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Anti‐tumor mechanisms of valproate: A novel role for an old drug
Author(s) -
Blaheta Roman A.,
Cinatl Jindrich
Publication year - 2002
Publication title -
medicinal research reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.868
H-Index - 130
eISSN - 1098-1128
pISSN - 0198-6325
DOI - 10.1002/med.10017
Subject(s) - wnt signaling pathway , histone deacetylase , gsk 3 , valproic acid , pharmacology , biology , glycogen synthase , cancer research , chemistry , anticonvulsant , mechanism of action , signal transduction , histone , biochemistry , epilepsy , in vitro , phosphorylation , neuroscience , gene
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