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 language | English |
|---|---|
| Pages (from-to) | 263-271 |
| Number of pages | 9 |
| Journal | Journal of Neuro-Oncology |
| Volume | 122 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Apr 2015 |
Cite this
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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 journal › Article › Academic › peer-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
PY - 2015/4
Y1 - 2015/4
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.
KW - Animals
KW - Antineoplastic Agents/administration & dosage
KW - Antineoplastic Combined Chemotherapy Protocols/administration & dosage
KW - Brain Neoplasms/drug therapy
KW - Cell Survival/drug effects
KW - Cells, Cultured
KW - Chemoradiotherapy/methods
KW - DNA Methylation
KW - DNA Modification Methylases/genetics
KW - DNA Repair Enzymes/genetics
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
U2 - 10.1007/s11060-014-1713-x
DO - 10.1007/s11060-014-1713-x
M3 - Article
VL - 122
SP - 263
EP - 271
JO - Journal of Neuro-Oncology
JF - Journal of Neuro-Oncology
SN - 0167-594X
IS - 2
ER -