Amlexanox enhances temozolomide-induced anti-tumor effects in human glioblastoma cells by inhibiting IKBKE and the Akt-mTOR signaling pathway

Abstract

Background: Temozolomide (TMZ), as the first-line chemotherapeutic agent for the treatment of glioblastoma multiforme (GBM), often fails to improve the prognosis of GBM patients due to the quick development of resistance. The need for more effective management of GBM is urgent. The aim of this study is to evaluate the efficacy of combined therapy with TMZ and amlexanox, a selective inhibitor of inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE), for GBM. Methods: in vitro, cell viability assay, apoptosis analysis, western blot, migration and invasion assay were used. In vivo, intracranial tumor models were constructed and the immunohistochemistry were used. Results: We found that combined treatment resulted in significant induction of cellular apoptosis and the inhibition of cell viability, migration and invasion in primary glioma cell and in the human glioma cell line, U87 MG. TMZ enhanced expression of phosphoration of adenosine 5‘-monophosphate-activated protein kinase (p-AMPK) and amlexanox led to reduction of IKBKE, with no impact on p-AMPK. Furthermore, we demonstrated that, compared to other groups treated with each component alone, TMZ combined with amlexanox effectively inhibited phosphorylation of protein kinase B (AKT) and mammalian target of rapamycin (mTOR). In addition, the combination treatment also clearly reduced in vivo tumor volume and prolonged median survival time in the xenograft mouse model. Conclusion: These results suggest that amlexanox sensitized primary glioma cell and U87 MG cell to TMZ at least partially though the suppression of IKBKE activation and the attenuation of AKT activation. Overall, combined treatment with TMZ and amlexanox may provide a promising possibility for improving the prognosis of glioblastoma patients in clinical practice.