Effect of valproic acid on the outcome of glioblastoma multiforme

Abstract

Background. Glioblastoma multiforme (GBM) is the most aggressive type of primary brain tumor. It is a rapidly progressive, highly recurrent, fatal intracranial neoplasm, and the demand for novel treatment is urgent. Valproic acid (VPA) is a potential anticancer agent that belongs to a class of histone deacetylase (HDAC) inhibitors, targeting the epigenetic control of gene functions in cancer cells. This drug has been administered for the prevention or treatment of seizure disorder in GBM patients; therefore, a retrospective analysis may further our understanding of the effect of VPA on GBM patients. Materials and methods. A retrospective analysis of 102 patients with GBM was conducted to study the effects of VPA on disease outcome. Tumor samples from seven patients receiving VPA treatment between the first and second operations were obtained in order to verify the HDAC inhibitory activity of VPA in these patients. Results. In univariate analysis, administration of VPA within 2 weeks of initial diagnosis seemed to confer a survival benefit. However, stratified analysis according to chemotherapy showed that VPA did not have significant impact on the GBM patients’ overall survival. Analysis of tissue samples from these patients revealed that a small subset of patients had increased histone acetylation after VPA treatment. Conclusion. VPA treatment, when administered according to a protocol targeting seizure control, may result in HDAC inhibition in a small subset of patients, but does not significantly affect overall patient survival. Early administration of VPA as an adjunct to temozolomide chemotherapy may have its merits, but the optimal dosing schedule and target serum level require further investigation.

Keywords::

• Glioblastoma multiforme
• histone deacetylase inhibitor
• valproic acid

Acknowledgements

We thank Tai-Wei Erich Wu for assistance with statistical analysis and Li-Ying Feng and Pei-Yun Li for help with tissue sample analysis. This work was supported by grants from the Department of Medical Research and Department Linko Branch, Chang-Gung Medical Foundation (CMRPG391321).

Declaration of interests: The authors report no conflicts of interest. The authors are alone responsible for the content and writing of the article.