Valproic acid as epigenetic cancer drug: preclinical, clinical and transcriptional effects on solid tumors.
Among many anticancer drugs collectively named "targeted or molecular therapies" epigenetic drugs are clearly promising. Differently from other agents targeting a single gene product, epigenetic drugs have chromatin as their target through inhibition of histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) therefore, yet unspecific, they may act upon most or all tumor types, as deregulation of the methylation and deacetylation machinery are a common hallmark of neoplasia. In the last years, valproic acid (VPA) as emerged as a promising drug for cancer treatment. VPA has shown potent antitumor effects in a variety of in vitro and in vivo systems, and encouraging results in early clinical trials either alone or in combination with demethylating and/or cytotoxic agents. In addition, whole genome expression by microarray analysis from the primary tumors of patients treated with VPA show significant up-regulation of hundred of genes belonging to multiple pathways including ribosomal proteins, oxidative phosphorylation, MAPK signaling; focal adhesion, cell cycle, antigen processing and presentation, proteasome, apoptosis, PI3K, Wnt signaling, calcium signaling, TGF-beta signaling, and ubiquitin-mediated proteolysis among others. Despite in general, industry is not particularly interested in funding the clinical development of VPA, -at least in comparison to novel HDAC inhibitors-, existing preclinical and preliminary clinical data strongly suggest that VPA could be a drug that eventually will be used in combination therapies, either with classical cytotoxics, other molecular-targeted drugs or radiation in a number of solid tumors.
Duenas-Gonzalez
Alfonso
A
Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas (IIB), Universidad Nacional Autonóma de Mexico (UNAM), Instituto Nacional de Cancerología (INCan), Mexico City, Mexico. alfonso_duenasg@yahoo.com
Candelaria
Myrna
M
Perez-Plascencia
Carlos
C
Perez-Cardenas
Enrique
E
de la Cruz-Hernandez
Erick
E
Herrera
Luis A
LA
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D044127:Epigenesis, Genetic; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D011499:Protein Processing, Post-Translational; D014635:Valproic Acid / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D014635:Valproic Acid