Ali Nasrollahzadeh - Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Majid Momeny - Turku Bioscience Centre, University of Turku and Åbo Akademi University, FI-۲۰۵۲۰, Turku, Finland.
Davood Bashash - Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Hassan Yousefi - Department of Biochemistry and Molecular Biology, LSUHSC, School of Medicine, New Orleans, USA.
Seyed Asadollah Mousavi - Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Seyed Hamidollah Ghaffari - Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Background: Glioblastoma (GBM), the most aggressive and common form of glioma, accounts for over ۱۳,۰۰۰ 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 ۴ 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. Methods: Anti-tumor effects of ATO as monotherapy and in combination with Bay ۱۱-۷۰۸۲ 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 ۱۱-۷۰۸۲ synergistically inhibited the proliferation and survival of GBM cells. Also, it was revealed that NF-κB inhibition using Bay ۱۱-۷۰۸۲ enhanced the inhibitory effects of ATO on migration of GBM cells via suppressing the expression of NF-κB target genes such as TWIST, MMP۲, ICAM-۱, and cathepsin B. Furthermore, combination treatment of GBM cells with ATO and Bay ۱۱-۷۰۸۲ significantly induce apoptotic cell death coupled with downregulation of NF-κB anti-apoptotic target genes including Bcl-۲ and IAP family members. Conclusions: Altogether, these findings suggest that combination therapy with ATO and Bay ۱۱-۷۰۸۲ may be a promising strategy for the treatment of GBM.

Arsenic trioxide (ATO), Bay ۱۱-۷۰۸۲, NF-κB signaling pathway, U۸۷ cells, Apoptosis.