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¹ Herbert Irving Comprehensive Cancer Center and ² Department of Anatomy and Cell Biology, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York and ³ OSI Pharmaceuticals, Inc., Farmingdale, New York

Requests for reprints: I. Bernard Weinstein, Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University Medical Center, 701 West 168th Street, Room 1509, New York, NY 10032. Phone: 212-305-6921; Fax: 212-305-6889. E-mail: ibw1{at}columbia.edu

Exisulind (sulindac sulfone) and three highly potent derivatives, OSI-461 (CP461), OSIP486823 (CP248), and OSIP487703, inhibit growth and induce apoptosis in SW480 human colon cancer cells, with IC₅₀s of 200, 2, 0.1, and 0.003 µmol/L, respectively. The latter three compounds, but not exisulind, induce marked M-phase cell cycle arrest in these cells. This effect seems to be independent of the known ability of these compounds to cause activation of protein kinase G. When tested at twice their IC₅₀ concentration for growth inhibition, OSI-461, OSIP486823, and OSIP487703 cause depolymerization of microtubules in interphase cells, inhibit spindle formation in mitotic cells, and induce multinucleated cells. In vitro tubulin polymerization assays indicate that all three compounds interact with tubulin directly to cause microtubule depolymerization and/or inhibit de novo tubulin polymerization. These results suggest that the dual effects of OSI-461, OSIP486823, and OSIP487703 on impairment of microtubule functions and protein kinase G activation may explain the potent antiproliferative and apoptotic effects of these compounds in cancer cells. [Mol Cancer Ther 2006;5(1):60–7]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ OSI Pharmaceuticals, unpublished data.

Received 7/19/05; revised 10/ 4/05; accepted 10/25/05.