|N-(2,6-Dimethoxypyridine-3-yl)-9-Methylcarbazole-3-Sulfonamide as a Novel Tubulin Ligand against Human Cancer|
|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|
|WOS标题词||Science & Technology|
|关键词[WOS]||SPINDLE ASSEMBLY CHECKPOINT ; TUMOR-CELL LINES ; MICROTUBULE DYNAMICS ; POLYMERIZATION DYNAMICS ; MITOTIC CHECKPOINT ; INDUCED APOPTOSIS ; ANTICANCER DRUGS ; M-PHASE ; DEATH ; AGENTS|
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.
|资助机构||National Natural Science Foundation of China ; Ministry of Science and Technology|
|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
|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.|
|APA||Wang, Yue-Ming.,Hu, Lai-Xing.,Liu, Zhen-Ming.,You, Xue-Fu.,Zhang, Sheng-Hua.,...&Jiang, Jian-Dong.(2008).N-(2,6-Dimethoxypyridine-3-yl)-9-Methylcarbazole-3-Sulfonamide as a Novel Tubulin Ligand against Human Cancer.CLINICAL CANCER RESEARCH,14(19),6218-6227.|
|MLA||Wang, Yue-Ming,et al."N-(2,6-Dimethoxypyridine-3-yl)-9-Methylcarbazole-3-Sulfonamide as a Novel Tubulin Ligand against Human Cancer".CLINICAL CANCER RESEARCH 14.19(2008):6218-6227.|