Inhibition of the NF-κB signaling pathway by the curcumin analog, 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31): Anti-inflammatory and anti-cancer properties

Abstract

Nuclear factor kappa B (NF-κB) is a key signaling molecule in the elaboration of the inflammatory response. Data indicate that curcumin, a natural ingredient of the curry spice turmeric, acts as a NF-κB inhibitor and exhibits both anti-inflammatory and anti-cancer properties. Curcumin analogues with enhanced activity on the NF-κB and other inflammatory signaling pathways have been developed including the synthetic monoketone compound termed 3,5-Bis(2-fluorobenzylidene)-4-piperidone (EF24). 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31) is a structurally-related curcumin analogue whose potency for NF-κB inhibition has yet to be determined. To examine the activity of EF31 compared to EF24 and curcumin, mouse RAW264.7 macrophages were treated with EF31, EF24, curcumin (1–100µM) or vehicle (DMSO 1%) for 1 hour. NF-κB pathway activity was assessed following treatment with lipopolysaccharide (LPS) (1µg/mL). EF31 (IC50 ~5µM) exhibited significantly more potent inhibition of LPS-induced NF-κB DNA binding compared to both EF24 (IC50~35µM) and curcumin (IC50 >50µM). In addition, EF31 exhibited significantly greater inhibition of NF-κB nuclear translocation as well as the induction of downstream inflammatory mediators including pro-inflammatory cytokine mRNA and protein (tumor necrosis factor-α, interleukin-1β, and interleukin-6). Regarding the mechanism of these effects on NF-κB activity, EF31 (IC50~1.92µM) exhibited significantly greater inhibition of IκB kinase β compared to EF24 (IC50~131µM). Finally, EF31 demonstrated potent toxicity in NF-κB-dependent cancer cell lines while having minimal and reversible toxicity in RAW264.7 macrophages. These data indicate that EF31 is a more potent inhibitor of NF-κB activity than either EF24 or curcumin while exhibiting both anti-inflammatory and anticancer activities. Thus, EF31 represents a promising curcumin analogue for further therapeutic development.

Rhenium–platinum antitumor systems

“…For example, chemical modification of the curcumin molecule led to more potent inhibitors curcuminoids of NF-κB activity than curcumin, while exhibiting both antiinflammatory and anticancer activities [100,101].…”

Anticancer effects of monocarbonyl analogs of curcumin: oxidative stress, nuclear translocation and modulation of AP-1 and NF-κB

“…51 In parallel, EF31 increases basal levels of MAPK transcription factor-DNA binding in mouse RAW264.7 macrophages. 9 To elucidate a global view of the anticancer/cytocidal actions of these compounds, we sought information regarding their drug targets by using microarrays, and examined cellular localization of EF24 and the activity of two key transcription factors, AP-1 and NF-κB, essential for cell survival and death.…”

“…5 We have found that four MACs with a common mechanism of action, including EF24, EF25, EF31 and UBS109, may be clinically useful. [6][7][8][9][10][11][12] Here, we summarize tumorigenic actions of the subset of MACs considered in this work. EF24, EF25, EF31 and UBS109 inhibit a wide variety of cancer cells.…”

“…EF24, EF25, EF31 and UBS109 inhibit a wide variety of cancer cells. 6-8, 10, 13-16 MACs also mediate inflammation 9 , disrupt the microtubule cytoskeleton and inhibit HIF-1 17 , in contrast to paclitaxel, which involves stabilization of cellular microtubules, thereby interfering with normal microtubule dynamics during cell division. Tissue factor (TF) is aberrantly expressed in cancer and its vasculature and causes thrombo-embolic complications.…”

The effects of short term stress on the central and peripheral nitrergic system

“…Madrigal and colleagues (2001) have demonstrated that inhibition of NF-κB translocation in the rat brain cortex decreased iNOS activity and expression following acute stress. Natural compounds such as curcumin, α-tocopherol, and resveratrol have also been shown to inhibit NF-κB activation and the associated neuroinflammatory response including both cytokines and iNOS induction (Suzuki and Packer, 1993;Lu et al, 2010;Olivera et al, 2012). Another important inflammatory signalling cascade involves cyclooxygenase-2 (COX-2), a constitutively expressed enzyme in the brain that converts arachidonic acid into prostaglandin.…”