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Herbert Irving Comprehensive Cancer Center [J-T. Y., D. X., I. B. W.], Department of Anatomy and Cell Biology [A. F. P., G. G. G.], Department of Neurological Surgery [J. N. B], College of Physicians and Surgeons, Columbia University, New York, NY 10032; Flow Cytometry Core Facility, Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [T. M. D.]; Department of Human Genetics, Mount Sinai School of Medicine, New York, New York 10029 [P. E. W]; and Cell Pathways Inc., Horsham, Pennsylvania 19044 [W. J. T., G. S., C. W., J. F., R. P.]

Exisulind (sulindac sulfone) and two potent derivatives, CP248 and CP461, have been shown previously to cause growth inhibition and apoptosis in several types of human carcinoma cell lines. These and related compounds have not been previously studied with respect to glioma cell lines. In the present study, we found that these three compounds caused marked growth inhibition in four rat glioma and eight human glioma cell lines, with IC₅₀ values of 150, 1, and 0.075 µM, respectively. When studied at these concentrations exisulind and CP461 had no significant effect on the cell cycle profile of glioma cells, but CP248 caused marked arrest in mitosis. Detailed studies of CP248 in the 9L rat gliosarcoma cell line indicated that treatment with 0.075 µM CP248 caused abnormalities in the spindle apparatus and activation of the spindle assembly check point. In interphase glioma cells, CP248 stabilized microtubules (MTs) at low concentrations (0.075 µM) and depolymerized MTs at higher concentrations (0.2–0.4 µM). In NIH 3T3 fibroblasts, 0.1 µM CP248 caused extensive MT depolymerization. CP248 also caused MT depolymerization when added to assembled MTs in vitro, which indicated that it can directly affect MTs, perhaps because it shares certain structural similarities with Colcemid. In glioma cells, the effects of CP248 on MTs were independent of the previously reported effects of this compound on activation of protein kinase G. Therefore, CP248 is a novel MT-active agent that may be useful in the treatment of glioblastoma, and possibly other types of cancer, because of its dual effects on protein kinase G and MTs.

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