Combination of levetiracetam and IFN-α increased temozolomide efficacy in MGMT-positive glioma

Purpose Glioma, especially glioblastoma (GBM), is the most aggressive malignant brain tumor and its standard therapy is often ineffective because of temozolomide (TMZ) resistance. Reversal of the TMZ resistance might improve the prognosis of glioma patients. We previously found that interferon-alpha (IFN-alpha) and anti-epileptic drug levetiracetam (LEV) could sensitize glioma to TMZ, respectively. In this study, we further investigated the efficiency of combining of LEV and IFN-alpha for improving the efficacy of TMZ. Methods We evaluated whether LEV and IFN-alpha could increase TMZ efficacy using colony formation assay and cell viability assay with MGMT-positive and MGMT-negative glioma cell lines in vitro. Subcutaneous xenografts and orthotopic xenografts mice models were used in vivo to observe the tumor growth and mice survival upon treatments with TMZ, TMZ + IFN-alpha, TMZ + LEV, or TMZ + LEV + IFN-alpha. The expression levels of MGMT, markers of pro-apoptotic and anti-apoptotic in tumor samples were analyzed by Western blotting. Results The combinational use of IFN-alpha, LEV, and TMZ showed the best anti-tumor activity in MGMT-positive cell lines (U138, GSC-1, U118, and T98 G). TMZ + LEV + IFN-alpha further obviously increased TMZ + LEV or TMZ + IFN-alpha efficiency in MGMT-positive cell lines, while not in negative cell lines (SKMG-4, U87, U373, and U251) in vitro, which were also observed in subcutaneous mice models (U138, GSC-1 compared to SKMG-4, U87) and orthotopic models (GSC-1) in vivo. Strikingly, the combination of LEV and IFN-alpha together with TMZ significantly prolonged the survival of mice with orthotopic GSC-1 glioma. Furthermore, we confirmed that the combination of LEV and IFN-alpha enhanced the inhibition of MGMT and the activation of apoptosis in U138 tumor on the basis of TMZ treatment. Conclusions The combination use of LEV and IFN-alpha could be an optimal method to overcome TMZ resistance through obvious MGMT inhibition in MGMT-positive glioma.