Anti-tumor mechanisms of valproate: A novel role for an old drug

Valproic acid (VPA, 2‐propylpentanoic acid) is an established drug in the long‐term therapy of epilepsy. During the past years, it has become evident that VPA is also associated with anti‐cancer activity. VPA not only suppresses tumor growth and metastasis, but also induces tumor differentiation in...

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Bibliographic Details
Published in:Medicinal research reviews 2002-09, Vol.22 (5), p.492-511
Main Authors: Blaheta, Roman A., Cinatl Jr, Jindrich
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Humans
Signal Transduction - drug effects
signaling cascade
Transcription, Genetic - drug effects
tumor differentiation
tumor growth
valproic acid
Valproic Acid - pharmacology
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Summary:Valproic acid (VPA, 2‐propylpentanoic acid) is an established drug in the long‐term therapy of epilepsy. During the past years, it has become evident that VPA is also associated with anti‐cancer activity. VPA not only suppresses tumor growth and metastasis, but also induces tumor differentiation in vitro and in vivo. Several modes of action might be relevant for the biological activity of VPA: (1) VPA increases the DNA binding of activating protein‐1 (AP‐1) transcription factor, and the expression of genes regulated by the extracellular‐regulated kinase (ERK)‐AP‐1 pathway; (2) VPA downregulates protein kinase C (PKC) activity; (3) VPA inhibits glycogen synthase kinase‐3β (GSK‐3β), a negative regulator of the Wnt signaling pathway; (4) VPA activates the peroxisome proliferator‐activated receptors PPARγ and †; (5) VPA blocks HDAC (histone deacetylase), causing hyperacetylation. The findings elucidate an important role of VPA for cancer therapy. VPA might also be useful as low toxicity agent given over long time periods for chemoprevention and/or for control of residual minimal disease. © 2002 Wiley Periodicals, Inc. Med Res Rev, 22, No. 5, 492–511, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/med.10017
ISSN:0198-6325
1098-1128
DOI:10.1002/med.10017