A novel oral indoline-sulfonamide agent, N-[1-(4-methoxybenzenesulfonyl)-2,3-dihydro-1H-indol-7-yl]-isonicotinamide (J30), exhibits potent activity against human cancer cells in vitro and in vivo through the disruption of microtubule.
We have previously synthesized a series of 7-aroylaminoindoline-1-sulfonamides as a novel class of antitubulin agents. Here we show that one of these new compounds, N-[1-(4-methoxybenzenesulfonyl)-2,3-dihydro-1H-indol-7-yl]-isonicotinamide (J30), is potently effective against various resistant and nonresistant cancer cell lines despite the status of multidrug resistance, multidrug-resistance associated protein, or other resistance factors in vitro. J30 inhibits assembly of purified tubulin by strongly binding to the colchicine-binding site. Western blot and immunofluorescence experiments demonstrate that J30 depolymerizes microtubules in the KB cell line, resulting in an accumulation of G2/M phase cells. Further studies indicate that J30 causes cell cycle arrest, as assessed by flow analyses and the appearance of MPM-2 (a specific mitotic marker), and is associated with up-regulation of cyclin B1, phosphorylation of Cdc25C, and dephosphorylation of Cdc2. J30 also causes Bcl-2 phosphorylation, cytochrome c translocation, and activation of the caspase-9 and caspase-3 cascades. These findings suggest that the J30-mediated apoptotic signaling pathway depends on caspases and mitochondria. Finally, we show that oral administration of J30 significantly inhibits tumor growth in NOD/scid mice bearing human oral, gastric, and drug-resistant xenografts. Together, our results suggest that J30 has potential as a chemotherapeutic agent for treatment of various malignancies.
Liou
Jing-Ping
JP
College of Pharmacy, Taipei Medical University, Taipei, Taiwan, Republic of China.
Hsu
Kuo-Shun
KS
Kuo
Ching-Chuan
CC
Chang
Chi-Yen
CY
Chang
Jang-Yang
JY
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D014404:Tubulin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C523984:N-(1-(4-methoxybenzenesulfonyl)-2,3-dihydro-1H-indol-7-yl)isonicotinamide; D013449:Sulfonamides; D014404:Tubulin; D009536:Niacinamide; D020169:Caspases