| Abstract: |
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. © 2002 American Association for Cancer Research. |
| Keywords: |
antineoplastic agents; flow cytometry; brain tumor; glioma; brain neoplasms; antineoplastic agent; cell cycle protein; mouse; animal; metabolism; animals; cell cycle proteins; mice; cell division; apoptosis; in vitro study; drug effect; pathology; enzyme immunoassay; immunoenzyme techniques; fluorescent antibody technique; sulindac; rat; drug derivative; phosphoproteins; mitosis spindle; mitotic spindle apparatus; rats; microtubule; microtubules; phosphoprotein; cell strain 3t3; thymidine; 3t3 cells; fluorescent antibody technique, indirect; cyclic gmp; cyclic gmp dependent protein kinase; cyclic gmp-dependent protein kinases; interphase; phosphodiesterase; phosphoric diester hydrolases; sulindac sulfone; humans; human; article; cp 461; 3',5' cyclic nucleotide phosphodiesterase; cgmp binding, cgmp specific 3',5' cyclic nucleotide phosphodiesterase; cgmp-binding, cgmp-specific 3',5'-cyclic nucleotide phosphodiesterase; cyclic gmp phosphodiesterase; mphosph1 protein, human; phosphodiesterase 2a; 3',5'-cyclic-gmp phosphodiesterase; 3',5'-cyclic-nucleotide phosphodiesterase
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