Inhibition of the growth of glioblastomas by CGP 41251, an inhibitor of protein kinase C, and by a phorbol ester tumor promoter.
Protein kinase C (PKC) plays a central role in signal transduction pathways that mediate the action of certain growth factors, tumor promoters, and cellular oncogenes. To explore whether PKC might be an appropriate target for the chemotherapy of human brain tumors, cell lines were established from five glioblastomas, one mixed gliosarcoma and glioblastoma, two astrocytomas, and one choroid plexus carcinoma. The staurosporine derivative CGP 41251, an inhibitor of PKC, inhibited cell proliferation in all nine cell lines with an IC50 in the range of 0.4 micrometer. Drug withdrawal and clonogenicity assays showed that CGP 41251 induced an irreversible growth arrest. Three cell lines were examined in detail: two human glioblastoma cell lines, GB-1 and GB-2, and one gliosarcoma cell line, GS-1. All of these three cell lines were highly aneuploid and displayed morphologies and immunohistochemical markers characteristic of the glial lineage. The compound 12-O-tetradecanoylphorbol-13-acetate (TPA), a tumor promoter and activator of PKC, also inhibited the growth of these cell lines. CGP 41251 in combination with TPA caused further growth inhibition. Cultures treated with CGP 41251 displayed an increase in the fraction of cells in G2-M, a decrease of cells in S phase, and no consistent effect on G0-G1. Immunohistochemical analyses demonstrated that growth inhibition by CGP 41251 was associated with the formation of giant nuclei with extensive fragmentation and apoptotic bodies. These effects of CGP 41251 were abrogated by withdrawal of serum from the medium or by exposure of these cells to aphidicolin, actinomycin D, cycloheximide, or TPA. In contrast to the effects seen with the glioblastoma cell lines, nontransformed astrocyte lines remained viable in the presence of 0.4 and 0.8 micrometer CGP 41251 and displayed only a slight increase in the fraction of giant nuclei with fragmentation. The antitumor activity of CGP 41251 was demonstrated in vivo against xenografts of the glioblastoma cell lines U87 MG and U373 MG. These findings suggest that CGP 41251 might be a useful agent for the treatment of glioblastomas.
Begemann
M
M
Columbia-Presbyterian Cancer Center, Departments of Radiation Oncology, Neurological Surgery, Division of Biostatistics in the School of Public Health, Columbia-Presbyterian Medical Center, New York, USA.
Kashimawo
S A
SA
Choi
Y A
YA
Kim
S
S
Christiansen
K M
KM
Duigou
G
G
Mueller
M
M
Schieren
I
I
Ghosh
S
S
Fabbro
D
D
Lampen
N M
NM
Heitjan
D F
DF
Schiff
P B
PB
Bruce
J N
JN
Weinstein
I B
IB
D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology; D001973:Bromodeoxyuridine / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011493:Protein Kinase C; D001973:Bromodeoxyuridine; D019311:Staurosporine; C059539:midostaurin; D013755:Tetradecanoylphorbol Acetate