Valproic acid inhibits glioblastoma multiforme cell growth via paraoxonase 2 expression

Abstract

We studied the potential mechanisms of valproic acid (VPA) in the treatment of glioblastoma multiforme (GBM). Using the human U87, GBM8401, and DBTRG-05MG GBM-derived cell lines, VPA at concentrations of 5 to 20 mM induced G2/M cell cycle arrest and increased the production of reactive oxygen species (ROS). Stress-related molecules such as paraoxonase 2 (PON2), cyclin B1, cdc2, and Bcl-xL were downregulated, but p27, p21 and Bim were upregulated by VPA treatment. VPA response element on the PON2 promoter was localized at position -400/−1. PON2 protein expression was increased in GBM cells compared with normal brain tissue and there was a negative correlation between the expression of PON2 and Bim. These findings were confirmed by the public Bredel GBM microarray (Gene Expression Omnibus accession: GSE2223) and the Cancer Genome Atlas GBM microarray datasets. Overexpression of PON2 in GBM cells significantly decreased intracellular ROS levels, and PON2 expression was decreased after VPA stimulation compared with controls. Bim expression was significantly induced by VPA in GBM cells with PON2 silencing. These observations were further shown in the subcutaneous GBM8401 cell xenograft of BALB/c nude mice. Our results suggest that VPA reduces PON2 expression in GBM cells, which in turn increases ROS production and induces Bim production that inhibits cancer progression via the PON2–Bim cascade.

Bladder Cancer Chemosensitivity Is Affected by Paraoxonase-2 Expression

“…In particular, the role played by PON2 as a metabolic regulator has been confirmed in a study carried out by Nagarajan et al In pancreatic ductal adenocarcinoma (PDAC) cell lines, the authors demonstrated that PON2 transcriptional repression is responsible for affecting the transport activity of glucose transporter 1 and subsequently, for an inhibition of PDAC tumor growth and metastasis [25]. Similarly, Tseng et al demonstrated that valproic acid, decreasing the PON2 expression, made glioblastoma multiforme-derived cell lines more sensitive to oxidative damage and cell death [27].…”

“…Over the past years, many studies have described the involvement of PON2 in cancer. In particular, PON2 expression was shown to be increased in some solid tumors, including pancreatic cancer [26], glioblastoma multiforme [27], and recently BC [28]. Concerning bladder cancer, in our previous study, we demonstrated that the enzyme levels were significantly higher in tumors compared with adjacent normal looking tissue samples from BC patients.…”

Valproic acid targets HDAC1/2 and HDAC1/PTEN/Akt signalling to inhibit cell proliferation via the induction of autophagy in gastric cancer

“…Therefore, a higher effective concentration of VPA may be needed to exhibit cytotoxic effects in vivo . A higher concentration of VPA for in vitro and in vivo studies has been reported . Nevertheless, humans cannot handle such high concentrations of VPA.…”

Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead

“…A review of the functional or molecular targeting effects of VPA in acute myeloid leukaemia (AML) cells as well as the relevant clinical trials suggested that clinical studies should investigate whether VPA, or any other drug, should be the preferred HDAC inhibitor in AML . More recent evidence indicating that VPA has anticancer activity has come from studies in cell lines from various cancers such as prostate, cervical, glioblastoma, pancreas, thyroid, breast and bladder . This distinct anticancer property of VPA is also believed to explain, at least partially, the mechanisms underpinning its teratogenic effects …”