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.

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.

• Authors: Jing-Ping Liou, Kuo-Shun Hsu, Ching-Chuan Kuo, Chi-Yen Chang, Jang-Yang Chang
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 323 Issue 1 Pg. 398-405 (Oct 2007) ISSN: 0022-3565 [Print] United States
• PMID: 17660383 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• N-(1-(4-methoxybenzenesulfonyl)-2,3-dihydro-1H-indol-7-yl)isonicotinamide
• Sulfonamides
• Tubulin
• Niacinamide
• Caspases

Topics

• Administration, Oral
• Animals
• Antineoplastic Agents (administration & dosage, pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Binding Sites
• Caspases (metabolism)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Humans
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Microtubules (drug effects, metabolism, pathology)
• Neoplasm Transplantation
• Neoplasms (drug therapy, metabolism, pathology)
• Niacinamide (administration & dosage, analogs & derivatives, pharmacology, therapeutic use)
• Sulfonamides (administration & dosage, pharmacology, therapeutic use)
• Tubulin (metabolism)
• Xenograft Model Antitumor Assays