N-(2,6-dimethoxypyridine-3-yl)-9-methylcarbazole-3-sulfonamide as a novel tubulin ligand against human cancer.
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.
Wang
Yue-Ming
YM
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Tiantan Xili, Beijing, People's Republic of China.
Hu
Lai-Xing
LX
Liu
Zhen-Ming
ZM
You
Xue-Fu
XF
Zhang
Sheng-Hua
SH
Qu
Jing-Rong
JR
Li
Zhuo-Rong
ZR
Li
Yan
Y
Kong
Wei-Jia
WJ
He
Hong-Wei
HW
Shao
Rong-Guang
RG
Zhang
Liang-Ren
LR
Peng
Zong-Gen
ZG
Boykin
David W
DW
Jiang
Jian-Dong
JD
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
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