A novel oral indoline-sulfonamide agent, N-[1-(4-Methoxy-benzenesulfonyl)-2,3-dihydro-1H-indol-7-yl]-Isonicotinam ide (J30), exhibits potent activity against human cancer cells in vitro and in vivo through the disruption of microtubule

作者：Liou Jing Ping; Hsu Kuo Shun; Kuo Ching Chuan; Chang Chi Yen; Chang Jang Yang^*

来源：Journal of Pharmacology and Experimental Therapeutics, 2007, 323(1): 398-405.

DOI：10.1124/jpet.107.126680

We have previously synthesized a series of 7-aroylaminoindoline1- -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 G(2)/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.

• 出版日期2007-10