NF-κB inhibitor with Temozolomide results in significant apoptosis in glioblastoma via the NF-κB(p65) and actin cytoskeleton regulatory pathways.

Abstract

Glioblastoma (GBM) is the most malignant brain tumor characterized by intrinsic or acquired resistance to chemotherapy. GBM tumors show nuclear factor-κB (NF-κB) activity that has been associated with tumor formation, growth, and increased resistance to therapy. We investigated the effect of NF-κB inhibitor BAY 11-7082 with Temozolomide (TMZ) on the signaling pathways in GBM pathogenesis. GBM cells and patient-derived GBM cells cultured in 3D microwells were co-treated with BAY 11-7082 and TMZ or BAY 11-7082 and TMZ alone, and combined experiments of cell proliferation, apoptosis, wound healing assay, as well as reverse-phase protein arrays, western blot and immunofluorescence staining were used to evaluate the effects of drugs on GBM cells. The results revealed that the co-treatment significantly altered cell proliferation by decreasing GBM viability, suppressed NF-κB pathway and enhanced apoptosis. Moreover, it was found that the co-treatment of BAY 11-7082 and TMZ significantly contributed to a decrease in the migration pattern of patient-derived GBM cells by modulating actin cytoskeleton pathway. These findings suggest that in addition to TMZ treatment, NF-κB can be used as a potential target to increase the treatment's outcomes. The drug combination strategy, which is significantly improved by NF-κB inhibitor could be used to better understand the underlying mechanism of GBM pathways in vivo and as a potential therapeutic tool for GBM treatment.

• Authors: Naze G Avci, Sadaf Ebrahimzadeh-Pustchi, Yasemin M Akay, Yoshua Esquenazi, Nitin Tandon, Jay-Jiguang Zhu, Metin Akay
• Journal: Scientific reports (Sci Rep) Vol. 10 Issue 1 Pg. 13352 (08 07 2020) ISSN: 2045-2322 [Electronic] England
• PMID: 32770097 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(4-methylphenylsulfonyl)-2-propenenitrile
• NF-kappa B
• Nitriles
• Sulfones
• Transcription Factor RelA
• Temozolomide

Topics

• Actin Cytoskeleton (drug effects, metabolism)
• Apoptosis (drug effects)
• Brain Neoplasms (drug therapy)
• Cell Line, Tumor
• Enzyme-Linked Immunosorbent Assay
• Glioblastoma (drug therapy)
• Humans
• Immunoblotting
• NF-kappa B (antagonists & inhibitors, metabolism)
• Nitriles (pharmacology)
• Signal Transduction (drug effects)
• Sulfones (pharmacology)
• Temozolomide (therapeutic use)
• Transcription Factor RelA (metabolism)