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

Anlys Olivera; Terry W. Moore; Fang Hu; Andrew P. Brown; Aiming Sun; Dennis C. Liotta; James P. Snyder; Younghyoun Yoon; Hyunsuk Shim; Adam I. Marcus; Andrew H. Miller; Thaddeus W.W. Pace

doi:10.1016/j.intimp.2011.12.009

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

Anlys Olivera, Terry W. Moore, Fang Hu, Andrew P. Brown, Aiming Sun, Dennis C. Liotta, James P. Snyder, Younghyoun Yoon, Hyunsuk Shim, Adam I. Marcus, Andrew H. Miller, Thaddeus W.W. Pace

Research output: Contribution to journal › Article › peer-review

192 Scopus citations

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 analogs with enhanced activity on NF-κB and other inflammatory signaling pathways have been developed including the synthetic monoketone compound 3,5-Bis(2-fluorobenzylidene)-4-piperidone (EF24). 3,5-Bis(2- pyridinylmethylidene)-4-piperidone (EF31) is a structurally-related curcumin analog 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 (1-100 μM) or vehicle (DMSO 1%) for 1 h. NF-κB pathway activity was assessed following treatment with lipopolysaccharide (LPS) (1 μg/mL). EF31 (IC ₅₀ ∼ 5 μM) exhibited significantly more potent inhibition of LPS-induced NF-κB DNA binding compared to both EF24 (IC ₅₀ ∼ 35 μM) and curcumin (IC ₅₀ > 50 μM). In addition, EF31 exhibited 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, EF31 (IC ₅₀ ∼ 1.92 μM) exhibited significantly greater inhibition of IκB kinase β compared to EF24 (IC ₅₀ ∼ 131 μM). 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 analog for further therapeutic development.

Original language	English (US)
Pages (from-to)	368-377
Number of pages	10
Journal	International immunopharmacology
Volume	12
Issue number	2
DOIs	https://doi.org/10.1016/j.intimp.2011.12.009
State	Published - Feb 2012
Externally published	Yes

Keywords

Anti-cancer
Curcumin
Inflammation
Macrophages
NF-κB

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Pharmacology

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10.1016/j.intimp.2011.12.009

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Olivera, A., Moore, T. W., Hu, F., Brown, A. P., Sun, A., Liotta, D. C., Snyder, J. P., Yoon, Y., Shim, H., Marcus, A. I., Miller, A. H., & Pace, T. W. W. (2012). 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. International immunopharmacology, 12(2), 368-377. https://doi.org/10.1016/j.intimp.2011.12.009

Olivera, A, Moore, TW, Hu, F, Brown, AP, Sun, A, Liotta, DC, Snyder, JP, Yoon, Y, Shim, H, Marcus, AI, Miller, AH & Pace, TWW 2012, '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', International immunopharmacology, vol. 12, no. 2, pp. 368-377. https://doi.org/10.1016/j.intimp.2011.12.009

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title = "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 analogs with enhanced activity on NF-κB and other inflammatory signaling pathways have been developed including the synthetic monoketone compound 3,5-Bis(2-fluorobenzylidene)-4-piperidone (EF24). 3,5-Bis(2- pyridinylmethylidene)-4-piperidone (EF31) is a structurally-related curcumin analog 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 (1-100 μM) or vehicle (DMSO 1%) for 1 h. NF-κB pathway activity was assessed following treatment with lipopolysaccharide (LPS) (1 μg/mL). EF31 (IC 50 ∼ 5 μM) exhibited significantly more potent inhibition of LPS-induced NF-κB DNA binding compared to both EF24 (IC 50 ∼ 35 μM) and curcumin (IC 50 > 50 μM). In addition, EF31 exhibited 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, EF31 (IC 50 ∼ 1.92 μM) exhibited significantly greater inhibition of IκB kinase β compared to EF24 (IC 50 ∼ 131 μM). 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 analog for further therapeutic development.",

keywords = "Anti-cancer, Curcumin, Inflammation, Macrophages, NF-κB",

author = "Anlys Olivera and Moore, {Terry W.} and Fang Hu and Brown, {Andrew P.} and Aiming Sun and Liotta, {Dennis C.} and Snyder, {James P.} and Younghyoun Yoon and Hyunsuk Shim and Marcus, {Adam I.} and Miller, {Andrew H.} and Pace, {Thaddeus W.W.}",

note = "Funding Information: This work was supported by the National Institutes of Mental Health [Grants R21MH085210 , and F31MH085460 (to T.W.W.P. and A.O., respectively)], the National Institute of Health [Grants R21CA82995-01A1 , 1P50CA128613 , and R01CA109366 (to M.S., J.D., and H.S., respectively)], the U.S. Department of Defense, Division of U.S. Army [Grants DAMD170010241 , and 1U54HG003918 (to M.S. and J.P.S., respectively)], and the Emory Institute for Drug Discovery .",

year = "2012",

month = feb,

doi = "10.1016/j.intimp.2011.12.009",

language = "English (US)",

volume = "12",

pages = "368--377",

journal = "International immunopharmacology",

issn = "1567-5769",

publisher = "Elsevier B.V.",

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TY - JOUR

T1 - Inhibition of the NF-κB signaling pathway by the curcumin analog, 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31)

T2 - Anti-inflammatory and anti-cancer properties

AU - Olivera, Anlys

AU - Moore, Terry W.

AU - Hu, Fang

AU - Brown, Andrew P.

AU - Sun, Aiming

AU - Liotta, Dennis C.

AU - Snyder, James P.

AU - Yoon, Younghyoun

AU - Shim, Hyunsuk

AU - Marcus, Adam I.

AU - Miller, Andrew H.

AU - Pace, Thaddeus W.W.

N1 - Funding Information: This work was supported by the National Institutes of Mental Health [Grants R21MH085210 , and F31MH085460 (to T.W.W.P. and A.O., respectively)], the National Institute of Health [Grants R21CA82995-01A1 , 1P50CA128613 , and R01CA109366 (to M.S., J.D., and H.S., respectively)], the U.S. Department of Defense, Division of U.S. Army [Grants DAMD170010241 , and 1U54HG003918 (to M.S. and J.P.S., respectively)], and the Emory Institute for Drug Discovery .

PY - 2012/2

Y1 - 2012/2

N2 - 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 analogs with enhanced activity on NF-κB and other inflammatory signaling pathways have been developed including the synthetic monoketone compound 3,5-Bis(2-fluorobenzylidene)-4-piperidone (EF24). 3,5-Bis(2- pyridinylmethylidene)-4-piperidone (EF31) is a structurally-related curcumin analog 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 (1-100 μM) or vehicle (DMSO 1%) for 1 h. NF-κB pathway activity was assessed following treatment with lipopolysaccharide (LPS) (1 μg/mL). EF31 (IC 50 ∼ 5 μM) exhibited significantly more potent inhibition of LPS-induced NF-κB DNA binding compared to both EF24 (IC 50 ∼ 35 μM) and curcumin (IC 50 > 50 μM). In addition, EF31 exhibited 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, EF31 (IC 50 ∼ 1.92 μM) exhibited significantly greater inhibition of IκB kinase β compared to EF24 (IC 50 ∼ 131 μM). 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 analog for further therapeutic development.

AB - 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 analogs with enhanced activity on NF-κB and other inflammatory signaling pathways have been developed including the synthetic monoketone compound 3,5-Bis(2-fluorobenzylidene)-4-piperidone (EF24). 3,5-Bis(2- pyridinylmethylidene)-4-piperidone (EF31) is a structurally-related curcumin analog 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 (1-100 μM) or vehicle (DMSO 1%) for 1 h. NF-κB pathway activity was assessed following treatment with lipopolysaccharide (LPS) (1 μg/mL). EF31 (IC 50 ∼ 5 μM) exhibited significantly more potent inhibition of LPS-induced NF-κB DNA binding compared to both EF24 (IC 50 ∼ 35 μM) and curcumin (IC 50 > 50 μM). In addition, EF31 exhibited 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, EF31 (IC 50 ∼ 1.92 μM) exhibited significantly greater inhibition of IκB kinase β compared to EF24 (IC 50 ∼ 131 μM). 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 analog for further therapeutic development.

KW - Anti-cancer

KW - Curcumin

KW - Inflammation

KW - Macrophages

KW - NF-κB

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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

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