Sensitizer drugs for the treatment of temozolomide-resistant glioblastoma

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor. Despite maximal cytoreductive surgery followed by chemoradiotherapy the prognosis is still poor. Although surgery and radiotherapy may have reached maximal effectiveness, chemotherapy has the potential to improve survival. The aim of this study was to evaluate in vitro the antitumor efficacy of tamoxifen (TAM), raloxifen (RAL), pyrimethamine (PYR) and alphanizomenon flos-aquae (AFA) in combination with temozolomide (TMZ) plus ionizing radiation against cultured glioblastoma stem-like cells and primary glioblastoma cells , as possible way to increase the treatment options in patients with therapy-refractory GBM. Stem-like tumor cells and glioblastoma cells isolated from two GBM biopsies were established by cell proliferation assays. TAM, RAL, PYR and AFA were added prior to TMZ and ionizing irradiation. All tested drugs enhanced the cytotoxic effect of TMZ and sensitized cancer cells to radiotherapy as demonstrated by MTT assay and different staining reagents (TMRE, Hoechst dye and Annexin V) used for monitoring of several events in apoptosis. The administration of certain selective estrogen receptor modulators (SERMs) (TAM and RAL), PYR and AFA before conventional postoperative chemo radiotherapy for glioblastoma might increase therapy efficiency compared to standard oncological treatment. These results need to be extended in vivo on laboratory animals in order to test the encouraging results obtained in vitro.