Inhibition of growth of established human glioma cell lines by modulators of the protein kinase-C system
- Montreal Neurological Hospital, Quebec (Canada)
The protein kinase-C (PKC) second messenger system contributes to regulation of cell growth and differentiation. This study was undertaken to examine the effects of modulators of the PKC enzyme system on the state of differentiation and proliferation rates of human gliomas in vitro. The administration of the PKC-activating phorbol esters 4-beta-phorbol-12,13-dibutyrate (PDB) and phorbol-12-myristate-13-acetate (PMA) resulted in a dose-related inhibition of growth of human glioma cell lines in vitro as measured by 3H-thymidine uptake. The synthetic nonphorbol PKC activator (SC-9) produced an even more pronounced decrease of 3H-thymidine uptake. Diacylglycerol, an endogenous activator of the system, applied externally, transiently decreased the proliferation, in concordance with its short-lived existence in vivo. Conversely, the administration of 4-alpha-phorbol-12,13-didecanoate (alpha-PDD), a phorbol ester that binds but does not activate the enzyme, had no effect on the proliferation rate. At the dosages that maximally decreased proliferation, there was no evidence of direct glioma cell lysis induced by these agents as measured by a chromium-release assay. Immunocytochemical analysis and cytofluorometric measurement of glial fibrillary acidic protein (GFAP) staining in the treated cultures revealed an increase in GFAP staining over control cultures. In contrast to the response of glioma cells, nonmalignant human adult astrocytes treated with the PKC activators responded by increasing their proliferation rate. The authors postulate that the diametrically opposed effects of PKC activators on nonmalignant astrocytes versus glioma growth may be due to a high intrinsic PKC activity in glioma cells, with resultant down-regulation of enzyme activity following the administration of the pharmacological activators.
- OSTI ID:
- 6507620
- Journal Information:
- Journal of Neurosurgery; (USA), Journal Name: Journal of Neurosurgery; (USA) Vol. 73:4; ISSN 0022-3085; ISSN JONSA
- Country of Publication:
- United States
- Language:
- English
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560300* -- Chemicals Metabolism & Toxicology
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANIMAL CELLS
ANIMALS
AZINES
BIOCHEMICAL REACTION KINETICS
BIOLOGICAL EFFECTS
CARCINOGENS
CELL DIFFERENTIATION
DISEASES
DOSE-RESPONSE RELATIONSHIPS
ENZYME ACTIVITY
ENZYMES
ESTERS
FETUSES
GLIOMAS
HETEROCYCLIC COMPOUNDS
HYDROGEN COMPOUNDS
INHIBITION
ISOTOPE APPLICATIONS
KINETICS
MAMMALS
MAN
NEOPLASMS
NERVE CELLS
NUCLEOSIDES
NUCLEOTIDES
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PHORBOL ESTERS
PHOSPHORUS-GROUP TRANSFERASES
PHOSPHOTRANSFERASES
PRIMATES
PYRIMIDINES
REACTION KINETICS
RIBOSIDES
SOMATIC CELLS
THYMIDINE
TRACER TECHNIQUES
TRANSFERASES
TRITIUM COMPOUNDS
TUMOR CELLS
VERTEBRATES