergistically inhibited the viability of osteosarcoma cells. In flow cytometric analysis, although tranilast alone did not induce significant apoptosis, the combination of tranilast and cisplatin induced early and late apoptotic cell death. Expression of cleaved caspase‑3, cleaved poly(ADP‑ribose) polymerase and p‑H2AX was enhanced by tranilast in combination with cisplatin. Tranilast alone increased expression of p21 and Bim protein in a dose‑dependent manner. Cell cycle analysis using flow cytometry demonstrated that the combination of tranilast and cisplatin increased the number of cells in the G2/M phase. Compared with cisplatin alone, the combination increased levels of phospho‑cyclin‑dependent kinase 1 (Y15). In the 143B xenograft model, tumor growth was significantly inhibited by combined tranilast and cisplatin compared with the controls, whereas cisplatin alone did not significantly inhibit tumor growth. In conclusion, tranilast has a cytostatic effect on osteosarcoma cells and enhances the effect of anticancer drugs, especially cisplatin. Enhanced sensitivity to cisplatin was mediated by increased apoptosis through G2/M arrest. Since tranilast has been clinically approved and has few adverse effects, clinical trials of osteosarcoma chemotherapy in combination with tranilast are expected. Takayuki Nakashima, Satoshi Nagano, Takao Setoguchi, Hiromi Sasaki, Yoshinobu Saitoh, Shingo Maeda, Setsuro Komiya, Noboru Taniguchi Tranilast enhances the effect of anticancer agents in osteosarcoma Oncology Reports 2019, 42(1) 176-188 https://doi.org/10.3892/or.2019.7150
• Format (IMT): application/pdf
• Access Restrictions: インターネット公開
• 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): 鹿児島大学 : 鹿児島大学リポジトリ

Table of Contents

Result_Nakashima_Takayuki_isk_541 other

Comments_Nakashima_Takayuki_isk_541 other

Diss_中島_隆之_ISK541_2019 fulltext

Abstract_中島_隆之_4514810175_2019 abstract