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Enhancement of Radiosensitivity by Eurycomalactone in Human Lung Adenocarcinoma Cells through G2/M Cell Cycle Arrest and Delayed DNA Double-strand Break Repair
https://repo.qst.go.jp/records/77452
https://repo.qst.go.jp/records/7745222f2fa0e-05b7-481d-8f6e-1dbaee759d3e
| アイテムタイプ | 学術雑誌論文 / Journal Article(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2019-05-07 | |||||
| タイトル | ||||||
| タイトル | Enhancement of Radiosensitivity by Eurycomalactone in Human Lung Adenocarcinoma Cells through G2/M Cell Cycle Arrest and Delayed DNA Double-strand Break Repair | |||||
| 言語 | ||||||
| 言語 | eng | |||||
| 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 | |||||
| アクセス権 | ||||||
| アクセス権 | metadata only access | |||||
| アクセス権URI | http://purl.org/coar/access_right/c_14cb | |||||
| 著者 |
Dukaew, Nahathai
× Dukaew, Nahathai× Konishi, Teruaki× Chairatvit, Kongthawat× Autsavapromporn, Narongchai× Soonthornchareonnon, Noppamas× Wongnoppavich, Ariyaphong× Konishi, Teruaki |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Radiotherapy (RT) is an important treatment for non-small cell lung cancer (NSCLC). However, the major obstacles to successful RT includes the low radiosensitivity of cancer cells and the restricted radiation dose which is given without damaging normal tissues. Therefore, the sensitizer that increases RT efficacy without dose escalation will be beneficial for NSCLC treatment. Eurycomalactone (ECL), an active quassinoid isolated from Eurycoma longifolia Jack, has been demonstrated to possess anticancer activity. In this study, we aimed to investigate the effect of ECL on sensitizing NSCLC cells to X-radiation (X-ray) as well as the underlying mechanisms. The results showed that ECL exhibited selective cytotoxicity against the NSCLC cells; A549 and COR-L23 as compared to the normal lung fibroblast. Clonogenic survival results indicated that ECL treatment prior to irradiation synergistically decreased the A549 and COR-L23 colony number. ECL treatment reduced the expression of CyclinB1 and CDK1/2 leading to induce cell cycle arrest at the radiosensitive G2/M phase. Moreover, ECL markedly delayed the repair of radiation-induced DNA double strand breaks (DSB). In A549 cells, pre-treatment with ECL not only delayed the resolving of radiation-induced γ-H2AX foci but also blocked the formation of 53BP1 foci at the DSB sites. In addition, ECL pre-treatment attenuated expression of DNA repair proteins, Ku80 and KDM4D in both NSCLC cells. Consequently, these effects led to an increase of apoptosis in irradiated cells. Thus, ECL radiosensitized the NSCLC cells to X-ray via G2/M arrest induction, delayed the repair of X-ray-induced DSB. This study offers a great potential for ECL as an alternative safer radiosensitizer for increasing the RT efficiency against NSCLC. Materials and methods: Cytotoxicity of ECL was determined using MTT assay on non-small cell lung cancer (NSCLC) cell lines (A549, Calu-1) and human lung fibroblast (WI-38) cells. The effects of ECL combined with X-rays were analyzed using clonogenic assays and that on cell cycle progression and apoptosis by flow cytometry and Western blotting. DNA double-strand breaks (DSB) and DSB repair capacity were evaluated by immunofluorescence and immunoblotting of DSB repair proteins. Results: ECL selectively inhibited the viability of A549 cells but not Calu-1 or WI-38 cells. Pre-treatment with non-cytotoxic (IC20) or cytotoxic (IC50) doses of ECL prior to irradiation synergistically decreased the colony formation rate of cells with the sensitizer enhancement ratios at 10% cell survival of 1.20 and 1.36, respectively. ECL reduced expression of CDK1/2 and cyclinB1, then induced cell cycle arrest at the radiosensitive G2/M transition, leading to increased apoptosis. ECL followed by irradiation delayed the number of γ-H2AX foci, blocked 53BP1 foci formation at the DSB sites, and attenuated expression of Ku80 and KDM4D. Conclusion: ECL radiosensitized the A549 cell to X-rays via induction of G2/M arrest, delayed X-rays-induced DNA damage repair and enhanced apoptosis. Finally, ECL holds promise as a radiosensitizer for increasing the efficiency of X-ray therapy against lung cancer. |
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| 書誌情報 |
Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 巻 28, 号 2, p. 161-175, 発行日 2019-11 |
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| 出版者 | ||||||
| 出版者 | Cognizant Communication Corporation | |||||
| ISSN | ||||||
| 収録物識別子タイプ | ISSN | |||||
| 収録物識別子 | 0965-0407 | |||||
| PubMed番号 | ||||||
| 識別子タイプ | PMID | |||||
| 関連識別子 | 31727206 | |||||
| DOI | ||||||
| 識別子タイプ | DOI | |||||
| 関連識別子 | 10.3727/096504019X15736439848765 | |||||
| 関連サイト | ||||||
| 識別子タイプ | URI | |||||
| 関連識別子 | https://www.ingentaconnect.com/content/cog/or/pre-prints/content-orm-a-3009_dukaew | |||||
