NF-κB-IKKβ Pathway as a Target for Drug Development: Realities, Challenges and Perspectives

Abstract

Although only proteasome inhibitors, such as bortezomib and carfilzomib, are a reality as therapeutically useful drugs among the known modulators of possible targets in the NF-κB-IKKβ pathway, some other prototypes described as IKKβ inhibitors have entered clinical stages as drug candidates for the control of inflammatory diseases. It is important to note that some classical drugs available on the pharmaceutical market, such as acetylsalicylic acid, were also described more recently as NF-κB pathway modulators as IKKβ inhibitors.

Evidence for the Involvement of the Master Transcription Factor NF-κB in Cancer Initiation and Progression

“…Since the ubiquitination of IκB by the SCF-B-TrCP ubiquitin ligase complex and the subsequent degradation by the 26S proteasome is a crucial step in the NF-κB activation pathways, preventing the degradation of IκBα is a potential method of treatment to prevent NF-κB activation [ 13 , 14 , 141 , 155 , 156 ].…”

Synergism in aluminum and mercury neurotoxicity

“…NF-kB family members are responsible for up-regulating dozens of genes including those expressing the pro-inflammatory cytokines, chemokines, immuno-receptors, cell adhesion molecules and microRNAs [ 1 – 6 , 59 – 62 ]. Because of this NF-kB signaling is often a central mediator of the immune and inflammatory response; its activation represents the common endpoint of a series of signal transduction events initiated by a vast array of stimuli related to many biological processes such as apoptosis, cell growth, differentiation, innate-immunity, inflammation, tumor cell growth and the presence of ROS generated by neurotoxic metals in the environment [ 59 , 60 ]. NF-kB (p50/p65) dimeric complexes are typically held in the cytoplasm in an inactive state complexed with an NF-kB inhibitor (I-kappa-B; IkB) protein; IkB is next typically phosphorylated by IkB kinases (IKKs) in response to different activators such as ROS from different sources and is subsequently degraded, thus liberating an active NF-kB (p50/p65) complex.…”

“…These next translocate to the nucleoplasm where they recognize and bind to NF-kB features of DNA, typically in the upstream promoter DNA and activate large numbers of NF-kB-sensitive genes [ 1 – 6 , 59 – 62 ]. The 551-amino acid NF-kB p65 subunit, also known as RELA or NFKB3, is encoded from a 1473 nucleotide gene located on human chr 1q13 and contains a N-terminal REL-homology domain (RHD) and a C-terminal transactivation domain (TAD); the RHD is involved in the actual DNA binding, dimerization and NF-κB/REL inhibitor interaction [ 1 , 2 , 59 , 60 ]. NF-kB p65 (RELA) is expressed alongside NF-kB p50 in various cell types, including epithelial, endothelial and neuronal tissues.…”

“… (A) primary human neuronal-glial (HNG) cells after ~2 weeks in primary co-culture; the cell density is approximately 75% neurons and 25% astroglia at ~70% confluency; human primary neuronal and glial “support” cell co-cultures are utilized because human neuronal cells do not culture well by themselves (28–32); HNG cells are triple stained; neuronal cells are stained with neuron-specific β-tubulin (red; λmax=690 nm), glial cells are stained with glial-specific glial fibrillary acidic protein (GFAP; green; λmax=525 nm), and nuclei are stained with DAPI/Hoechst 33258 stain (blue; λmax=470 nm); photo magnification ~30x; (B) ELISA results presented in bar graph format using an NF-κB (p65) transcription factor assay (Cat № 10007889 kit; Cayman Chemical, Ann Arbor MI USA; https://www.caymanchem.com/pdfs/10007889.pdf ) to measure effects of incubation with 0, 20, 50, 200, 500 or 1000 nM ambient aluminum sulfate or mercury sulfate either alone or together; detection of NF-kB p65 is the equivalent of the NF-kB p50/p65 complex since the p65 subunit is always associated with the p50 subunit and is seldom found as a discrete single entity [ 1 , 2 , 59 , 60 ]; aluminum and mercury sulfate together exhibited synergistic induction of the pro-inflammatory transcription factor NF-kB (p65) under the conditions used; see text for further details); experiments were performed N=3 to 5 times per concentration analyzed; the background reading of 0.1 was established at ‘0 nM’ on the ‘x’ axis which was used for a comparison against all other levels; a dashed horizontal line at 0.1 has been added for ease of comparison; * p <0.05; ** p <0.01, *** p <0.001, ANOVA) …”

NF-κB signaling and crosstalk during carcinogenesis

“…However, as a disruption of homeostasis in NF-jB signaling also results in the consequent various activation/ deactivation of pathways, the expectations may have to be toned down, especially as it has been shown that some classical drugs may act as NF-jB modulators or IKKb inhibitors [404]. For example, the compound salvianolic acid C (SalC) isolated from the plant, Salvia miltiorrhiza Bunge, can inhibit "LPS-induced inflammatory response and NF-jB activation through the activation of AMPK/Nrf2 signaling both in vivo and in vitro" [405].…”