Hh. Engelhard et al., INHIBITORY EFFECTS OF PHENYLBUTYRATE ON THE PROLIFERATION, MORPHOLOGY, MIGRATION AND INVASIVENESS OF MALIGNANT GLIOMA-CELLS, Journal of neuro-oncology, 37(2), 1998, pp. 97-108
The purpose of this study was to characterize the effects of sodium 4-
phenylbutyrate (phenylbutyrate) on the proliferation, morphology, migr
ation and invasiveness of malignant glioma cells in vitro. Phenylbutyr
ate is a novel differentiating and cytotoxic compound used clinically
with low toxicity in the treatment of beta-thalassemia, sickle cell an
emia and urea cycle disorders. Preliminary clinical trials testing phe
nylbutyrate as an anticancer agent have included patients with maligna
nt glioma. However, little information is available regarding the effe
cts of phenylbutyrate on glioma cells, particularly with respect to th
e expression of genes important in the pathogenesis of glial malignanc
y. In experiments reported here, glioma cell lines and explant cells f
rom a tumor patient were exposed to 2, 4 and 8 mM phenylbutyrate and c
ompared to untreated control cells. The effect on cellular proliferati
on was assessed using cell counts and DNA flow cytometry. Changes in m
orphology were evaluated using vimentin staining. Scratch and Matrigel
assays were performed to assess changes in cellular migration and inv
asiveness. 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, migratio
n, invasiveness and c-myc and urokinase expression. Mean growth-inhibi
tory (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 % G(0)/G(1) cells, and produced morphologic c
hanges consistent with induction of differentiation. 24 hours of treat
ment 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 noncytotoxic doses. We conclude that phenylbutyrate
is a promising candidate compound for treating patients with malignan
t glioma.