Temozolomide (TMZ) is a methylating agent with promising antitumor efficacy for the treatment of melanomas and intermediate-grade gliomas. Unfortunately, its use in the management of high-grade gliomas (glioblastomas) is limited by multifaceted resistance mechanisms. The aim of this study was to evaluate the possibility to improve the cytotoxic response of two human glioblastoma cell lines, U87MG and U373MG, to TMZ by the use of Tempol (TPL), a low molecular weight piperidine nitroxide that has been shown to inhibit in vitro and in vivo growth of murine glioma cells. To this purpose, we used two different schedules for the combined exposure to the two agents. Our data indicate that TPL synergizes with TMZ in both U87MG and U373MG cells for both schedules tested. This effect is accompanied by an increase in apoptotic cell death and by changes in the expression of genes involved in control of the apoptotic process. TPL was also observed to induce a cell-type specific decrease in GSH levels and in GSH-related enzyme activities that could contribute to its sensitizing effect.

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