CP248, a derivative of exisulind, causes growth inhibition, mitotic arrest, and abnormalities in microtubule polymerization in glioma cells.
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 microm, 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 microM 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 microM) and depolymerized MTs at higher concentrations (0.2-0.4 microM). In NIH 3T3 fibroblasts, 0.1 microM 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.
Yoon
Jung-Taek
JT
Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Palazzo
Alexander F
AF
Xiao
Danhua
D
Delohery
Thomas M
TM
Warburton
Peter E
PE
Bruce
Jeffrey N
JN
Thompson
W Joseph
WJ
Sperl
Gerhard
G
Whitehead
Clark
C
Fetter
John
J
Pamukcu
Rifat
R
Gundersen
Gregg G
GG
Weinstein
I Bernard
IB
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D016475:3T3 Cells / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D066298:In Vitro Techniques; D007399:Interphase / Q000187:drug effects; D016547:Kinesins; D051379:Mice; D008870:Microtubules / Q000187:drug effects*; D010750:Phosphoproteins / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D051381:Rats; D008941:Spindle Apparatus / Q000187:drug effects*; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013936:Thymidine / Q000378:metabolism
C439285:(5-fluoro-2-methyl-1-(4-pyridyl)methylene-3-(N-benzyl)-indene)-acetamide hydrochloride; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D013467:Sulindac; D017869:Cyclic GMP-Dependent Protein Kinases; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; C517275:PDE2A protein, human; C517277:Pde2a protein, mouse; C517278:Pde2a protein, rat; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; C517382:Pde5a protein, mouse; C517384:Pde5a protein, rat; C438388:KIF20B protein, human; D016547:Kinesins; D006152:Cyclic GMP; C025463:sulindac sulfone; D013936:Thymidine