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.
From: College of Pharmacy, Taipei Medical University, Taipei, Taiwan, Republic of China.
The Journal of pharmacology and experimental therapeutics
- Publish Date: Oct 2007
- ISSN: 0022-3565
- Volume: 323
- Issue: 1
- Pages: 398-405
- Medium: Print
- Language: English
- Citation (JAMA): Liou Jing-Ping, Hsu Kuo-Shun, Kuo Ching-Chuan, et al. 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.. J. Pharmacol. Exp. Ther. Oct 2007;323:398-405
Abstract
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.
Mesh Headings (Keywords): Administration, Oral, Animals, Antineoplastic Agents, Apoptosis, Binding Sites, Caspases, Cell Cycle, Cell Line, Tumor, Cell Proliferation, Drug Resistance, Neoplasm, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Microtubules, Neoplasm Transplantation, Neoplasms, Niacinamide, Sulfonamides, Tubulin, Xenograft Model Antitumor Assays
Check for Full Text / PubMed Unique Identifier (PMID): 17660383
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