The Synergistic Therapeutic Effect of Temozolomide and Hyperbaric Oxygen on Glioma U251 Cell Lines is Accompanied by Alterations in Vascular Endothelial Growth Factor and Multidrug Resistance-Associated Protein-1 Levels

Abstract

OBJECTIVE: Temozolomide (TMZ) is an oral alkylating agent widely used in the treatment of refractory glioma. Its efficacy is limited, however, by poor cancer cell penetration and drug resistance. The present study, therefore, aimed to investigate whether hyperbaric oxygen (HBO) may facilitate drug delivery and enhance the anticancer effect of TMZ. METHODS: Cultured glioma U251 cells were treated with HBO, TMZ, or TMZ + HBO, or were untreated (controls). Rates of growth inhibition, cell death and apoptosis were investigated using the 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, propidium iodide staining and flow cytometry, respectively. Protein levels of vascular endothelial growth factor (VEGF) and multidrug resistance-associated protein-1 (MRP-1) were evaluated by enzyme-linked immunosorbent assay. RESULTS: Compared with TMZ or HBO alone, combined treatment with both therapies synergistically inhibited growth and induced apoptosis and death of cultured glioma U251 cells, which was accompanied by a significant decrease in levels of VEGF and MRP-1. CONCLUSIONS: TMZ and HBO synergistically induced the apoptosis of glioma cells, possibly through reduced vascularization and inhibition of drug resistance. The combination of TMZ and HBO may be a powerful treatment for malignant glioma.