Valproic acid in the complex therapy of malignant tumors
Language English Country United Arab Emirates Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Acetylation drug effects MeSH
- Apoptosis drug effects physiology MeSH
- Azacitidine analogs & derivatives pharmacology MeSH
- Cell Cycle drug effects physiology MeSH
- Drug Resistance, Neoplasm MeSH
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy MeSH
- Decitabine MeSH
- Epilepsy drug therapy MeSH
- Histone Deacetylases drug effects MeSH
- Histones drug effects physiology MeSH
- Angiogenesis Inhibitors pharmacology MeSH
- Histone Deacetylase Inhibitors pharmacology MeSH
- Topoisomerase II Inhibitors pharmacology MeSH
- Clinical Trials as Topic MeSH
- Drug Therapy, Combination MeSH
- Combined Modality Therapy MeSH
- Valproic Acid pharmacology MeSH
- Humans MeSH
- Tumor Suppressor Protein p53 drug effects physiology MeSH
- Neoplasms drug therapy MeSH
- Drug Repositioning MeSH
- Drug Synergism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Azacitidine MeSH
- Decitabine MeSH
- Histone Deacetylases MeSH
- Histones MeSH
- Angiogenesis Inhibitors MeSH
- Histone Deacetylase Inhibitors MeSH
- Topoisomerase II Inhibitors MeSH
- Valproic Acid MeSH
- Tumor Suppressor Protein p53 MeSH
Valproic acid (VPA) has been used for epilepsy treatment since the 1970s. Recently, it was demonstrated that it inhibits histone deacetylases (HDAC), modulates cell cycle, induces tumor cell death and inhibits angiogenesis in various tumor models. The exact anticancer mechanisms of VPA remains unclear, but HDAC inhibition, extracellular-regulated kinase activation, protein kinase C inhibition, Wnt-signaling activation, proteasomal degradation of HDAC, possible downregulation of telomerase activity and DNA demethylation participate in its anticancer effect. Hyperacetylation of histones, as a result of HDAC inhibition, seems to be the most important mechanism of VPA's antitumor action. Preclinical data suggest that the anticancer effect of chemotherapy is augmented when VPA is used in combination with cytostatics. Besides the effects of pretreatment with HDAC inhibitors, which increases the efficiency of 5-aza-2'-deoxycytidine, VP-16, ellipticine, doxorubicin and cisplatin, pre-exposure to VPA increases the cytotoxicity of topoisomerase II inhibitors. There are two suggested cell death mechanisms caused by potentiation of anticancer drugs by HDAC inhibitors that are neither exclusive nor synergistic. The first involves apoptosis and can be both p53 dependent or independent; the second involves mechanisms other than apoptosis. In resistant chronic myeloid leukemia (CML), VPA restores sensitivity to imatinib. We have demonstrated the synergistic effects of VPA and cisplatin in neuroblastoma cells. VPA can be taken orally, crosses the blood brain barrier and can be used for extended periods. Clinical trials in patients with malignancies are being conducted. The use of VPA prior to or together with anticancer drugs may thus prove a beneficial treatment.
References provided by Crossref.org
Valproic acid overcomes hypoxia-induced resistance to apoptosis
