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Selective Cytotoxicity of Dihydroorotate Dehydrogenase Inhibitors to Human Cancer Cells Under Hypoxia and Nutrient-Deprived Conditions
http://hdl.handle.net/10069/38616
http://hdl.handle.net/10069/38616c9d6ac81-c678-43e8-a453-e5828738bda3
| 名前 / ファイル | ライセンス | アクション |
|---|---|---|
FiPha9_997.pdf (2.4 MB)
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| Item type | 学術雑誌論文 / Journal Article(1) | |||||
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| 公開日 | 2018-10-15 | |||||
| タイトル | ||||||
| タイトル | Selective Cytotoxicity of Dihydroorotate Dehydrogenase Inhibitors to Human Cancer Cells Under Hypoxia and Nutrient-Deprived Conditions | |||||
| 言語 | ||||||
| 言語 | eng | |||||
| キーワード | ||||||
| 主題Scheme | Other | |||||
| 主題 | Anticancer activity | |||||
| キーワード | ||||||
| 主題Scheme | Other | |||||
| 主題 | Ascofuranone | |||||
| キーワード | ||||||
| 主題Scheme | Other | |||||
| 主題 | Crystal structure | |||||
| キーワード | ||||||
| 主題Scheme | Other | |||||
| 主題 | Pyrimidine de novo biosynthesis | |||||
| キーワード | ||||||
| 主題Scheme | Other | |||||
| 主題 | Structure-activity relationship | |||||
| キーワード | ||||||
| 主題Scheme | Other | |||||
| 主題 | Tumor bioenergetics | |||||
| キーワード | ||||||
| 主題Scheme | Other | |||||
| 主題 | Tumor microenvironment | |||||
| キーワード | ||||||
| 主題Scheme | Other | |||||
| 主題 | Ubiquinone binding-site inhibitor | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_6501 | |||||
| 資源タイプ | journal article | |||||
| 著者 |
Miyazaki, Yukiko
× Miyazaki, Yukiko× Inaoka, Daniel K.× Shiba, Tomoo× Saimoto, Hiroyuki× Sakura, Takaya× Amalia, Eri× Kido, Yasutoshi× Sakai, Chika× Nakamura, Mari× Moore, Anthony L.× Harada, Shigeharu× Kita, Kiyoshi |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Human dihydroorotate dehydrogenase (HsDHODH) is a key enzyme of pyrimidine de novo biosynthesis pathway. It is located on the mitochondrial inner membrane and contributes to the respiratory chain by shuttling electrons to the ubiquinone pool. We have discovered ascofuranone (1), a natural compound produced by Acremonium sclerotigenum, and its derivatives are a potent class of HsDHODH inhibitors. We conducted a structure-activity relationship study and have identified functional groups of 1 that are essential for the inhibition of HsDHODH enzymatic activity. Furthermore, the binding mode of 1 and its derivatives to HsDHODH was demonstrated by co-crystallographic analysis and we show that these inhibitors bind at the ubiquinone binding site. In addition, the cytotoxicities of 1 and its potent derivatives 7, 8, and 9 were studied using human cultured cancer cells. Interestingly, they showed selective and strong cytotoxicity to cancer cells cultured under microenvironment (hypoxia and nutrient-deprived) conditions. The selectivity ratio of 8 under this microenvironment show the most potent inhibition which was over 1000-fold higher compared to that under normal culture condition. Our studies suggest that under microenvironment conditions, cancer cells heavily depend on the pyrimidine de novo biosynthesis pathway. We also provide the first evidence that 1 and its derivatives are potential lead candidates for drug development which target the HsDHODH of cancer cells living under a tumor microenvironment. | |||||
| 書誌情報 |
Frontiers in Pharmacology 巻 9, p. art.no.997, 発行日 2018-09-04 |
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| 出版者 | ||||||
| 出版者 | Frontiers Media S.A. | |||||
| EISSN | ||||||
| 収録物識別子タイプ | ISSN | |||||
| 収録物識別子 | 16639812 | |||||
| DOI | ||||||
| 関連タイプ | isIdenticalTo | |||||
| 識別子タイプ | DOI | |||||
| 関連識別子 | 10.3389/fphar.2018.00997 | |||||
| 権利 | ||||||
| 権利情報 | c 2018 Miyazaki, Inaoka, Shiba, Saimoto, Sakura, Amalia, Kido, Sakai, Nakamura, Moore, Harada and Kita. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. | |||||
| 著者版フラグ | ||||||
| 出版タイプ | VoR | |||||
| 出版タイプResource | http://purl.org/coar/version/c_970fb48d4fbd8a85 | |||||
| 引用 | ||||||
| 内容記述タイプ | Other | |||||
| 内容記述 | Frontiers in Pharmacology, 9, art.no.997; 2018 | |||||
