Synergistic Suppression of Glioblastoma Cell Growth by Combined Application of Temozolomide and Dopamine D2 Receptor Antagonists.

Abstract

The current standard treatment of malignant glioma is maximal resection followed by chemotherapy and radiotherapy. Temozolomide (TMZ) has been the first-line chemotherapeutic agent used, although to achieve a satisfactory clinical effect. TMZ chemoresistance could result from glioblastoma stem cells, which are critical for tumor initiation, recurrence, and therapeutic resistance and are potential targets. Moreover, signals mediated by the dopamine D2 receptor (DRD2) can positively regulate proliferation and tumorigenesis of glioma cells. To enhance TMZ's antitumor effect, we treated glioma cells with combinations of TMZ and DRD2 antagonists (DDRAs). The combined application of TMZ and DDRAs (haloperidol or risperidone) had synergistic effects and inhibited proliferation of glioma cells more significantly than did monotherapy. The combined treatment increased the levels of γH2AX (a marker of DNA damage) more significantly than did TMZ alone, although DDRAs alone had no effect on γH2AX levels. Moreover, the expression of DRD2 transcripts in U251 glioma cells and glioblastoma stem cells were significantly elevated after TMZ treatment, suggesting crosstalk between TMZ- and DRD2-mediated signaling. To explore the underlying mechanisms, we measured the expression of prosurvival proteins after treatment with either TMZ or DDRAs alone or combined. The results showed that DDRAs could inhibit the extracellular signal-related kinase signaling pathway and block TMZ-induced protective autophagy, which could explain why DDRAs increased the cytotoxicity of TMZ. We have provided evidence showing the synergistic effects of TMZ and DDRAs on suppressing glioma cell growth. Our study has provided novel insights on enhancing the effectiveness of chemotherapy against malignant glioma and eventually improving the clinical outcomes of patients with glioblastoma multiforme.