Valproic acid is an inhibitor of class I histone deacetylases. Epigenetic therapies in cancer have been focus of a keen interest and HDAC inhibitors in particular have been approved for certain types of hematologic malignancies. Valproic acid is an attractive candidate for valproic acid and anticancer agents therapy due to its mechanism of action, its low cost and generally good clinical tolerability.
In the following editorial we will review its role as monotherapy for cancer, its place in combination epigenetic therapy, and its role as chemosensitizer, immunomodulator and cancer preventative agent. With the discovery of its function as inhibitor of class I and IIa histone deacetylases, significant interest in establishing a possible role of valproic acid, VPA a well-established anti-seizure drug, for cancer therapy arose 12.
Epigenetic changes such as aberrant DNA methylation and histone acetylation are common in cancer, providing a strong rationale for the use of epigenetic therapies. Moreover, the completion of The Cancer Genome Atlas TCGA project has demonstrated frequent mutations in critical epigenetic regulators, further strengthening a link between genetic and epigenetic events in cancer.
Due to its low cost, favorable side effect profile and wellbutrin addiction and withdrawl timeline ease in crossing the blood brain barrier, VPA is an attractive drug candidate for a variety of possible indications.
The experience with VPA as monotherapy valproic acid and anticancer agents cancer is limited. Interesting findings exist in metastatic neuroendocrine carcinomas, where VPA exposure has been shown to increase NOTCH1-expression 3 considered to serve as tumor suppressor gene.
High level Notch-1 induction was associated with partial response to VPA, valproic acid and anticancer agents. In myeloid malignancies, valproic acid and anticancer agents, VPA has been shown in vitro to induce both apoptosis and differentiation in leukemic blasts, leading to trials assessing its role as monotherapy or in combination with all-trans-retinoic acid ATRA in either acute myelogenous leukemia AML or myelodysplastic syndrome MDS.
Given the modest benefit for VPA in the monotherapy of cancer, it is not surprising that the majority of evidence for a possible role of VPA as anticancer drug is valproic acid and anticancer agents on its effects observed in combination with other drugs. For simplicity sake, these can be categorized into combination therapies with other epigenetic modifiers, valproic acid and anticancer agents, combinations with cytotoxic chemotherapy agents and combinations with immune-modulators.
The discovery in that treatment with the DNAmethyltransferase DNMT1 inhibitor azacytidine was associated with dramatically improved overall survival compared with conventional care HR 0. In this study, responses correlated with demethylation of several aberrantly methylated promoter regions.
However, this could partly be explained by patient selection and number of previous treatment regimens. It does raise the important question, however, valproic acid and anticancer agents, if HDAC inhibition adds clear benefit to that of demethylating agents alone. Neurotoxicity was also a major dose limiting toxicity in a phase I study of 8 patients with advanced non-small cell lung cancer NSCLC. No responses were seen in this small cohort and somnolence, lethargy and disorientation was observed at low concentrations 9.
The precise mechanism for this observation remains unclear. Based on the hypothesis that HDACi mediated changes in chromatin structure favoring a more euchromatic chromatin pattern, VPA has been studied in combination with cytotoxic chemotherapy, particularly with DNA damaging agents: Potential synergy between VPA and doxorubicin was also observed in a phase II study of 16 patients with unresectable and platinum-refractory mesothelioma 13a clinical scenario for which no accepted treatment options exist.
Similar results were observed in other studies in which VPA based epigenetic therapies were combined with platinum based chemotherapies in an attempt to overcome previous platinum resistance A recent report from our laboratory showed that class I HDAC mediated stabilization of DNMT1 protein expression is an early event in smoke carcinogen induced transformation of bronchial epithelial cells This was associated with uncoupling of DNMT1 expression from the usually tight limitation to the S-phase of the cell cycle, leading to de-novo methylation and epigenetic silencing of tumor suppressor genes.
Importantly, treatment with VPA partially reversed aberrant DNA methylation, leading to re-expression of previously silenced genes and suppression of anchorage independent colony formation. We hypothesized based on these data that VPA may play an important role in chemoprevention of smoke-related malignancies such as lung- head-and neck- and bladder cancer.
Risk for lung- bladder- prostate- and colon- cancers were not statistically different between VPA users and non-users. The lack of effect on lung- colon- and prostate-cancer risk is confirmed in a study from Denmark, which did not find a significant correlation between VPA use and cancer risk between VPA users and non-users, but did not specifically investigate head-and neck cancer risk The increased risk for colon cancer was neither seen in our study nor in the Danish study, making an uneven distribution of risk factors the most likely explanation for this phenomenon.
The risk reduction for head and neck cancer in our study is interesting and seems to be largely limited to patients with non-oropharyngeal head-and neck cancer making an antiviral effect of VPA against HPV driven cancers less likely as etiology.
It will need to be seen in further studies if his effect can be generalized to other smoking-related squamous cell carcinomas of the upper aerodigestive tract such as those of the lung and the esophagus. Despite its large size, our study lacked sufficient number of cases to conclusively answer this question. Likewise, our study does not answer the question if resistance to VPA emerges in the epithelium of the head and neck after long-term exposure and by which mechanism it is mediated.
Grant support for J Brandes: Financial and competing interests disclosure. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of valproic acid and anticancer agents manuscript. National Center for Biotechnology InformationU.
Expert Rev Anticancer Ther. Author manuscript; available in PMC Oct 1, valproic acid and anticancer agents. Johann C Brandes, valproic acid and anticancer agents, M. See other articles in PMC that cite the published article. Valproic acid and anticancer agents Valproic acid is an inhibitor of class I histone deacetylases.
VPA as epigenetic combination therapy for cancer Given the modest benefit for VPA in the monotherapy of cancer, it is not surprising that the majority of evidence for a possible role of VPA as anticancer drug is based on its effects observed in combination with other drugs, valproic acid and anticancer agents.
Acknowledgments Grant support for J Brandes: Footnotes Financial and competing interests disclosure The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2.
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