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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

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

College of Pharmacy, Taipei Medical University (J.-P.L.), Taipei, Taiwan, Republic of China; National Institute of Cancer Research, National Health Research Institutes (K.-S.H., C.-C.K, C.-Y.C., J.-Y.C.), Taipei, Taiwan, Republic of China; and Division of Hematology/Oncology, Department of Internal Medicine, Tri-service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China (J.-Y.C.)

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.

Address correspondence to: Dr. Jang-Yang Chang, National Institute of Cancer Research, National Health Research Institutes, 7th Floor, No.161, Section 6, Ming-Chuan East Road, Taipei 114, Taiwan, R.O.C. E-mail: jychang{at}nhri.org.tw

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