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Dual targeting of microtubule and topoisomerase II by alpha-carboline derivative YCH337 for tumor proliferation and growth inhibition

文献类型：期刊论文

作者Yi, Jun-Mei1; Zhang, Xiao-Fei2; Huan, Xia-Juan1; Song, Shan-Shan1; Wang, Wei1; Tian, Qian-Ting1; Sun, Yi-Ming1; Chen, Yi1; Ding, Jian1; Wang, Ying-Qing1
刊名ONCOTARGET
出版日期2015-04-20
卷号6期号:11页码:8960-8973
关键词YCH337 alpha-carboline derivative microtubule topoisomerase II antitumor activity
ISSN号1949-2553
DOI10.18632/oncotarget.3264
文献子类Article
英文摘要Both microtubule and topoisomerase II (Top2) are important anticancer targets and their respective inhibitors are widely used in combination for cancer therapy. However, some combinations could be mutually antagonistic and drug resistance further limits their therapeutic efficacy. Here we report YCH337, a novel alpha-carboline derivative that targets both microtubule and Top2, eliciting tumor proliferation and growth inhibition and overcoming drug resistance. YCH337 inhibited microtubule polymerization by binding to the colchicine site and subsequently led to mitotic arrest. It also suppressed Top2 and caused DNA double-strand breaks. It disrupted microtubule more potently than Top2. YCH337 induced reversible mitotic arrest at low concentrations but persistent DNA damage. YCH337 caused intrinsic and extrinsic apoptosis and decreased MCL-1, cIAP1 and XIAP proteins. In this aspect, YCH337 behaved differently from the combination of vincristine and etoposide. YCH337 inhibited proliferation of tumor cells with an averaged IC50 of 0.3 mu M. It significantly suppressed the growth of HT-29 xenografts in nude mice too. Importantly, YCH337 nearly equally killed different-mechanism-mediated resistant tumor cells and corresponding parent cells. Together with the novelty of its chemical structure, YCH337 could serve as a promising lead for drug development and a prototype for a dual microtubule/Top2 targeting strategy for cancer therapy.
WOS关键词MULTIDRUG-RESISTANCE ; CANCER-CHEMOTHERAPY ; ANTICANCER THERAPY ; TUBULIN INHIBITORS ; BINDING-SITE ; CELL-LINE ; AGENTS ; APOPTOSIS ; DNA ; MECHANISMS
资助项目National Natural Science Foundation of China[81202548] ; National Natural Science Foundation of China[81321092] ; National Basic Research Program of China[2012CB932502] ; National Science & Technology Major Project of China[2012ZX09301-001-002] ; "Interdisciplinary Cooperation Team" Program for Science and Technology Innovation of the Chinese Academy of Sciences[00000000] ; State Key Laboratory of Drug Research[00000000]
WOS研究方向Oncology ; Cell Biology
语种英语
WOS记录号WOS:000358774600038
出版者IMPACT JOURNALS LLC
源URL[http://119.78.100.183/handle/2S10ELR8/276569]  
专题药理学第一研究室
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
药物化学研究室
通讯作者Miao, Ze-Hong
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China;
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Med Chem, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Yi, Jun-Mei,Zhang, Xiao-Fei,Huan, Xia-Juan,et al. Dual targeting of microtubule and topoisomerase II by alpha-carboline derivative YCH337 for tumor proliferation and growth inhibition[J]. ONCOTARGET,2015,6(11):8960-8973.
APA Yi, Jun-Mei.,Zhang, Xiao-Fei.,Huan, Xia-Juan.,Song, Shan-Shan.,Wang, Wei.,...&Miao, Ze-Hong.(2015).Dual targeting of microtubule and topoisomerase II by alpha-carboline derivative YCH337 for tumor proliferation and growth inhibition.ONCOTARGET,6(11),8960-8973.
MLA Yi, Jun-Mei,et al."Dual targeting of microtubule and topoisomerase II by alpha-carboline derivative YCH337 for tumor proliferation and growth inhibition".ONCOTARGET 6.11(2015):8960-8973.

入库方式： OAI收割

来源：上海药物研究所

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