Therapeutic Effects of Sodium Butyrate on Glioma Cells in Vitro and in the Rat C6 Glioma Model

Engelhard, Herbert H.; Duncan, Holly A.; Kim, Samuel; Criswell, Peggy S.

doi:10.1097/00006123-200103000-00035

Cited by 39 publications

(24 citation statements)

References 45 publications

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“…That is, these data suggest that at clinically achievable serum concentrations (1-10 mM), VPA may have significant anti-GBM effects as a monotherapy. Interestingly these concentrations are in the range of the anti-proliferative concentration of 2 mM seen in the treatment of primary and established glioma cells with commonly used HDACi, butyrate [27]. Subsequently, three of the five cultures assayed showed uniformly additive effects when a clinically relevant concentration of VPA (1 mM) was added 24 h before treatment with TMZ and/or irradiation.…”

Section: Discussionmentioning

confidence: 94%

The effect of valproic acid in combination with irradiation and temozolomide on primary human glioblastoma cells

et al. 2015

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Glioblastoma multiforme (GBM) has nearly uniformly fatal with a median survival of less than 2 years. While there have not been any novel anti-GBM therapeutics approved for many years, there has been the gradual accumulation of clinical data suggesting that the widely used anti-convulsant agent, valproic acid (VPA) may significantly prolong survival in GBM patients. This pre-clinical study aimed to determine the potential clinical utility of VPA in the treatment of GBM. Primary GBM cells were treated with VPA as a monotherapy and in combination with temozolomide and irradiation. At clinically achievable concentrations, VPA was shown to be effective as a monotherapy agent in the five primary lines tested. VPA was then used as a sensitizing agent to in vitro radiation and showed significant augmentation of in vitro irradiation therapy. In addition, when VPA, radiation and temozolomide were combined an additive, rather than synergistic effect was noted. Gene expression profiling demonstrated close clustering of triple treated cells with VPA mono-treated cells while untreated cells clustered closer with TMZ-irradiation dual treated cells. These microarray data suggest a dominant role of VPA at the gene expression level when combining these different treatment options. Moreover, in an in vivo tumor transplantation model, we were able to demonstrate an increase in animal survival when cells were pre-treated with irradiation-VPA and when triple treated. These findings provide a significant rationale for the investigation of VPA in the treatment of GBM patients.

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Section: Discussionmentioning

confidence: 94%

The effect of valproic acid in combination with irradiation and temozolomide on primary human glioblastoma cells

et al. 2015

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“…The C6 orthotropic glioma model is simple, reliable, and easily reproducible, which has been extensively used to study growth kinetics, mechanisms of angiogenesis, as well as the expression of growth factors and receptors involved in the progression of astrocytic tumor [10,26]. Many studies indicate that the C6 glioma model best mimics the cell biological stages of early glioma progression in human.…”

Section: Discussionmentioning

confidence: 99%

Brainstem glioma progression in juvenile and adult rats

Liu

Kashyap

et al. 2008

JNS

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Objective Brainstem gliomas are common in children and have the worst prognosis of any brain tumor in children. On the other hand, brainstem gliomas are rare in adult, and clinical studies have suggested different biological behavior between young and adult. The present study was designed to develop an orthotropic C6 brainstem glioma model in young and adult rats, and to investigate the tumor biological behavior in the two age groups. Methods C6 glioma cells were stereotactically implanted into the pons of young or adult male rats. Neurological presentation and survival time were recorded. Tumor proliferation and apoptosis in brainstem gliomas of young and adult rats were determined by immunohistochemical staining of Ki-67 and TUNEL assay, respectively. Results Striking difference were found between young and adult brainstem glioma in the onset of neurological signs, duration of symptoms, survival time, tumor growth pattern, as well as tumor proliferation and apoptosis. Relatively focal tumors were observed in adult rats harboring brainstem glioma, while diffusive tumors were found in young rats. Furthermore, brainstem gliomas in adult rats were less proliferative and had more apoptosis than those in young rats. Conclusion The present study demonstrated that C6 brainstem glioma model in young and adult rats closely imitates human brainstem glioma in neurological findings and histopathology. Our findings suggest that the different growth pattern and invasiveness of brainstem glioma between children and adult could be due to the different host cellular environments between the two age groups, hence, warrant further investigation of the different host-response between childhood and adult brainstem glioma in human.

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“…Note that relatively few examples of retro virus-mediated transfer of the p16 cDNA in animal models of glioma are reported in the literature [29], although using a different cell line and several reports demonstrate the adeno viral transfer of p16 [30-32]. The C6/Wistar rat model continues to be widely used [33,34] and this study adds a new component to this system: retrovirus-mediated transfer followed by assessment of p1 6 function in tissue culture and in vivo. The p1 6 protein acts through a well defined pathway and has strong suppressive activity in experimental models, including the C6/Wistar rat system.…”

Section: Discussionmentioning

confidence: 99%

Retroviral transfer of the p16INK4a cDNA inhibits C6 glioma formation in Wistar rats

et al. 2002

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BackgroundThe p16INK4A gene product halts cell proliferation by preventing phosphorylation of the Rb protein. The p16INK4a gene is often deleted in human glioblastoma multiforme, contributing to unchecked Rb phosphorylation and rapid cell division. We show here that transduction of the human p16INK4a cDNA using the pCL retroviral system is an efficient means of stopping the proliferation of the rat-derrived glioma cell line, C6, both in tissue culture and in an animal model. C6 cells were transduced with pCL retrovirus encoding the p16INK4a, p53, or Rb genes. These cells were analyzed by a colony formation assay. Expression of p16INK4a was confirmed by immunohistochemistry and Western blot analysis. The altered morphology of the p16-expressing cells was further characterized by the senescence-associated β-galactosidase assay. C6 cells infected ex vivo were implanted by stereotaxic injection in order to assess tumor formation.ResultsThe p16INK4a gene arrested C6 cells more efficiently than either p53 or Rb. Continued studies with the p16INK4a gene revealed that a large portion of infected cells expressed the p16INK4a protein and the morphology of these cells was altered. The enlarged, flat, and bi-polar shape indicated a senescence-like state, confirmed by the senescence-associated β-galactosidase assay. The animal model revealed that cells infected with the pCLp16 virus did not form tumors.ConclusionOur results show that retrovirus mediated transfer of p16INK4a halts glioma formation in a rat model. These results corroborate the idea that retrovirus-mediated transfer of the p16INK4a gene may be an effective means to arrest human glioma and glioblastoma.

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Therapeutic Effects of Sodium Butyrate on Glioma Cells in Vitro and in the Rat C6 Glioma Model

Abstract: These data support further consideration of direct interstitial infusion of sodium butyrate in a Phase I clinical study for patients with recurrent glioblastoma multiforme.

Cited by 39 publications

References 45 publications

The effect of valproic acid in combination with irradiation and temozolomide on primary human glioblastoma cells

The effect of valproic acid in combination with irradiation and temozolomide on primary human glioblastoma cells

Brainstem glioma progression in juvenile and adult rats

Retroviral transfer of the p16INK4a cDNA inhibits C6 glioma formation in Wistar rats

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