Valproic Acid in the Complex Therapy of Malignant Tumors

Abstract

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.

Neuroblastoma stem cells – mechanisms of chemoresistance and histonedeacetylase inhibitors

“…Valproic acid (VPA) has been used for treatment of epilepsy since the 1970s and it was demonstrated that it also inhibits histone deacetylases (HDAC). Recently, this drug has been tested in differentiation therapy of AML and MDS [66]. In contrast to the experiments, which show that VPA caused differentiation in AML, it found to increase the percentage of normal haematopoietic stem cells (HSC) more than in differentiated cells.…”

“…HDAC inhibitors facilitate decondensation of chromatin by increasing the acetylation of several histones, hence relaxed chromatin is more sensitive to ionizing radiation and DNAdamaging agents. They also reduce double strand break repair capacity [66]. The data that show the diverse influence of VPA on normal and cancer stem cells seem to be very important for clinical practice.…”

Enhanced antitumor efficacy of telomerase-specific oncolytic adenovirus with valproic acid against human cancer cells

“…VPA is also known to inhibit HDAC activities and is undergoing several clinical trials as an antitumor drug in various cancers. 15,16 Recent studies have demonstrated that VPA improves the antitumor efficacy of oncolytic herpes simplex virus in human glioma cells 17 and of adenovirus-mediated gene therapy in human head and neck squamous cell carcinoma. 18 Although OBP-301 is currently being evaluated as a monotherapy in clinical trials, 19 multimodal therapeutics aimed at enhancing antitumor efficacy might be essential for a successful clinical outcome.…”

“…It has been reported that VPA itself has several antitumor effects including alteration of transcriptional activity, 15,16 stimulation of antitumor immune systems 23 and inhibition of tumor angiogenesis. 24 We previously showed that OBP-301 replication produced the endogenous danger signaling molecule, uric acid, in infected human cancer cells.…”

Novel trans-platinum complexes of the histone deacetylase inhibitor valproic acid; synthesis, in vitro cytotoxicity and mutagenicity

“…3), a clinically used drug for the treatment of epilepsy, has also been shown to possess HDAC inhibitory activity, along with anti-metastatic and anticancer activities [23]. Consequently, it is currently undergoing clinical trials as an anti-cancer agent either as a single agent, or as part of different combination regimens [24]. In addition, VPA has been shown to exhibit synergistic activity with cisplatin [25] and resensitise cells that have acquired resistance to cisplatin [26].…”