Valproic acid: an old drug newly discovered as inhibitor of histone deacetylases
- PMID: 15124690
- DOI: 10.1007/s00277-004-0850-2
Valproic acid: an old drug newly discovered as inhibitor of histone deacetylases
Abstract
Fusion proteins encoded by several types of chromosomal translocations in promyelocytic leukemia can serve as aberrant transcriptional repressors relying on recruitment of histonedeacetylases (HDACs) into DNA-associated multi-protein complexes. Thus, inappropriate modulation of chromatin structure by HDACs and subsequently repression of gene expression that is critical for myeloid differentiation appear to be major factors in the development of the disease. They identify inhibitors of HDACs as prime candidates for novel anti leukemic drugs. Over the last years several candidate compounds have been introduced into clinical trials and have successfully been used in compassionate use protocols. Amongst them phenylbutyrate served as the first example to establish proof of principle. Novel drugs such as suberoylanilide hydroxamic acid (SAHA) are developed for example by modifications of the microbial HDAC inhibitory compound trichostatin A with a hydroxamic acid as the key structural element. The branched chain carboxylic acid valproic acid (VPA) that is in use as antiepileptic drug over decades was also discovered to inhibit HDACs and preferentially class I HDACs. HDAC inhibition is likely to mediate the teratogenic side effects of VPA but not the antiepileptic activity. In contrast to other HDAC inhibitors VPA also induces proteasomal degradation of HDAC2. None of the currently available compounds may be the optimum HDAC inhibitory drug but each of them may serve to answer urgent questions concerning the concept of HDAC inhibition in the treatment of malignant diseases. Prominent questions are i) whether and by which mechanisms HDAC inhibition can be expected to affect a malignant disease not only in the early stage but also at later stages that have acquired additional genetic defects, ii) which forms of cancer in addition to myelocytic leukemia respond to HDAC inhibition, iii) by which markers those susceptible forms could be identified and iv) which individual HDACs are the most critical isoenzymes to address in treatment of malignant diseases.
Similar articles
-
Teratogenic effects mediated by inhibition of histone deacetylases: evidence from quantitative structure activity relationships of 20 valproic acid derivatives.Chem Res Toxicol. 2006 Feb;19(2):272-8. doi: 10.1021/tx0502241. Chem Res Toxicol. 2006. PMID: 16485903
-
The histone deacetylase inhibitors suberoylanilide hydroxamic (Vorinostat) and valproic acid induce irreversible and MDR1-independent resistance in human colon cancer cells.Int J Oncol. 2007 Sep;31(3):633-41. Int J Oncol. 2007. PMID: 17671692
-
Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors.Biochem J. 2008 Jan 15;409(2):581-9. doi: 10.1042/BJ20070779. Biochem J. 2008. PMID: 17868033
-
Drug insight: Histone deacetylase inhibitors--development of the new targeted anticancer agent suberoylanilide hydroxamic acid.Nat Clin Pract Oncol. 2005 Mar;2(3):150-7. doi: 10.1038/ncponc0106. Nat Clin Pract Oncol. 2005. PMID: 16264908 Review.
-
Zn(II)-dependent histone deacetylase inhibitors: suberoylanilide hydroxamic acid and trichostatin A.Int J Biochem Cell Biol. 2009 Apr;41(4):736-9. doi: 10.1016/j.biocel.2008.05.026. Epub 2008 Aug 3. Int J Biochem Cell Biol. 2009. PMID: 18725319 Review.
Cited by
-
Neuropharmacological Modulation of N-methyl-D-aspartate, Noradrenaline and Endocannabinoid Receptors in Fear Extinction Learning: Synaptic Transmission and Plasticity.Int J Mol Sci. 2023 Mar 21;24(6):5926. doi: 10.3390/ijms24065926. Int J Mol Sci. 2023. PMID: 36983000 Free PMC article. Review.
-
PAMAM-G4 protect the N-(2-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA) and maintain its antiproliferative effects on MCF-7.Sci Rep. 2023 Feb 28;13(1):3383. doi: 10.1038/s41598-023-30144-7. Sci Rep. 2023. PMID: 36854957 Free PMC article.
-
The Monoterpenoid Perillyl Alcohol: Anticancer Agent and Medium to Overcome Biological Barriers.Pharmaceutics. 2021 Dec 16;13(12):2167. doi: 10.3390/pharmaceutics13122167. Pharmaceutics. 2021. PMID: 34959448 Free PMC article. Review.
-
The Untouchable Ventral Nucleus of the Trapezoid Body: Preservation of a Nucleus in an Animal Model of Autism Spectrum Disorder.Front Integr Neurosci. 2021 Sep 29;15:730439. doi: 10.3389/fnint.2021.730439. eCollection 2021. Front Integr Neurosci. 2021. PMID: 34658803 Free PMC article.
-
IDH1 mutant glioma is preferentially sensitive to the HDAC inhibitor panobinostat.J Neurooncol. 2021 Sep;154(2):159-170. doi: 10.1007/s11060-021-03829-0. Epub 2021 Aug 23. J Neurooncol. 2021. PMID: 34424450 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources