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Blockade of Nuclear Factor-Kb (Nf-Kb) Pathway Using Bay 11-7082 Enhances Arsenic Trioxide-Induced Antiproliferative Activity in U87 Glioblastoma Cells Publisher



Nasrollahzadeh A1 ; Momeny M2 ; Bashash D3 ; Yousefi H4 ; Mousavi SA1 ; Ghaffari SH1
Authors
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Authors Affiliations
  1. 1. Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  2. 2. Turku Bioscience Centre, University of Turku and Abo Akademi University, Turku, FI-20520, Finland
  3. 3. Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  4. 4. Department of Biochemistry and Molecular Biology, LSUHSC, School of Medicine, New Orleans, United States

Source: Reports of Biochemistry and Molecular Biology Published:2022


Abstract

Background: 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-kB signaling pathway plays a crucial role in tumorigenesis and chemo-resistance, targeting this oncogenic pathway may sensitize GBM cells to lower concentrations of ATO. Methods: 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. Results: Our results revealed that ATO and Bay 11-7082 synergistically inhibited the proliferation and survival of GBM cells. Also, it was revealed that NF-kB inhibition using Bay 11 -7082 enhanced the inhibitory effects of ATO on migration of GBM cells via suppressing the expression of NF-kB 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-kB 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. © 2022. All Rights Reserved.
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