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Inhibitory
effects of phenylbutyrate on the proliferation, morphology, migration and
invasiveness of malignant glioma cells
Engelhard
HH, Homer RJ, Duncan HA, Rozental J
Department
of Surgery, Northwestern University Medical School, Chicago, IL, USA
The
purpose of this study was to characterize the effects of sodium 4-phenylbutyrate
(phenylbutyrate) on the proliferation, morphology, migration and invasiveness of
malignant glioma cells in vitro.
Phenylbutyrate is a novel differentiating and cytotoxic compound used clinically
with low toxicity in the treatment of beta-thalassemia, sickle cell anemia and
urea cycle disorders.
Preliminary clinical trials testing phenylbutyrate as an anti-cancer agent have
included patients with malignant glioma.
However, little information is available regarding the effects of phenylbutyrate
on glioma cells, particularly with respect to the expression of genes important
in the pathogenesis of glial malignancy.
In experiments reported here, glioma cell lines and explant cells from a tumor
patient were exposed to 2, 4 and 8 mM phenylbutyrate and compared to untreated
control cells.
The effect on cellular proliferation was assessed using cell counts and DNA flow
cytometry.
Changes in morphology were evaluated using vimentin staining.
Scratch and Matrigel assays were performed to assess changes in cellular
migration and invasiveness.
Finally, Northern blot analysis was used to study c-myc and urokinase
expression.
Phenylbutyrate was found to have dose-dependent inhibitory effects on glioma
cell proliferation, morphology, migration, invasiveness and c-myc and urokinase
expression.
Mean growth-inhibitory (IC50) phenylbutyrate concentrations ranged from 0.5 mM
for T98G cells to 5.0 mM for explant cells.
Phenylbutyrate treatment reduced % S phase cells, increased % G0/G1 cells, and
produced morphologic changes consistent with induction of differentiation.
24 hours of treatment with 4 mM phenylbutyrate resulted in a 50% reduction in
migration and invasiveness.
Northern blots showed a decrease in urokinase and c-myc expression at non-cytotoxic
doses.
We conclude that phenylbutyrate is a promising candidate compound for treating
patients with malignant glioma.
PMID:
9524087 [PubMed - indexed for MEDLINE]
Source:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9524087&dopt=Abstract
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