Inhibition of NF-κB results in anti-glioma activity and reduces temozolomide-induced chemoresistance by down-regulating MGMT gene expression

The introduction of temozolomide (TMZ) has improved chemotherapy for malignant gliomas. However, many gliomas are refractory to TMZ, so there is a pressing need for more effective therapeutic options. Here we demonstrated that glioma specimens and cell lines have constitutively high levels of nuclear factor kappa B (NF-kappa B) activity. Notably, the expression levels of this transcription factor correlated with malignant grades in glioblastoma multiforme (GBM) and inversely correlated with overall survival. Conversely, knockdown of NF-kappa B inhibits glioma cell proliferation and treating a panel of established glioma cell lines with pharmacological NF-kappa B inhibitors markedly decreased glioma viability, led to S cell cycle arrest, and induced apoptosis. We also found a significant correlation between NF-kappa B expression and O6-methylguanine-DNA methyltransferase (MGMT) expression in gliomas with different origins, and immunohistochemistry confirmed these findings. Genetic or pharmacological (especially parthenolide) inhibition of NF-kappa B activity down-regulated MGMT gene expression and substantially restored TMZ chemosensitivity in vitro and in vivo. Importantly, the TMZ sensitizing effect of siNF-kappa B(p65) or parthenolide were rescued by MGMT cDNA expression. These findings suggest that NF-kappa B is a potential target for inducing cell death in gliomas. A targeted combination strategy in which the response to TMZ is synergistically enhanced by the addition of parthenolide which may be useful, especially in chemoresistant gliomas with high MGMT expression. (C) 2018 Elsevier B.V. All rights reserved.