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論文
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Higuchi, Takashi ; Takeuchi, Akihiko ; Munesue, Seiichi ; Yamamoto, Norio ; Hayashi, Katsuhiro ; Kimura, Hiroaki ; Miwa, Shinji ; Inaki, Hiroyuki ; Shimozaki, Shingo ; Kato, Takashi ; Aoki, Yu ; Abe, Kensaku ; Taniguchi, Yuta ; Aiba, Hisaki ; Murakami, Hideki ; Harashima, Ai ; Yamamoto, Yasuhiko ; Tsuchiya, Hiroyuki ; 武内 , 章彦 ; 棟居, 聖一 ; 山本, 憲男 ; 林 , 克洋 ; 三輪, 真嗣 ; 谷口, 裕太 ; 原島, 愛 ; 山本, 靖彦 ; 土屋, 弘行
概要:
金沢大学医薬保健研究域医学系<br />Surgical resection is the only treatment for chondrosarcomas, because of their resistance to chemoth
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erapy and radiotherapy; therefore, additional strategies are crucial to treat chondrosarcomas. Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor, which has been reported as a possible therapeutic target in certain malignancies including chondrosarcomas. In this study, we demonstrated that a nonsteroidal anti-inflammatory drug, zaltoprofen, could induce PPARγ activation and elicit anti-tumor effects in chondrosarcoma cells. Zaltoprofen was found to induce expressions of PPARγ mRNA and protein in human chondrosarcoma SW1353 and OUMS27 cells, and induce PPARγ-responsible promoter reporter activities. Inhibitory effects of zaltoprofen were observed on cell viability, proliferation, migration, and invasion, and the activity of matrix metalloproteinase-2 (MMP2); these effects were dependent on PPARγ activation and evidenced by silencing PPARγ. Moreover, we showed a case of a patient with cervical chondrosarcoma (grade 2), who was treated with zaltoprofen and has been free from disease progression for more than 2 years. Histopathological findings revealed enhanced expression of PPARγ and reduced expression of MMP2 after administration of zaltoprofen. These findings demonstrate that zaltoprofen could be a promising drug against the malignant phenotypes in chondrosarcomas via activation of PPARγ and inhibition of MMP2 activity. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.<br />29573200
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| 2.
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論文
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El‑Far, Ali Hafez Ali MohammedTsuchiya Hiroshi Yamamoto Hazem M.E. Shaheen Yasser S. El‑Sayed Shuhei Kawano Sei‑Ichi Tanuma Yasuhiko Yamamoto ; Munesue, Seiichi ; Harashima, Ai ; Satoh, Akira ; Shindo, Mika ; Nakajima, Shingo ; Inada, Mana ; Tanaka, Mariko ; Takeuchi, Akihiko ; Tsuchiya, Hiroyuki ; Yamamoto, Hiroshi ; Shaheen, Hazem M.E. ; El‑Sayed, Yasser S. ; Kawano, Shuhei ; Tanuma, Sei‑Ichi ; Yamamoto, Yasuhiko ; 棟居, 聖一 ; 原島, 愛 ; 武内 , 章彦 ; 土屋, 弘行 ; 山本, 靖彦
概要:
金沢大学医薬保健研究域医学系<br />Receptor for advanced glycation end-products (RAGE) is a pattern recognition receptor implicated in
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the pathogenesis of certain types of cancer. In the present study, papaverine was identified as a RAGE inhibitor using the conversion to small molecules through optimized‑peptide strategy drug design system. Papaverine significantly inhibited RAGE‑dependent nuclear factor κ‑B activation driven by high mobility group box‑1, a RAGE ligand. Using RAGE‑ or dominant‑negative RAGE‑expressing HT1080 human fibrosarcoma cells, the present study revealed that papaverine suppressed RAGE‑dependent cell proliferation and migration dose‑dependently. Furthermore, papaverine significantly inhibited cell invasion. The results of the present study suggested that papaverine could inhibit RAGE, and provided novel insights into the field of RAGE biology, particularly anticancer therapies.<br />Embargo Period 6 months
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| 3.
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論文
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Takeuchi, Akihiko ; Yamamoto, Yasuhiko ; Munesue, Seiichi ; Harashima, Ai ; Watanabe, Takuo ; Yonekura, Hideto ; Yamamoto, Hiroshi ; Tsuchiya, Hiroyuki
概要:
医薬保健研究域医学系<br />The receptor for advanced glycation end products (RAGE) is a pattern-recognition receptor and its engage
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ment by ligands such as high mobility group box 1 (HMGB1) is implicated in tumor growth and metastasis. Low molecular weight heparin (LMWH) has an antagonistic effect on the RAGE axis and is also reported to exert an antitumor effect beyond the known activity of anticoagulation. However, the link between the anti-RAGE and antitumor activities of LMWH has not yet to be fully elucidated. In this study, we investigated whether LMWH could inhibit tumor cell proliferation, invasion, and metastasis by blocking the RAGE axis using in vitro and in vivo assay systems. Stably transformed HT1080 human fibrosarcoma cell lines were obtained, including human full-length RAGE-overexpressing (HT1080RAGE), RAGE dominant-negative, intracellular tail-deleted RAGE-overexpressing (HT1080dnRAGE), and mock-transfected control (HT1080mock) cells. Confocal microscopy showed the expression of HMGB1 and RAGE in HT1080 cells. The LMWH significantly inhibited HMGB1-induced NFκB activation through RAGE using an NFκB-dependent luciferase reporter assay and the HT1080 cell lines. Overexpression of RAGE significantly accelerated, but dnRAGE expression attenuated HT1080 cell proliferation and invasion in vitro, along with similar effects on local tumor mass growth and lung metastasis in vivo. Treatment with LMWH significantly inhibited the migration, invasion, tumor formation, and lung metastasis of HT1080RAGE cells, but not of HT1080mock or HT1080dnRAGE cells. In conclusion, this study revealed that RAGE exacerbated the malignant phenotype of human fibrosarcoma cells, and that this exacerbation could be ameliorated by LMWH. It is suggested that LMWH has therapeutic potential in patients with certain types of malignant tumors. © 2013 Japanese Cancer Association.
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