Blockade Of Nuclear Factor-kb (nf-kb) Pathway Using Bay 11-7082 Enhances Arsenic Trioxide-induced Antiproliferative Activity In U87 Glioblastoma Cells
Reports of Biochemistry and Molecular Biology
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.
Nasrollahzadeh, Ali; Momeny, Majid; Bashash, Davood; Yousefi, Hassan; Mousavi, Seyed Asadollah; and Ghaffari, Seyed Hamidollah, "Blockade Of Nuclear Factor-kb (nf-kb) Pathway Using Bay 11-7082 Enhances Arsenic Trioxide-induced Antiproliferative Activity In U87 Glioblastoma Cells" (2022). School of Medicine Faculty Publications. 1482.