title: N-(2,6-dimethoxypyridine-3-yl)-9-methylcarbazole-3-sulfonamide as a novel tubulin ligand against human cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 mumol/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.
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Tiantan Xili, Beijing, People's Republic of China.
authors.forename: Yue-Ming
authors.initials: YM
authors.lastname: Wang
authors.forename: Lai-Xing
authors.initials: LX
authors.lastname: Hu
authors.forename: Zhen-Ming
authors.initials: ZM
authors.lastname: Liu
authors.forename: Xue-Fu
authors.initials: XF
authors.lastname: You
authors.forename: Sheng-Hua
authors.initials: SH
authors.lastname: Zhang
authors.forename: Jing-Rong
authors.initials: JR
authors.lastname: Qu
authors.forename: Zhuo-Rong
authors.initials: ZR
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Wei-Jia
authors.initials: WJ
authors.lastname: Kong
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: He
authors.forename: Rong-Guang
authors.initials: RG
authors.lastname: Shao
authors.forename: Liang-Ren
authors.initials: LR
authors.lastname: Zhang
authors.forename: Zong-Gen
authors.initials: ZG
authors.lastname: Peng
authors.forename: David W
authors.initials: DW
authors.lastname: Boykin
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Jiang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D051379:Mice; D008819:Mice, Nude; D008870:Microtubules / Q000378:metabolism; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology; D014404:Tubulin / Q000737:chemistry*; D050257:Tubulin Modulators / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002227:Carbazoles; D008024:Ligands; C533034:N-(2,6-dimethoxypyridine-3-yl)-9-methylcarbazole-3-sulfonamide; D013449:Sulfonamides; D014404:Tubulin; D050257:Tubulin Modulators