Valproic acid  for the treatment of malignant gliomas: review of the preclinical rationale and published clinical results.
BACKGROUND
Glioblastoma multiforme is the most common and aggressive primary brain tumor. Valproate has been used as an anti-epileptic drug and mood stabilizer for decades. Recently, it was found to inhibit the proliferation of various cancers including glioblastoma multiforme.


METHODS
We provide a comprehensive review of the mechanisms of action of valproate in gliomas, of its potential side effects and of the published clinical results obtained with this drug in glioblastomas. Valproate inhibits a subset of histone deacetylases and cellular kinases, and affects gene transcription through histone hyperacetylation, DNA hypomethylation and the modulation of several transcription factors. As a result, VPA induces differentiation of glioma cells, can prevent their invasion in surrounding tissues and may inhibit tumor angiogenesis. VPA can also inhibit DNA repair, thereby potentiating cytotoxic treatments such as chemotherapies or radiation therapy. Based on these mechanisms and case reports of glioblastoma remissions following VPA treatment, several clinical studies currently assess the therapeutic potential of VPA in glioma therapy.


CONCLUSIONS
The combination of VPA treatment with chemotherapy and radiotherapy in glioblastoma appears a rational option that deserves well-designed prospective clinical trials that assess the efficacy and the molecular characteristics of the responding tumors in these patients.
UMC Utrecht, Utrecht, Netherlands.
Sharon
S
Berendsen
Marike
M
Broekman
Tatjana
T
Seute
Tom
T
Snijders
Corine
C
van Es
Filip
F
de Vos
Luca
L
Regli
Pierre
P
Robe
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy; D004260:DNA Repair / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D014635:Valproic Acid / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D014635:Valproic Acid