Amlexanox Enhances Temozolomide-Induced Antitumor Effects in Human Glioblastoma Cells by Inhibiting IKBKE and the Akt-mTOR Signaling Pathway.

Jinbiao Xiong,Lianmei Guo,Yiyao Cao,Gaochao Guo,Ruilong Li,Weidong Yang,Yang Nan,Xuejun Yang,Jun Dong,Qiang Huang,Zhijuan Chen,Xun Jin,Zengguang Wang

doi:10.1021/acsomega.0c05399

Abstract

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 IKBKE, for GBM. We found that the combined treatment resulted in significant induction of cellular apoptosis and the inhibition of cell viability, migration, and invasion in primary glioma cells and in the human glioma cell line, U87 MG. As expected, TMZ enhanced the expression of p-AMPK and amlexanox led to the 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 reversed the TMZ-induced activation of Akt and inhibited the phosphorylation of mTOR. In addition, the combination treatment also clearly reduced in vivo tumor volume and prolonged median survival time in the xenograft mouse model. These results suggest that amlexanox sensitized the primary glioma cells and U87 MG cells to TMZ at least partially through the suppression of IKBKE activation and the attenuation of TMZ-induced Akt activation. Overall, combined treatment with TMZ and amlexanox may provide a promising possibility for improving the prognosis of glioblastoma patients in clinical practice.

Highlights

Glioblastoma multiforme (GBM), which accounts for more than 60−70% of all gliomas, is the most aggressive and most deadly primary brain tumor in adults.[1,2] Over the past few decades, there has been progress in human GBM treatment, currently including maximal surgical resection followed by chemotherapy and/or radiotherapy, the prognosis of patients diagnosed with GBM remains extremely grim, with a median survival of approximately 14.6 months and a 5-year survival rate of only 9.8%.3,4 there is an overwhelming need for more efficacious therapeutic approaches for this malignancy.Temozolomide (TMZ), a novel oral alkylating agent, is the drug that is most frequently used against malignant glioma, and it has broad-spectrum antitumor activity.[5]
We demonstrated that amlexanox enhanced the sensitization of GBM cells to TMZ in vitro and in vivo
We found that amlexanox could indirectly inhibit the expression of Akt through reducing activity of IKBKE, which suggested a connection between Akt and IKBKE in the development of GBM and might be a potential inhibitory target of GBM

Summary

Introduction

Temozolomide (TMZ), a novel oral alkylating agent, is the drug that is most frequently used against malignant glioma, and it has broad-spectrum antitumor activity.[5] TMZ is considered the most promising chemotherapeutic drug against GBM, most patients suffer from tumor recurrence within 7 months due to the development of resistance to TMZ.[6] Accumulating evidence demonstrates that the activation of Akt is responsible for the evolution of resistance in different types of cancers.[7−9] Akt phosphorylates several substrates associated with various cellular processes, such as cell growth, survival, and metabolism.[10,11] Interestingly, Akt activation is enhanced by TMZ treatment, which, in turn, attenuates TMZ-induced apoptosis.[12,13] Recently, Akt is reported to be phosphorylated by IKBKE (known as IKKε and IKKi) in breast cancer,[14] nonsmall-cell cancer (NSCLC),[15] and other cells or tissues.[16]

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