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

Abdel Nasser Hosein, Yi Chieh Lim, Bryan Day, Brett Stringer, Stephen Rose, Richard Head, Leah Cosgrove, Peter Sminia, Michael Fay, Jennifer H Martin

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)263-271
Number of pages9
JournalJournal of Neuro-Oncology
Volume122
Issue number2
DOIs
Publication statusPublished - Apr 2015

Cite this

Hosein, Abdel Nasser ; Lim, Yi Chieh ; Day, Bryan ; Stringer, Brett ; Rose, Stephen ; Head, Richard ; Cosgrove, Leah ; Sminia, Peter ; Fay, Michael ; Martin, Jennifer H. / The effect of valproic acid in combination with irradiation and temozolomide on primary human glioblastoma cells. In: Journal of Neuro-Oncology. 2015 ; Vol. 122, No. 2. pp. 263-271.
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title = "The effect of valproic acid in combination with irradiation and temozolomide on primary human glioblastoma cells",
abstract = "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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Hosein, AN, Lim, YC, Day, B, Stringer, B, Rose, S, Head, R, Cosgrove, L, Sminia, P, Fay, M & Martin, JH 2015, 'The effect of valproic acid in combination with irradiation and temozolomide on primary human glioblastoma cells' Journal of Neuro-Oncology, vol. 122, no. 2, pp. 263-271. https://doi.org/10.1007/s11060-014-1713-x

The effect of valproic acid in combination with irradiation and temozolomide on primary human glioblastoma cells. / Hosein, Abdel Nasser; Lim, Yi Chieh; Day, Bryan; Stringer, Brett; Rose, Stephen; Head, Richard; Cosgrove, Leah; Sminia, Peter; Fay, Michael; Martin, Jennifer H.

In: Journal of Neuro-Oncology, Vol. 122, No. 2, 04.2015, p. 263-271.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - The effect of valproic acid in combination with irradiation and temozolomide on primary human glioblastoma cells

AU - Hosein, Abdel Nasser

AU - Lim, Yi Chieh

AU - Day, Bryan

AU - Stringer, Brett

AU - Rose, Stephen

AU - Head, Richard

AU - Cosgrove, Leah

AU - Sminia, Peter

AU - Fay, Michael

AU - Martin, Jennifer H

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N2 - 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.

AB - 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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KW - Antineoplastic Agents/administration & dosage

KW - Antineoplastic Combined Chemotherapy Protocols/administration & dosage

KW - Brain Neoplasms/drug therapy

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KW - Chemoradiotherapy/methods

KW - DNA Methylation

KW - DNA Modification Methylases/genetics

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KW - Dacarbazine/administration & dosage

KW - Dose-Response Relationship, Drug

KW - Gene Expression Profiling

KW - Glioblastoma/drug therapy

KW - Humans

KW - Mice, Inbred NOD

KW - Mice, SCID

KW - Microarray Analysis

KW - Neoplasm Transplantation

KW - Promoter Regions, Genetic

KW - Radiation-Sensitizing Agents/administration & dosage

KW - Tumor Suppressor Proteins/genetics

KW - Valproic Acid/administration & dosage

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DO - 10.1007/s11060-014-1713-x

M3 - Article

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EP - 271

JO - Journal of Neuro-Oncology

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