Natural Small Molecules Targeting NF-κB Signaling in Glioblastoma

Abstract

Nuclear factor-κB (NF-κB) is a transcription factor that regulates various genes that mediate various cellular activities, including propagation, differentiation, motility, and survival. Abnormal activation of NF-κB is a common incidence in several cancers. Glioblastoma multiforme (GBM) is the most aggressive brain cancer described by high cellular heterogeneity and almost unavoidable relapse following surgery and resistance to traditional therapy. In GBM, NF-κB is abnormally activated by various stimuli. Its function has been associated with different processes, including regulation of cancer cells with stem-like phenotypes, invasion of cancer cells, and radiotherapy resistance identification of mesenchymal cells. Even though multimodal therapeutic approaches such as surgery, radiation therapy, and chemotherapeutic drugs are used for treating GBM, however; the estimated mortality rate for GBM patients is around 1 year. Therefore, it is necessary to find out new therapeutic approaches for treating GBM. Many studies are focusing on therapeutics having less adverse effects owing to the failure of conventional chemotherapy and targeted agents. Several studies of compounds suggested the involvement of NF-κB signaling pathways in the growth and development of a tumor and GBM cell apoptosis. In this review, we highlight the involvement of NF-κB signaling in the molecular understanding of GBM and natural compounds targeting NF-κB signaling.

The Sesquiterpene Lactone Cynaropicrin Manifests Strong Cytotoxicity in Glioblastoma Cells U-87 MG by Induction of Oxidative Stress

“…NF-κB and the MAPK signaling pathways have been ranked among the most common dysregulated pathways in glioblastoma cells, commonly implicated in the proliferation and survival of cancer cells [ 31 , 32 ].…”

Cyclooxygenase-2 Upregulated by Temozolomide in Glioblastoma Cells Is Shuttled In Extracellular Vesicles Modifying Recipient Cell Phenotype

“…The ability of TMZ to induce an upregulation of COX-2 expression could be ascribed to the action exerted by the drug at the EGF/EGFR pair level leading to the NF-kB transcription factor activation able to upregulate the COX-2 expression due to the presence in the COX-2 promotor of the NF-kB response element (35). The NF-kB/COX-2 signaling is a crucial regulator of the malignant phenotype and chemoresistance in GBM (36). NF-kB signaling pathway has also been reported to influence radiotherapy tolerance of glioma cells through regulating COX-2 expression, with potential therapeutic approaches for the treatment of glioma (37).…”

Rationally Designed Molecules Synergistically Modulate Multifaceted Aβ Toxicity, Microglial Activation, and Neuroinflammation

“…The amyloid toxicity in AD is mediated through metal–Aβ42 complex formation, ROS generation, and metal-dependent aggregation, wherein Cu II and Zn II contribute significantly to disease pathology. , Di-2-picolylamine (DPA) binds to metal ions, and its Zn II chelation is well demonstrated. ,, This motivated us to use the DPA moiety as a metal chelator on the NMI scaffold. Our group and others have reported synthetic and natural products with the catechol moiety exhibiting metal chelation, antioxidant activity, reduced ROS levels, anti-neuroinflammatory property, and inhibition of Aβ42 aggregation in vitro and in cellulo. ,− We incorporated DPA and dopamine with metal chelation, antioxidant and anti-neuroinflammatory properties onto the aggregation modulator NMI scaffold to obtain multifunctional modulators M1–M4 (Figure A). We envisage identifying a lead candidate with the synergistic effect of aggregation modulation, metal chelation, ROS quenching, and antioxidant and anti-inflammatory activities.…”