Parthenolide may be useful in chemoresistant gliomas. - GreenMedInfo Summary
Inhibition of NF-κB results in anti-glioma activity and reduces temozolomide-induced chemoresistance by down-regulating MGMT gene expression.
Cancer Lett. 2018 Aug 1 ;428:77-89. Epub 2018 Apr 27. PMID: 29705182
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 factorκB (NF-κB) 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-κB inhibits glioma cell proliferation and treating a panel of establishedglioma cell lines with pharmacological NF-κB inhibitors markedly decreased glioma viability, led to S cell cycle arrest, and induced apoptosis. We also found a significant correlation between NF-κB 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-κB activity down-regulated MGMT gene expression and substantially restored TMZ chemosensitivity in vitro and in vivo. Importantly, the TMZ sensitizing effect of siNF-κB(p65) or parthenolide were rescued by MGMT cDNA expression. These findings suggest that NF-κB 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.