TY - JOUR T1 - A Novel Oral Indoline-Sulfonamide Agent, <em>N-</em>[1-(4-Methoxybenzenesulfonyl)-2,3-dihydro-1<em>H</em>-indol-7-yl]-Isonicotinamide (J30), Exhibits Potent Activity against Human Cancer Cells in Vitro and in Vivo through the Disruption of Microtubule JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 398 LP - 405 DO - 10.1124/jpet.107.126680 VL - 323 IS - 1 AU - Jing-Ping Liou AU - Kuo-Shun Hsu AU - Ching-Chuan Kuo AU - Chi-Yen Chang AU - Jang-Yang Chang Y1 - 2007/10/01 UR - http://jpet.aspetjournals.org/content/323/1/398.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -