Anti-Convulsant Drug Valproic Acid in Cancers and in Combination Anti-Cancer Therapeutics

Abstract

The traditional anti-convulsant drug Valproic Acid (VPA) has been found to be involved in suppressing cancer progression while modulating various cancer-associated signaling pathways. In particular, VPA acts as either a Histone Deacetylase (HDAC) inhibitor or a Notch signaling activator in suppressing tumor growth. VPA is less toxic, and by itself, has limited anti-tumor effects. Thus, VPA has been used as an adjuvant in combination with a variety of other anti-cancer agents for many types of cancers. These combination strategies display potential applications in cancer treatments. In particular, VPA could up-regulate certain G Protein-Coupled Receptors (GPCRs) in some cancer cells. Some of these GPCRs are highly expressed naturally in many cancer cells and these characteristics have been applied towards novel enhanced combination therapeutics with VPA and specific receptor-targeted cytotoxic peptide-drug conjugates.

Anticonvulsant valproic acid and other short-chain fatty acids as novel anticancer therapeutics: Possibilities and challenges

“…It was also observed that VPA significantly increased the expression of GPCRs such as gastrin-releasing peptide receptor and somatostatin receptor type 2 in HCC cells (6). Moreover, several cell surface receptors have their specific ligands and antibodies, which can be conjugated with different anticancer agents for better drug delivery.…”

“…Several members of class A GPCRs, such as protease-activated receptors, have been detected in cancer cells and can be used for the receptor-targeted cancer treatment. As a consequence, the compounds with activity towards GPCRs appear as crucial agents in tumor growth and metastasis (6). GPCRs were shown to exist in more than one conformation, which allows binding of more than one ligand and affects various signaling pathways.…”

“…VPA, by affecting numerous signaling pathways, can modulate different processes in cancer cells and suppress tumor growth (5). First of all, VPA acts as a histone deacetylase (HDAC) inhibitor (HDI), being involved in the epigenetic regulation of gene expression (6). Additionally, VPA was shown to induce apoptosis and cell differentiation as well as regulate Notch signaling (7).…”

“…Additionally, VPA was shown to induce apoptosis and cell differentiation as well as regulate Notch signaling (7). Moreover, VPA was found to up-regulate the expression of certain G protein-coupled receptors (GP-CRs), being involved in various signaling pathways associated with cancer (6,8).…”

Effect of valproic acid on cisplatin-resistant ovarian cancer cell lines

“…Valproic acid (VPA), a branched short-chain fatty acid, is mainly used to treat epilepsy and bipolar disorders. Recently, VPA has been widely studied for its anti-cancer effects in many cancers (9)(10)(11). In this regard, VPA induces cell cycle arrest, apoptosis, differentiation, and senescence.…”