N-(2,6-Dimethoxypyridine-3-yl)-9-Methylcarbazole-3-Sulfonamide as a Novel Tubulin Ligand against Human Cancer

• Published in: Clinical cancer research 2008-10, Vol.14 (19), p.6218-6227
• Main Authors: WANG, Yue-Ming, HU, Lai-Xing, SHAO, Rong-Guang, ZHANG, Liang-Ren, PENG, Zong-Gen, BOYKIN, David W, JIANG, Jian-Dong, LIU, Zhen-Ming, YOU, Xue-Fu, ZHANG, Sheng-Hua, QU, Jing-Rong, LI, Zhuo-Rong, YAN LI, KONG, Wei-Jia, HE, Hong-Wei
• Format: Article
• Language: English
• Subjects: Animals; anticancer; Antineoplastic agents; Antineoplastic Agents - pharmacology; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological and medical sciences; Carbazoles - chemistry; Carbazoles - pharmacology; Cell Line, Tumor; drug resistance; Drug Screening Assays, Antitumor; Female; Humans; IG-105; Inhibitory Concentration 50; Ligands; Medical sciences; Mice; Mice, Nude; microtubule assembly; Microtubules - metabolism; Neoplasm Transplantation; Neoplasms - drug therapy; Neoplasms - pathology; Pharmacology. Drug treatments; Sulfonamides - chemistry; Sulfonamides - pharmacology; Tubulin - chemistry; tubulin ligand; Tubulin Modulators - metabolism
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-0550

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 μmol/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.