gms | German Medical Science

Objective: Resistance to temozolomide, the standard chemotherapy for gliomas in humans, represents an important issue in current therapy schemes. Emerging evidence suggests that nitric oxide may potentially lead to a sensitization of tumor cells to a variety of chemotherapeutic compounds. The nitric oxide donor PABA/NO selectively releases nitric oxide in GST-pi overexpressing glioma cells after enzymatic activation. We tested the hypothesis that PABA/NO may enhance the growth-inhibitory effect of temozolomide in U87 cells in vitro.

Methods: We exposed U87 cells to temozolomide concentrations between 1 µM and 100 µM alone as well as concomitantly with PABA/NO concentrations between 5 µM and 50 µM for 24 h. Viability was assessed after 24 h incubation, as well as 48 h and 72 h after drug removal by MTT assay. Statistical analysis was performed by ANOVA.

Results: The IC50 concentrations for PABA/NO and temozolomide alone were 45 µM and 100 µM, respectively. PABA/NO significantly enhanced the growth-inhibitory effect of temozolomide in U87 glioma cells (p<0.0001). PABA/NO concentrations between 5 and 25 µM which did not have an intrinsic antiproliferative effect alone, lead to a significant increase in temozolomide cytotoxicity. Concomitant treatment of U87 cells with PABA/NO and temozolomide concentrations as low as 1 µM reduced cell viability up to 80%.

Conclusions: The nitric oxide donor PABA/NO significantly enhances the cytotoxic effect of temozolomide in U87 glioma cells in vitro. Using a nitric oxide donor to overcome resistance to temozolomide might be a new strategy to improve the efficacy of multimodal glioma treatment.