Identification of DW532 as a novel anti-tumor agent targeting both kinases and tubulin
文献类型：期刊论文
| 作者 | Peng, Ting1; Wu, Jian-rui2; Tong, Lin-jiang1; Li, Meng-yuan1; Chen, Fang2; Leng, Yi-xin2; Qu, Rong1; Han, Kun1; Su, Yi1; Chen, Yi1
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 2014-07 |
| 卷号 | 35期号:7页码:916-928 |
| 关键词 | anti-cancer agent hematoxylin combretastatin tyrosine kinase EGFR VEGFR tubulin cell cycle spindle assembly checkpoint anti-angiogenesis |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/aps.2014.33 |
| 文献子类 | Article |
| 英文摘要 | Aim: 7,8-Dihydroxy-4-(3-hydroxy-4-methoxyphenyl)-2H-chromen-2-one (DW532) is one of simplified analogues of hematoxylin that has shown broad-spectrum inhibition on tyrosine kinases and in vitro anti-cancer activities. The aim of this study was to identify DW532 as a agent targeting both kinases and tubulin, and to investigate its anti-cancer and anti-angiogenesis activities. Methods: In vitro tyrosine kinases activity was examined with ELISA, and tyrosine kinases activity in cells was evaluated with Western blot analysis. Tubulin turbidity assay, surface plasmon resonance and immunofluorescence technique were used to characterize the tubulin inhibitory activity. Cell proliferation was examined with SRB assay, and cell apoptosis and cell cycle distribution were analyzed with Annexin-V/PI staining and flow cytometry. Tube formation, aortic ring and chick chorioallantoic membrane assays were used to evaluate the anti-angiogenesis efficacy. Results: DW532 inhibited EGFR and VEGFR2 in vitro kinase activity (the IC50 values were 4.9 and 5.5 mu mol/L, respectively), and suppressed their downstream signaling. DW532 dose-dependently inhibited tubulin polymerization via direct binding to tubulin, thus disrupting the mitotic spindle assembly and leading to abnormal cell division. In a panel of human cancer cells, DW532 (1 and 10 mu mol/L) induced G(2)/M phase arrest and cell apoptosis, which subsequently resulted in cytotoxicity. Knockdown of BubR1 or Mps1, the two core proteins of the spindle assembly checkpoint dramatically decreased DW532-induced cell cycle arrest in MDA-MB-468 cells. Moreover, treatment with DW532 potently and dose-dependently suppressed angiogenesis in vitro and in vivo. Conclusion: DW532 is a dual inhibitor against tubulin and tyrosine kinases, and deserves further development as a novel anti-cancer agent. |
| WOS关键词 | ENDOTHELIAL GROWTH-FACTOR ; SPINDLE ASSEMBLY CHECKPOINT ; MICROTUBULE DYNAMICS ; FACTOR RECEPTOR ; CANCER ; ANGIOGENESIS ; INHIBITION ; ARREST ; CELLS ; EXPRESSION |
| 资助项目 | National Natural Science Foundation of China[81173080] ; National Natural Science Foundation of China[81273365] ; National Natural Science Foundation of China[81321092] ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program" of China[2012ZX09103101-024] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| CSCD记录号 | CSCD:5181249 |
| WOS记录号 | WOS:000338910500008 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277004]  |
| 专题 | 药物化学研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 药理学第一研究室 |
| 通讯作者 | Duan, Wen-hu |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Peng, Ting,Wu, Jian-rui,Tong, Lin-jiang,et al. Identification of DW532 as a novel anti-tumor agent targeting both kinases and tubulin[J]. ACTA PHARMACOLOGICA SINICA,2014,35(7):916-928. |
| APA | Peng, Ting.,Wu, Jian-rui.,Tong, Lin-jiang.,Li, Meng-yuan.,Chen, Fang.,...&Ding, Jian.(2014).Identification of DW532 as a novel anti-tumor agent targeting both kinases and tubulin.ACTA PHARMACOLOGICA SINICA,35(7),916-928. |
| MLA | Peng, Ting,et al."Identification of DW532 as a novel anti-tumor agent targeting both kinases and tubulin".ACTA PHARMACOLOGICA SINICA 35.7(2014):916-928. |
入库方式： OAI收割
来源：上海药物研究所
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