Blockade of Nuclear Factor-Κb (NF-Κb) Pathway Using Bay 11-7082 Enhances Arsenic Trioxide-Induced Antiproliferative Activity in U87 Glioblastoma Cells.

Hassan Yousefi,Davood Bashash,Majid Momeny,Seyed Asadollah Mousavi,Ali Nasrollahzadeh,Seyed Hamidollah Ghaffari

doi:10.52547/rbmb.10.4.602

Abstract

Glioblastoma (GBM), the most aggressive and common form of glioma, accounts for over 13,000 death per year in the United States which indicates the importance of developing novel strategies for the treatment of this fatal malignancy. Although Arsenic trioxide (ATO) hinders the growth and survival of GBM cells, the requirement of concentrations higher than 4 µM for triggering apoptotic cell death has questioned its safety profile. Since the NF-κB signaling pathway plays a crucial role in tumorigenesis and chemo-resistance, targeting this oncogenic pathway may sensitize GBM cells to lower concentrations of ATO. Anti-tumor effects of ATO as monotherapy and in combination with Bay 11-7082 were determined using MTT, crystal violet staining, Annexin V/PI staining and scratch assays. Quantitative reverse transcription-PCR (qRT-PCR) analysis was applied to elucidate the molecular mechanisms underlying the anti-tumor activity of this combination therapy. Our results revealed that ATO and Bay 11-7082 synergistically inhibited the proliferation and survival of GBM cells. Also, it was revealed that NF-κB inhibition using Bay 11-7082 enhanced the inhibitory effects of ATO on migration of GBM cells via suppressing the expression of NF-κB target genes such as TWIST, MMP2, ICAM-1, and cathepsin B. Furthermore, combination treatment of GBM cells with ATO and Bay 11-7082 significantly induce apoptotic cell death coupled with downregulation of NF-κB anti-apoptotic target genes including Bcl-2 and IAP family members. Altogether, these findings suggest that combination therapy with ATO and Bay 11-7082 may be a promising strategy for the treatment of GBM.

Highlights

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor with an average incidence rate of 3.22 per 100,000 people [1, 2]
Arsenic trioxide (ATO) and Bay 11-7082 synergistically inhibit the growth and proliferation of U87 glioblastoma cells Given the significant regulatory role of NF-κB signaling pathway in cell survival and tumorigenesis, it was tempting to evaluate the inhibitory effects of Bay 11-7082, an inhibitor of IκB kinase (IKK), on viability of cancer cells [22]
Since U87 cells were more sensitive to combination therapy with ATO and Bay 117082, this cell line was selected for further experiments

Summary

Introduction

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor with an average incidence rate of 3.22 per 100,000 people [1, 2]. Synergistic Interactions of ATO and Bay 11-7082 antibody that binds to vascular endothelial growth factor, has been clinically approved for the treatment of recurrent GBM [5]. Despite these advances, the prognosis of GBM remains poor and only 5% of patients survive more than five years [6] which highlights the necessity of developing new therapeutic strategies for this fatal malignancy. Combination treatment of GBM cells with ATO and Bay 11-7082 significantly induce apoptotic cell death coupled with downregulation of NF-κB anti-apoptotic target genes including Bcl-2 and IAP family members. Conclusions: Altogether, these findings suggest that combination therapy with ATO and Bay 11-7082 may be a promising strategy for the treatment of GBM

Methods

Results

Conclusion