Sulfasalazine intensifies temozolomide cytotoxicity in human glioblastoma cells

Abstract

Temozolomide (TMZ) is an alkylating agent used to treat glioblastoma. This tumor type synthesizes the antioxidant glutathione through system X c (-) , which is inhibited by sulfasalazine (SAS). We exposed A172 and T98G human glioblastoma cells to a presumably clinically relevant concentration of TMZ (25 µM) and/or 0.5 mM SAS for 1, 3, or 5 days and assessed cell viability. For both cell lines, TMZ alone did not alter viability at any time point, while the coadministration of TMZ and SAS significantly reduced cell viability after 5 days. The drug combination exerted a synergistic effect on A172 cells after 3 and 5 days. Therefore, this particular lineage was subjected to complementary analyses on the genetic (transcriptome) and functional (glutathione and proliferating cell nuclear antigen (PCNA) protein) levels. Cellular pathways containing differentially expressed genes related to the cell cycle were modified by TMZ alone. On the other hand, SAS regulated pathways associated with glutathione metabolism and synthesis, irrespective of TMZ. Moreover, SAS, but not TMZ, depleted the total glutathione level. Compared with the vehicle-treated cells, the level of PCNA protein was lower in cells treated with TMZ alone or in combination with SAS. In conclusion, our data showed that the association of TMZ and SAS is cytotoxic to T98G and A172 cells, thus providing useful insights for improving TMZ clinical efficacy through testing this novel drug combination. Moreover, the present study not only reports original information on differential gene expression in glioblastoma cells exposed to TMZ and/or SAS but also describes an antiproliferative effect of TMZ, which has not yet been observed in A172 cells.

β-Elemene Selectively Inhibits the Proliferation of Glioma Stem-Like Cells Through the Downregulation of Notch1

“…An increased antitumor effect was observed in the combination group compared with the single treatment group []. Silencing of NrF2 (nuclear factor erythroid 2‐related factor 2) and inhibition of glutathione greatly enhanced cell death with TMZ treatment both in vitro and in vivo [, ].…”

Interactions between Tumor Cells, Neurons, and Microglia in the Glioma Microenvironment

“…It is also encouraging that talampanel did not increase the hematological side Glioma cell-derived xCT is, at least, partly responsible for promoting cortical hyperexcitability, brain edema, and neuronal cell death [25,[86][87][88]. Further, pharmacological antagonism with the FDA-approved compound sulfasalazine diminishes cortical hyperexcitability and augments temozolomide efficacy against glioma cells in vitro [86,89]. Unfortunately, available clinical evidence suggests that sulfasalazine also augments the hematological side effects of radiation + temozolomide [90].…”

Oxidative Stress Activated by Sorafenib Alters the Temozolomide Sensitivity of Human Glioma Cells Through Autophagy and JAK2/STAT3-AIF Axis

“…However, the development of TMZ resistance promotes the survival of glioma cells and leads to poor prognosis of patients. To overcome TMZ resistance, studies have found that metformin or sulfasalazine could enhance the cytotoxicity of TMZ in glioblastoma cells ( Ignarro et al, 2016 ). Mechanistically, DNA repair systems, including DNA mismatch repair (MMR) ( Perazzoli et al, 2015 ) and base excision repair (BER) ( Tang et al, 2011 ), play important roles in the mechanisms of TMZ resistance.…”