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学科主题: 药学
题名:
N-(2,6-Dimethoxypyridine-3-yl)-9-Methylcarbazole-3-Sulfonamide as a Novel Tubulin Ligand against Human Cancer
作者: Wang, Yue-Ming1,2; Hu, Lai-Xing1,2,4; Liu, Zhen-Ming3; You, Xue-Fu1,2; Zhang, Sheng-Hua1,2; Qu, Jing-Rong5; Li, Zhuo-Rong1,2; Li, Yan5; Kong, Wei-Jia1,2; He, Hong-Wei1,2; Shao, Rong-Guang1,2; Zhang, Liang-Ren5; Peng, Zong-Gen1,2; Boykin, David W.4; Jiang, Jian-Dong1,2
刊名: CLINICAL CANCER RESEARCH
发表日期: 2008-10-01
DOI: 10.1158/1078-0432.CCR-08-0550
卷: 14, 期:19, 页:6218-6227
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Oncology
研究领域[WOS]: Oncology
关键词[WOS]: SPINDLE ASSEMBLY CHECKPOINT ; TUMOR-CELL LINES ; MICROTUBULE DYNAMICS ; POLYMERIZATION DYNAMICS ; MITOTIC CHECKPOINT ; INDUCED APOPTOSIS ; ANTICANCER DRUGS ; M-PHASE ; DEATH ; AGENTS
英文摘要:

Purpose: We have synthesized a new tubulin ligand N-(2,6-dimethoxypyridine-3-yl) -9-methylcarbazole-3-sulfonamide (IG-105). This work investigates its anticancer effect and mechanism.

Experimental Design: Anticancer efficacy was evaluated at the molecular target, cancer cells and nude mice. The mechanism was explored at submolecular, molecular, and cellular levels.

Results: IG-105 showed a potent activity against human leukemia and solid tumors in breast, liver, prostate, lung, skin, colon, and pancreas with IC(50) values between 0.012 and 0.298 mu mol/L. It was also active in drug-resistant tumor cells and not a P-glycoprotein substrate. It inhibited microtubule assembly followed by M-phase arrest, Bcl-2 inactivation, and then apoptosis through caspase pathways. The colchicine pocket on tubulin is the binding site of IG-105. Nude mice experiments showed that IG-105 monotherapy at 100 mg/kg i.p. (q2d) yielded 81% inhibition of Bel-7402 hepatoma growth and at 275 mg/kg i.p. (q2d) completely inhibited the tumor growth. MCF-7 breast cancer in nude mice showed a similar therapeutic response to IG-105. Acute toxicity of IG-105 was not found even at 1,000 mg/kg i.p. In combination with oxaliplatin or doxorubicin, IG-105 converted each of these subcurative compounds into a curative treatment with complete inhibition for tumor growth in the hepatoma-bearing nude mice. The combination was more active than either drug. In no experiment was toxicity increased by combination chemotherapy.

Conclusions: IG-105 inhibits microtubule assembly by binding at colchicine pocket. It shows a potent anticancer activity in vitro and in vivo and has good safety in mice. We consider IG-105 merits further investigation.

语种: 英语
所属项目编号: 30371673
项目资助者: National Natural Science Foundation of China ; Ministry of Science and Technology
WOS记录号: WOS:000260142500035
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/68251
Appears in Collections:北京大学药学院_期刊论文

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作者单位: 1.Chinese Acad Med Sci, Inst Med Biotechnol, Beijing 100050, Peoples R China
2.Peking Union Med Coll, Beijing 100021, Peoples R China
3.Peking Univ, State Key Lab Nat & Biomimet Drugs, Sch Pharmaceut Sci, Beijing 100871, Peoples R China
4.Georgia State Univ, Dept Chem, Atlanta, GA 30303 USA
5.Mt Sinai Sch Med, Dept Med, New York, NY USA

Recommended Citation:
Wang, Yue-Ming,Hu, Lai-Xing,Liu, Zhen-Ming,et al. N-(2,6-Dimethoxypyridine-3-yl)-9-Methylcarbazole-3-Sulfonamide as a Novel Tubulin Ligand against Human Cancer[J]. CLINICAL CANCER RESEARCH,2008,14(19):6218-6227.
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