Combination Therapy with Sulfasalazine and Valproic Acid Promotes Human Glioblastoma Cell Death Through Imbalance of the Intracellular Oxidative Response

Abstract

Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor and still lacks effective therapeutic strategies. It has already been shown that old drugs like sulfasalazine (SAS) and valproic acid (VPA) present antitumoral activities in glioma cell lines. SAS has also been associated with a decrease of intracellular glutathione (GSH) levels through a potent inhibition of xc- glutamate/cystine exchanger leading to an antioxidant deprotection. In the same way, VPA was recently identified as a histone deacetylase (HDAT) inhibitor capable of activating tumor suppression genes. As both drugs are widely used in clinical practice and their profile of adverse effects is well known, the aim of our study was to investigate the effects of the combined treatment with SAS and VPA in GBM cell lines. We observed that both drugs were able to reduce cell viability in a dose-dependent manner and the combined treatment potentiated these effects. Combined treatment also increased cell death and inhibited proliferation of GBM cells, while having no effect on human and rat cultured astrocytes. Also, we observed high protein expression of the catalytic subunit of xc- in all the examined GBM cell lines, and treatment with SAS blocked its activity and decreased intracellular GSH levels. Noteworthy, SAS but not VPA was also able to reduce the [C]-ascorbate uptake. Together, these data indicate that SAS and VPA exhibit a substantial effect on GBM cell's death related to an intracellular oxidative response imbalance, making this combination of drugs a promising therapeutic strategy.

Hypoxia-derived exosomes induce putative altered pathways in biosynthesis and ion regulatory channels in glioblastoma cells

“…With a very poor survival of 14–16 months in newly diagnosed patients, GBM accounts for more than 50% of malignant gliomas [1] , [2] , [3] . Surgical resection of tumors with accompanying or concurrent radiation or chemotherapy, either alone or in combination, has not been an entirely successful curative approach for treating GBM.…”

Short Survival-Related Genes Harbor EMT Processes and Dendritic Cell Infiltration in Glioblastoma

“…Barneh's research shown that valproic acid inhibits stromal cell function and exerts anticancer effects [57]. In GBM, valproic acid is considered a favourable SR drug that acts through multiple mechanisms [58][59][60][61].…”

The Anti-Tumorigenic Activity of Sema3C in the Chick Embryo Chorioallantoic Membrane Model

“…It is done by an increasing production of reactive oxygen species, p21 expression, G2/M cell cycle arrest, suppressing the repair of DNA double strand break, and activating pro-apoptotic signaling [25,26,27,28]. It was shown that NaVP alone and in combination with other chemotherapeutic drugs has an antiangiogenetic and antiproliferative effect on GBM cells and on in vivo rodent glioma tumors [29,30,31]. In line with these studies, we observed an antiproliferative effect on GBM cells by NaVP treatment (Figure 6), without, however, significant effects on cell viability under our experimental conditions (Figure 5).…”