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Published on: February 16, 2015
Sulfasalazine intensifies temozolomide cytotoxicity in human glioblastoma cells
Raffaela Silvestre Ignarro1, Gustavo Facchini1, André Schwambach Vieira2
1Department of Anatomical Pathology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Av. Tessália Vieira De Camargo, 126, Campinas, SP, 13083-887, Brazil.
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.
Insights
The combination of temozolomide (TMZ) and sulfasalazine (SAS) shows cytotoxic effects against glioblastoma cells. This novel drug combination may improve the clinical efficacy of TMZ in treating brain tumors.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Glioblastoma utilizes system X c (-) to synthesize glutathione, an antioxidant.
- Sulfasalazine (SAS) inhibits system X c (-) , a pathway targeted in glioblastoma treatment.
- Temozolomide (TMZ) is a standard alkylating agent for glioblastoma therapy.
Purpose of the Study:
- To investigate the combined cytotoxic effects of TMZ and SAS on human glioblastoma cells.
- To explore the impact of TMZ and SAS on cellular pathways, glutathione levels, and proliferation.
- To assess the potential of this drug combination for enhancing TMZ's clinical efficacy.
Main Methods:
- A172 and T98G glioblastoma cells were treated with TMZ and/or SAS.
- Cell viability was assessed over 1, 3, and 5 days.
- Transcriptome, glutathione, and PCNA protein levels were analyzed.
Main Results:
- TMZ alone did not affect cell viability, while TMZ plus SAS significantly reduced it after 5 days.
- The combination demonstrated synergistic cytotoxicity in A172 cells.
- SAS depleted glutathione levels, and both treatments reduced PCNA protein levels.
Conclusions:
- The combination of TMZ and SAS exhibits significant cytotoxicity against glioblastoma cells.
- This drug combination offers potential for improving TMZ's therapeutic effectiveness.
- The study provides novel insights into gene expression and antiproliferative effects in glioblastoma.
