Inhibition of proliferation and induction of differentiation in medulloblastoma- and astrocytoma-derived cell lines with phenylacetate

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✓ The authors investigated the effects of a nontoxic differentiation inducer, phenylacetate (PA), on neuroectodermal tumor—derived cell lines. Treatment of medulloblastoma (Daoy and D283 MED) and glioma (U-251MG, C6, and RG2) cell lines resulted in a dose-dependent decline in DNA synthesis and cell proliferation, associated with accumulation in the G0/G1 phase of the cell cycle. Phenylacetate decreased transforming growth factor (TGF)—β2 production by medulloblastoma Daoy cells. Neutralizing antibodies against either TGFβ2 or TGFβ1 failed to block the growth arrest observed. This suggests that, unlike other differentiation agents, such as retinoic acid, the effect of PA on medulloblastoma proliferation is not mediated by a TGFβ pathway. In addition to cytostasis, PA induced marked morphological changes in U-251MG and C6 glioma cells associated with increased abundance of glial fibrillary acidic protein—positive processes. Although the morphology of PA-treated medulloblastoma cells was not significantly altered, the D283 MED cells exhibited increased expression of neurofilament proteins and Hu antigen, indicative of differentiation along a neuronal pathway. The effects of PA on the medulloblastoma cell lines were compared to its effects on the human neuroblastoma cell line BE(2)C, which is capable of a bidirectional differentiation toward a neuronal or a glial/schwann cell pathway. In BE(2)C cells, PA induced differentiation toward a schwann/glial cell-like phenotype, suggesting that the choice of differentiation pathway is cell type and agent specific. These in vitro antiproliferative and differentiation inducing effects of PA suggest that this agent warrants further evaluation as a potential therapeutic modality for the treatment of medulloblastoma and malignant glioma in humans.

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Address reprint requests to: Frank S. Lieberman, M.D., Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021.

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    Left: Graph showing the growth inhibitory effects of phenylacetate (PA) on various neuroectodermal tumor cell lines. The cells were grown in 96-well microtiter plates in Eagle's minimal essential medium (MEM) containing 10% fetal calf serum (FCS) and treated with various concentrations of PA or medium alone for 96 hours. Then 1 µCi of [3H]thymidine was added to each well. After 4 hours the cells were harvested using a semiautomated cell harvester and the amount of [3H]thymidine uptake was determined by liquid scintillation counting. Data represent the mean of quadruplicate values; the standard error was within 5%. Right: Graph showing the effect of washout of PA after a 48-hour exposure on the growth of Daoy cells. The cells were grown in MEM containing 10% FCS with or without 10 mM PA for 48 hours. Then the medium was removed and replaced with fresh MEM + 10% FCS. At various time points after washout, 1 µCi of [3H]thymidine per well was added. The cells were then harvested and [3H]thymidine uptake was determined as described in Fig. 1 left. Data represent the mean of quadruplicate values. Vertical bars indicate the standard error of the means.

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    Photomicrographs depicting the effects of phenylacetate (PA) treatment on U-251MG cell morphology. Cells were grown in Eagle's minimal essential medium containing 10% fetal calf serum alone (left) or with added 10 mM (center) or 20 mM (right) PA for 96 hours, after which the medium was removed and the cells were fixed for 10 minutes in cold acetone. The cells were then incubated with a murine monoclonal antibody (mAb) directed against vimentin, and immunoreactivity was detected using the avidin-biotin-peroxidase method. (Reaction with an irrelevant isotype-matched control mAb demonstrated no staining (not shown)). Original magnification × 400.

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    Photomicrographs displaying the effect of phenylacetate (PA) treatment on glial fibrillary acidic protein (GFAP) immunocytochemical staining of C6 rat glioma cells. Cells were grown in Eagle's minimal essential medium containing 10% fetal calf serum alone (upper) or with 10 mM PA (lower) for 96 hours, after which the medium was removed and the cells were fixed for 10 minutes in cold acetone. The cells were then incubated with a murine monoclonal antibody (mab) directed against GFAP, and immunoreactivity was detected using the avidin-biotin-peroxidase method. (Reaction with an irrelevant isotype-matched control mAb demonstrated no staining (not shown)). Original magnification × 400.

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    Western blotting (left) and reverse transcriptase—polymerase chain reaction (RT-PCR) (right) analyses for Hu expression in various cell lines. Left: For Western blotting analysis, cells were solubilized in 50 mM Tris buffer containing 0.5% NP-40 and boiled for 7 minutes in the presence of 2-mercaptoethanol. Proteins were separated on 10% sodium dodecylsulfate—polyacrylamide gels and transferred to nitrocellulose by electroblotting. Immunoreactivity was determined by exposing the blots to a human serum with high-titer anti-Hu antibodies or serum from a normal donor and then incubated with horseradish peroxidase—conjugated sheep anti—human immunoglobulin G. The blots were then autoradiographed using an enhanced chemiluminescent system. One microgram of Hu fusion protein (Lane 1) and 8 µg of protein extracts of cortical neurons (Lane 2) served as positive controls. For the various cell lines (Lanes 3–6) 40 µg of protein was loaded. Lane 3 = U-251MG cells; Lane 4 = Daoy cells; Lane 5 = D283 MED cells; and Lane 6 = BE(2)C cells. No bands were seen on blots reacted with normal human serum (not shown). Right: For RT-PCR analysis, 1 µg of total RNA from normal human brain and tumor cell lines was reverse transcribed with random hexamers (portion of lane with + sign); reactions in the absence of RT were included as a negative control (adjoining unmarked portion of lane). One-twentieth of the RT reaction product was amplified with Hud, Huc, and β-actin specific primers. The PCR products were size fractionated using a 6% polyacrylamide gel and detected by autoradiography. Lane 1 = normal human brain; Lane 2 = U-251MG cells; Lane 3 = Daoy cells; Lane 4 = D283 MED = cells; Lane 5 = BE(2)C cells.

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    Western blotting analyses for Hu (left) and NF-M (right) expression of untreated and phenylacetate (PA) (10 mM, 7 days)—treated D283 MED cells lysed in 50 mM Tris containing 0.5% NP-40 and separated under denaturing conditions by electrophoresis through 10% sodium dodecylsulfate—polyacrylamide gels and transferred to nitrocellulose paper by electroblotting. Specific immunoreactivity was determined using human serum containing high titer anti-Hu antibodies and murine anti-NF-M monoclonal antibodies (mAbs), respectively, and an enhanced chemiluminescent technique. Normal human serum or the appropriate isotype matched irrelevant mAb served as control (not shown). Left: Lanes 1, 2, and 3 show increasing amounts of protein extracts from cortical neurons (2, 4, and 8 µg protein); Lanes 4 and 5 show 20 and 40 µg protein from PA-treated cells; Lanes 6 and 7, 20 and 40 µg protein from untreated cells. Right: Lane 1 shows 40 µg protein from PA-treated compared to Lane 2, which shows untreated D283 MED cells.

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    Western blotting analysis showing effects of a 7-day exposure to phenylacetate (PA) (10 mM) on the expression of Hu (left), vimentin, and NF-M (right) in BE(2)C cells. Cells were lysed using 50 mM Tris containing 0.5% NP-40 and then the proteins were separated under denaturing conditions by electrophoresis through 10% sodium dodecylsulfate—polyacrylamide gels and transferred to nitrocellulose paper by electroblotting. Specific immunoreactivity was determined using murine antivimentin monoclonal antibody (mAb), human serum containing high-titer anti-Hu antibodies, and murine anti-NF-M, respectively, and an enhanced chemiluminescent technique. Normal human serum or the appropriate isotype-matched irrelevant mAb served as control (not shown). Left: Lanes 1, 2, and 3 = 2, 4, and 8 µg protein from cortical neurons, respectively; Lanes 4 and 5 = 15 and 30 µg protein from PA-treated BE(2)C cells, respectively; Lanes 6 and 7 = 15 and 30 µg protein from untreated cells, respectively. Right: Lanes 1 and 2 = 15 µg protein from PA-treated; untreated BE(2)C cells, respectively.

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    Graph showing that neutralizing antibodies against human transforming growth factor (TGF)—β1 or TGFβ2 failed to antagonize the antiproliferative effect of phenylacetate (PA) on U-251MG cells. The U-251MG cells were grown in 96-well microtiter plates in serum-free media (Ultraculture) in the presence or absence of 10 mM PA. Neutralizing antibodies directed against TGFβ1 or TGFβ2 were added to the wells containing PA at the beginning of the incubation period. Normal immunoglobulin G of the corresponding species served as a control. The rate of cell proliferation was determined by adding 1 µCi of [3H]thymidine to each well and harvesting the cells after 4 hours. The [3H]thymidine incorporation was determined by liquid scintillation counting. Data represent the mean of quadruplicate values and the vertical bars represent the standard error of the means.

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