Plant derived inhibitors of NF-κB Avi Golan

Plant derived inhibitors of NF-κB
Avi Golan-Goldhirsh & Jacob Gopas
Phytochemistry Reviews
Fundamentals and Perspectives of
Natural Products Research
ISSN 1568-7767
Volume 13
Number 1
Phytochem Rev (2014) 13:107-121
DOI 10.1007/s11101-013-9293-5
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Author's personal copy
Phytochem Rev (2014) 13:107–121
DOI 10.1007/s11101-013-9293-5
Plant derived inhibitors of NF-jB
Avi Golan-Goldhirsh • Jacob Gopas
Received: 3 January 2013 / Accepted: 11 April 2013 / Published online: 19 April 2013
Ó Springer Science+Business Media Dordrecht 2013
Abstract Plant secondary metabolites (natural products) have been a source for many of our medicines.
Their functions in plants remain often unknown, but in
recent years there are more and more new compounds
isolated and identified and their medicinal potential
investigated. The major classes of plant natural
products and various derivatives thereof are: phenolics, terpenoids, alkaloids and lignans. The major
transcription factor, nuclear factor-jB (NF-jB) is a
central downstream regulator of inflammation, cell
proliferation and apoptosis that controls the expression
of more than 500 genes. It plays an essential role in
several aspects of human health including the development of innate and adaptive immunity. The deregulation of NF-jB is associated with many ailments
including cancer and chronic inflammatory diseases.
In spite of a vast literature describing NF-jB inhibitors
A. Golan-Goldhirsh (&)
French Associates Institute for Agriculture and
Biotechnology of Drylands, Albert Katz Department of
Dryland Biotechnologies, The Jacob Blaustein Institutes
for Desert Research, Ben Gurion University of the Negev,
Sede Boqer Campus, 84990 Midreshet Ben Gurion, Israel
e-mail: [email protected]
J. Gopas (&)
The Shraga Segal Department of Microbiology and
Immunology and Genetics, Faculty of Health Sciences
and Laboratory of Oncology, Soroka University Medical
Center, Ben Gurion University of the Negev,
84105 Beer Sheva, Israel
e-mail: [email protected]
from many natural or synthetic sources, such modulators have not been fully tapped for therapeutic
purposes and the search for effective and specific
inhibitors for therapeutic use and minimal side effects
is still relevant and ongoing. Plant-derived phytochemicals are promising lead compounds to develop
potent and safe inhibitors for cancer and inflammatory
disorders driven by NF-jB. We briefly review the
recent knowledge on plant derived phytochemicals
and their major NF-jB molecular targets.
Keywords Cancer Inflammation NF-jB Phytochemicals
Abbreviations
AMPK
Adenosine monophosphate- activated
protein kinase
AKT
Protein Kinase B
CBP
CREB binding protein
COX
Cyclooxygenase
CXCR CXC Chemokine receptor
EGF
Epidermal growth factor
ERK
Extracellular signal-regulated kinase
FAK
Focal adhesion kinase
IAP
Inhibitor of apoptosis
ICAM
Intracellular adhesion molecule
IjB
Inhibitor of NF-jB
IKK
Inhibitor of NF-jB Kinase
IL-1
Interleukin-1
LPS
Lipopolysacharide
MAPK
Mitogen-activated protein kinase
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108
MMP
PI3K
RHD
ROS
c-T3
TBP
TLR
TNF
TNFR
VEGF
XIAP
Phytochem Rev (2014) 13:107–121
Matrix metalloproteinase
Phosphoinositide 3-kinase
REL homology domain
Reactive oxygen species
c-tocotrienol
TATA binding protein
Toll-like receptor
Tumor necrosis factor
Tumor necrosis factor receptor
Vascular endothelial factor
X-linked inhibitor of apoptosis protein
Targeting NF-jB pathways by phytochemicals
The nuclear factor-jB (NF-jB) family of transcription
factors regulates the expression of hundreds of genes
that are associated with diverse cellular processes,
such as proliferation, differentiation and death, as well
as innate and adaptive immune responses.
The area of research involving NF-jB has grown
tremendously in the past decade. This is evident from
the fact that although NF-jB was discovered only
25 years ago (Sen and Baltimore 1986) and is one of
approximately 2,000 estimated transcription factors in
humans (GuhaThakurta 2006), approximately 10 % of
research articles listed in PubMed on the subject of
transcription factors are associated with NF-jB.
NF-jB is constitutively active in many cancers, and
many of the signaling pathways implicated, are likely
to be networked to its activation (Chaturvedi et al.
2011). NF-jB can be modulated by diverse stimuli and
by highly networked pathways, therefore suggesting a
multi-targeted approach in anti-inflammation and anticancer therapies. Plant derived molecules that are in
focus of this review, target multiple steps in the NF-jB
pathways are emerging as promising agents for the
prevention and treatment of cancers. NF-jB plays a
major role in inflammation, immune reactions and
carcinogenesis (Baker et al. 2011; Perkins 2012) as
well as in related diseases that are not yet well defined
in molecular terms such as fatigue, depression, sleepdisorders etc., (Gupta et al. 2011b). Therefore, NF-jB
is considered an important target for therapeutic
modulation by synthetic and natural new drugs
(Gilmore and Herscovitch 2006; Gupta et al. 2010a).
The diversity of molecular targets for the same
phytochemical complicates the understanding of the
123
cellular mechanism of action and yet may be effective
in therapy. Several major common drugs used in the
clinic are originally phytochemicals that have been
discovered from plant extracts, like aspirin from
willow bark, taxol from Pacific yew and metformin
from French lilac. The potential of plants as a source of
medicines is at its infancy and there are thousands of
compounds that have not been identified yet that can
be used directly or as lead structures for modification
and organic synthesis of new drugs. There have been a
few comprehensive recent reviews covering natural
products at large, which inhibit/modulate NF-jB by
Salminen et al. (2012), Chen (2011) and Gupta et al.
(2010b). In this article we review most of the
compounds derived solely from plants, since these
reviews were published. A summary of the recent
plant derived inhibitors of NF-jB is presented in
Table 1. In several cases like with Kahweol, compounds that seemed to have a potentially important
effect, but were not cited again since they were first
published in the context of NF-jB were added. Also
extract mixtures of e.g., phenolics (ADEE) or of
sesquiterpenoid lactones, which provide either new or
better understanding of the mechanism of action of
these groups of compounds, were included. The table
is arranged according to the major chemical classes of
plant secondary metabolites and alphabetically within
each group. The largest group of inhibitors is the
phenolic with 22 out 59 (1–22, Table 1), 5 quinones
(23-27, Table 1) 21 isoprenoids and derviatives
(28–48, Table 1), 7 alkaloids (49–55, Table 1), and
4 others (56–59, Table 1). The table provides information about plant species and family origin of the
compound, plant tissue from which the compound was
isolated, a brief note about the reported mode of action
and a recent reference (not all recent references could
be included because of size limitations of the review).
Many of the major secondary metabolites of plants
(phytochemicals), phenolic, isoprenoids and alkaloids
possess significant therapeutic properties including
anti-inflammatory and anti-cancer effects. They are
differentially distributed among limited taxonomic
groups in the plant kingdom. Among the 59 compounds reviewed in this paper only the Asteraceae
family had 5 compounds in various species, 21
families had one compound, 3 families had 2 compounds, 6 families had 3 compounds and 2 families
had 4 compounds. Most of these molecules showed an
inhibitory effect on the expression of NF-jB. More
Active compounds
ADEE
Anacardic acid
Butein
Cardamonin
Carnosic acid
Carnosol
Catechin
Cudraflavone B
Curcumin
(Curcuminoids)
No.
1
2
3
4
5
6
7
8
9
Phenolics (mixture)
Phenolic, prenylated flavone
Phenolic, flavan-3-ol
Phenolic diterpenoid
Phenolic, benzenediol
abietane diterpenoid
Phenolic, chalconoid
Phenolic, mixture of
cumarins, phellopterin,
isoimperatorin,
imperatorin,
alloimperatorin,
byakangelicin,
isooxypeucedanin, and
pimpinellin (Ethanolic
extract)
Phenolic acid, derivative of
salicylic acid
Phenolic, chalconoid
Chemical class
Table 1 Plant derived NF-jB inhibitors
Curcuma domestica and
Curcuma longa
(Zingiberaceae)
Camellia sinensis
(Theaceae), other fruits
and vegetables
Morus alba (Moraceae)
Rosmarinus officinalis
(Lamiaceae)
Anacardium occidentale
(Anacardiaceae)
Toxicodendron vernicifluum
(Anacardiaceae)
Alpinia rafflesiana
(Zingiberaceae) and other
species in the family
Rosmarinus officinalis
(Lamiaceae)
Angelica dahurica
(Apiaceae)
Plant species (Family)
Rhizome
Root
Leaves and other
plant organs
Leaves
Leaves
Fruit
Shell of cashew
nut
Stem
Root
Plant tissue
Inhibition of the translocation of
NF-jB to the nucleus in
macrophages
Inhibition of IjBa
phosphorylation and p65
phosphorylation and
acetylation and nuclear
translocation
Blocked the nuclear
translocation of NF-jB and its
upstream signaling including
Syk/Src, phosphoinositide
3-kinase (PI3 K), Akt, IKK
and IjBa
Pretreatment abolishes NF-jB
translocation and
transcriptional activity
Down-regulation the expression
of NF-jB
Down-regulation of NF-jB.
Synergistic to Lunasin peptide
Suppress NF-jB, attenuates
VEGF, MMP-9 activities
Attenuated NF-jB DNA
binding activity
Inhibited NF-jB translocation
to the nucleus by IjBa
degradation
Mechanism of action
Buhrmann et al.
(2011)
Hosˇek et al.
(2011)
Bharrhan et al.
(2011)
Lian et al. (2010)
Oh et al. (2012)
Hsieh, et al.
(2011)
Moon et al.
(2010a)
Chow et al.
(2012)
Lee et al. (2011)
Reference
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123
123
DEDC
Epigallocatechin
gallate
Hesperitin
metabolites
10
11
Isoliquiritigenin
Luteolin
Naringenin
Piceatannol
Quercetin
Quince polyphenols
Resveratrol
13
14
15
16
17
18
19
12
Active compounds
No.
Table 1 continued
Phenolic, stilbenoid
Phenolics
Phenolic, flavonol
Camellia sinensis
(Theaceae), other fruits
and vegetables
Cydonia oblonga Miller
(Rosaceae)
Vitis vinifera (Vitaceae)
Picea abies (Pinaceae)
Citrus 9 paradisi
(Rutaceae)
Apium graveolens
(Apiaceae) and other
species
Glycyrrhiza glabra
(Fabaceae)
Camellia sinensis
(Theaceae)
Citrus genus (Rutaceae)
Macrothelypteris torresiana
(Gaud.)
(Thelypteridaceae)
Plant species (Family)
Fruit skin
Fruit peel
Leaves and other
plant organs
Root
Fruit
Leaves
Root
Fruit
Leaves
Root
Plant tissue
Inhibited the LPS-mediated
activation of NF-jB
Decreased the expression of p65
and IjB-a in treated rats
Activated NF-jB. Induced
apoptosis via ROS.
Suppressing NF-jB pathway
by pyrrolidine
dithiocarbamate significantly
increased neuroblastoma cell
sensitivity to the pro-apoptotic
effect of DEDC
Down-regulation of NF-kB,
c-Jun and caspase-3
Down-regulated LPS-induced
NF-kB activation followed by
suppression of IjB
degradation and
phosphorylation of c-Jun
N-terminal kinase1/2 (JNK1/
2) and p38 MAPKs
Inhibited LPS-induced TLR4
dimerization resulting in
inhibition of NF-jB
Produced intracellular ROS in
turn mediate AMPK-NF-jB
signaling in HepG2
hepatocarcinoma cells
Down-regulated ROS
production and inhibited NFjB activity via EGFR-PI3KAkt/ERK MAPKinase
signaling pathway
Supressed TNFa shedding,
leading to inhibition of TNFa/
NFjB pathway
Modulated the NF-jB p65
nuclear translocation
Mechanism of action
Essafi-Benkhadir
et al. (2012)
Kumar and
Sharma (2010)
Bhaskar et al.
(2011)
Liu and Chang
(2012)
Yang et al.
(2011)
Hwang et al.
(2011)
Park and Youn
(2010)
Giakoustidis et al.
(2008)
Yang et al.
(2012)
Liu et al. (2012)
Reference
110
Phenolic, stilbenoid
Phenolic, flavanone
Phenolic, flavonoid
Phenolic, licorice
chalconoid
Phenolic, catechin esterified
to gallic acid
Phenolic, flavanones
Phenolic, flavonoid
Chemical class
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Active compounds
Rosmarinic acid
Wedelolactone
Xanthohumol
Embelin
Citreorosein
Isoeleutherin
Plumbagin
Thymoquinone
Artemisinin
Bharangin
No.
20
21
22
23
24
25
26
27
28
29
Table 1 continued
Diterpenoid quinonemethide
Sesquiterpenoid lactone
Quinone
Naphtoquinone
Naphtoquinone
Anthroquinone
Benzoquinone
Phenolic, prenylated
chalconoid
Phenolic, coumestan
Phenolic, flavonoid
Chemical class
Premna herbacea
(Lamiaceae)
Eleutherine bulbosa
(Miller)(Iridaceae)
Plumbago zeylanica
(Plumbaginaceae) also in
Droseraceae,
Ancestrocladaceae, and
Dioncophyllaceae families
Nigella sativa
(Ranunculaceae)
Artemisia annua
(Asteraceae)
Polygoni cuspidati
(Polygonaceae)
Embelia ribes Burm.,
(Myrsinaceae)
Eclipta alba and Wedelia
calendulacea (Asteraceae)
Humulus lupulus
(Cannabaceae)
Rosmarinus officinalis
(Lamiaceae)
Plant species (Family)
Root
Above ground
organs
Inhibited phosphorylation and
degradation of IjBa and the
nuclear translocation of the
NF-jB p65 subunit
Abolished constitutive and
Inducible NF-jB activation by
modifying p65 on cysteine 38
and reduced IjBa kinase
activation, inhibited binding
of p65 to DNA
NF-jB inhibitor
Seed
Root
Bulb
Root
Basal levels of FAK, AKT and
NF-jB signaling pathways
were down-regulated
Suppressed NF-jB activation
and inhibition of IjBa
phosphorylation and IjBa
degradation
Inhibited NF-jB p65 subunit
and its cognate DNA-binding
activity
Inhibits transcriptional
activation by LPS
Inhibited phosphorylation and
DNA-binding activity of NFjB. Binds cys38 in p65.
Activation was also reported
Inhibited TNF-a-induced ROS
generation and NF-jB
activation, and enhances TNFa induced apoptosis
Selective IjB kinase inhibitor
Mechanism of action
Female
inflorescence
(Hops)
Fruit
Stem
Leaves
Plant tissue
Gupta et al.
(2011a)
Connelly et al.
(2011)
Wang et al.
(2011)
Hafeez et al.
(2012)
Subramaniya
et al. (2011)
Song et al. (2009)
Lu et al. (2012)
Reuter et al.
(2010a)
Zhang et al.
(2012)
Benelli et al.
(2012)
Moon et al.
(2010b)
Reference
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123
123
Sesquiterpenoid
b-Caryophyllene
Celastrol
Diosgenin
Escin
Ginsenoside Rg3
Ginsenoside Rh2
Impressic acid
Kahweol
Lupeol
Lycopene
30
31
32
33
34
35
36
37
38
39
Tetraterpenoid, carotenoid
Triterpenoid
Solanum lycopersicum
(Solananceae)
Mangifera indica
(Anacardiaceae) and other
species
Acanthopanax koreanum
(Araliaceae)
Coffea arabica (Rubiaceae)
Panax ginseng (Araliaceae)
Panax ginseng (Araliaceae)
Dioscorea althaeoides
Knuth (Dioscoreaceae)
and other species
Aesculus hippocastanum
(Sapindaceae)
Tripterygium wilfordii
(Celastraceae)
Piper nigrum (Piperaceae)
and other species
Plant species (Family)
Fruit
Fruit
Seed
Leaves
Root
Root
Seed
Tuber
Root
Fruit
Plant tissue
Inhibited tumor TNF-a induced
NF-jB activity
Inhibited NF-jB-dependent
transcriptional activity
Inhibited cell survival by
inactivation of NF-jB through
upregulation of its inhibitor
Ijba
Inhibited activation of NF-jB
Inhibited activation of NF-jB
through inhibition of IKK,
leading to down-regulation of
NF-jB regulated cell survival
and metastatic gene products,
resulting in sensitization of
cells to cytokines and
chemotherapeutic agents
Enhanced susceptibility of
colon cancer cells to
Docetaxel
Decreased p65
Inhibited the activation of
extracellular signal-regulated
kinase 1/2, NF-jB, IjBkinase a/b, cAMP response
element binding and the
expression of caspase-3 and
Ki-67
Induced ROS. Inhibited IjBa
kinase activation,
phosphorylation of IjBa and
p65
Decreased induced NF-jB
Mechanism of action
Bae and Bae
(2011)
Prasad et al.
(2009)
Kim et al. (2006)
Kim et al. (2011)
Bi et al. (2012)
Kim et al. (2009)
Harikumar et al.
(2010a)
Jung et al. (2010)
Kannaiyan et al.
(2011)
Bento et al.
(2011)
Reference
112
Diterpenoid
Triterpene glycoside,
Steroidal saponin
Lupane-type triterpenoid
Triterpene glycoside
Pentacyclic tritepenoid
Terpenoid, Steroidal saponin
Triterpenoid acid, Quinone
methide
Chemical class
Active compounds
No.
Table 1 continued
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Active compounds
Maslinic acid
Nimbolide
NUP
Parthenolide
Picroliv
Santamarin
Sesquiterpene
lactones
c-Tocotrienol
No.
40
41
42
43
44
45
46
47
Table 1 continued
Germacranolides,
heliangolides,
guaianolides,
pseudoguaianolides,
hypocretenolides,
eudesmanolides
Isoprenoid, Vitamin E
derivative
Sesquiterpene lactone
Terpenoid, iridoid glycoside
Thio alkaloid-sesqui
terpenelactones. A mixture
of nupharidines and other
unidentified compounds
Sesquiterpene lactone
Tetranortriterpenoid
Pentacyclic triterpenoidic
acid
Chemical class
Found in several food
plants, found in rice,
barley, oats, and palm
Picrorhiza kurrooa
(Scrophulariaceae)
Saussurea lappa C.B.
Clarke (Asteraceae)
Various species of
Asteraceae
Tanacetum parthenium
(Asteraceae)
Azadirachta indica A. Juss
(Meliaceae)
Nuphar lutea (Nymphaceae)
Olea europaea (Oleaceae)
Plant species (Family)
Fruit
Various organs
Root
Root
Leaves
Leaves and
flowers
Leaf and rhizome
Fruit skin
Plant tissue
Inhibited NF-jB activation by
c-T3 and a suppression of key
cellular regulators. Inhibited
the growth of human
pancreatic tumors and
sensitized them to
gemcitabine by suppressing
NF-jB–mediated
inflammatory pathways linked
to tumorigenesis
Inhibited phosphorylation of
IjB
Alkylating cysteine38 in the
DNA binding domain of the
p65. 103 compounds that
showed anti-NF-jB activity
are detailed
Suppressed TNFa-induced NFjB activation, inhibited
TNFa-induced IjBa
degradation, p65
phosphorylation, and nuclear
translocation. Decreased the
expression NF-jB regulated
genes
Abrogated canonical NF-jB.
Inhibitd binding to DNA
Down-regulated NF-jB and
induced apoptosis. Activated
NF-jB in Leishmania infected
cells
NF-jB- and STAT-inhibitionmediated transcriptional
suppression of pro-apoptotic
genes. Acted at the
transcriptional level and by
direct inhibition of IKK-b
Binds cys38 in p65
Mechanism of action
Kunnumakkara
et al. (2010)
Siedle et al.
(2004)
Anand et al.
(2008)
Choi et al. (2012)
Mathema et al.
(2011)
Kavitha et al.
(2012)
Ozer et al. (2009,
2010)
Li et al. (2010)
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123
Active compounds
Triptolide
Berbamine
Berberine
Cepharanthine
Cryptopleurine
Dauricine
Noscapine
Sinomenine
Butylidene-phthalide
(BP)
Crotepoxide
Thiocolchicoside
Sesamin
No.
48
49
50
51
52
53
54
55
56
57
58
59
Table 1 continued
123
Lignan
Glucoside
Cyclohexane diepoxide
Angelica sinensis
(Apiaceae)
Kaempferia pulchra
(Zingiberaceae)
Gloriosa superba
(Colchicaceae)
Sesamum indicum
(Pedaliaceae)
Papaver somniferum
(Papaveraceae)
Sinomenium Acutum
(Menispermaceae)
Berberis amurensis
(Berberidaceae)
Berberis aquifolium
(Berberidaceae) and other
species
Stephania cepharantha
Hayata (Menispermaceae)
Boehmeria pannosa
(Urticaceae)
Menispermum dauricum
DC. (Menispermaceae)
Tripterygium wilfordii
Hook.f (Celastraceae)
Plant species (Family)
Root, seed and
other plant parts
Seed
Rhizome
Root
Root
Seed
Rhizome
Root
Leaves
Roots, rhizome,
stems and bark
Roots, rhizome,
stems and bark
Various organs
Plant tissue
Inhibited NF-jB and NF-jB–
regulated gene products
Suppressed pathways linked to
the NF-jB signaling
Inhibited NF-jB activation by
inhibiting the IKK pathway
Inhibited NF-jB activation
pathway
Suppressed NF-jB activity and
the expression profile of its
down-stream genes
Suppressed the NF-jB signaling
pathway
Decrease the mRNA expression
of TNF-a by inhibiting the
NF-jB) binding activity
Suppressed NF-jB-dependent
pathways
Suppressed NF-jB expression
Suppressed constitutive and
inducible NF-jB activation,
but did not directly inhibit
binding of p65 to the DNA. It
did block TNF-induced
ubiquitination,
phosphorylation, and
degradation of IjBa, and
inhibited acetylation of p65
through suppression of
binding of p65 to CBP/p300.
It also inhibited IKK and
phosphorylation of p65 at
serine 276, 536.
Inhibited NF-jB and
phosphorylation of IjBa
Inhibition of IjB
phosphorylation
Mechanism of action
Prasad et al.
(2010)
Reuter et al.
(2010b)
Harikumar et al.
(2010b)
Fu et al. (2011)
Chai et al. (2012)
Sung et al. (2010)
Yang et al.
(2010)
Kudo et al.
(2011)
Jin et al. (2012)
Liang et al.
(2009)
Goto et al. (2012)
Park et al. (2011)
Reference
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Phtalide derivative
Alkaloid
Benzylisoquinoline alkaloid
Phenanthroquinolizidine
alkaloid
Alkaloid
Alkaloid
Isoquinoline alkaloid
Isoquinoline alkaloid
Diterpenoid triepoxide
Chemical class
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than 700 natural products affecting NF-jB activation
pathways were recently reported by Gupta et al.
(2010b), including antioxidants, peptides, small
RNA/DNA, microbial and viral proteins, small molecules, and engineered dominant-negative or constitutively active polypeptides.
The underlying hypothesis in this review is that
natural plant derived molecules have a better potential
than synthetic ones to fit and interact with macromolecules in humans and animals, since they underwent
the evolutionary screening to fit metabolic targets in
living organisms, because of molecular conservation
and commonality among them.
The centrality of NF-jB in cell cycle and metabolism makes its regulation quite complex. One can
envision NF-jB in the focus of several pathways of
regulation that affect its expression (DiDonato et al.
2012). NF-jB modulators in the cell include protein
kinases, protein phosphatases, ubiquitination and
protein degradation, acetylation, methylation, nuclear
translocation and DNA binding (Fig. 1). Thus it is
clear that phytochemicals may inhibit NF-jB by direct
binding and/or indirectly through modulating
enzymes. Ideally, the search for natural inhibitors of
NF-jB, should seek specificity for the isoenzymes
directly involved in its metabolic processing. This
Fig. 1 Schematic presentation of the major NF-jB activation
pathways. The regulatory targets, at which the different classes
of the compounds act are shown, based on the following
categories: upstream signaling; IKK modulation; IkB modulation and translocation; NF-jB nuclear translocation; NF-jB
modulation; NF-jB transcription activity (for compounds in
each category see text and Table 1). In the classical pathway,
binding to cell membrane receptors triggers the sequential
recruitment of adaptor proteins according to the type of stimuli
and cell type. The adaptor proteins recruit and activate the IKK
complex which in turn leads to the phosphorylation and
ubiquitination of IjB, followed by its degradation via the
proteasome pathway. The heterodimer p50-p65 is then released
and migrates to the nucleus where it undergoes a series of
posttranslational modifications and binding to jB sites which
enable transcription of target genes. The alternative pathway
activates the IKKa dimer inducing the processing of p100 to the
release of p52 which together with RELB translocate to the
nucleus, triggering transcription of NF-jB target genes.
Individual plant derived molecules can inhibit one or more of
the main NF-jB activation crossroads
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116
opens-up potentially many targets to modulate the
expression of NF-jB with therapeutic application.
The NF-jB signaling pathway
Detailed descriptions of the NF-jB pathway can be
found in a series of excellent recent reviews (DiDonato et al. 2012; Ghosh and Hayden 2012; Perkins
2012,), it is worth highlighting a few key principles to
reiterate the concept of regulatory complexity and the
effect of phytochemicals on components of this
pathway.
There are five subunits that make-up the mammalian NF-jB complex family, which all share a related
DNA-binding and dimerization domain, termed the
REL homology domain (RHD). The carboxy termini
of Rel A (p65), REL B, and REL (c-Rel) all contain
transactivation domains, which are capable of mediating interactions with basal transcription factors and
cofactors such as TATA binding protein (TBP),
TFIIB, E1A binding protein 300KD (p300) and CREB
binding protein (CBP). The other two family members, NF-jB1 (p105) and NF-jB2 (p100) encode
longer precursor proteins to the active DNA-binding
forms p50 and p52, respectively (Fig. 1). NF-jB
activation constitutes a rapidly inducible first line of
defense against infection and stress. Before exposure
to an inducing stimulus, NF-jB is kept in the inactive
state in the cytosol. To keep NF-jB in this inactive
state there exist a family of inhibitors of NF-jB
(IjBs). Typically, IjBs bind to NF-jB complexes,
inhibiting their translocation to the nucleus and
binding to DNA. Stimulation is achieved through the
phosphorylation of the IjBs by the IjB kinase (IKK)
complex, promoting their ubiquitination and proteosome-mediated degradation with consequent NF-jB
translocation to the nucleus and localization at
selected promoters on DNA, binding to accessory
proteins and enabling gene transcription. NF-jB
activity is modulated through p65 phosphorylation,
acetylation and methylation. In addition, IjB can
localize to the nucleus, bind to and remove NF-jB
complexes from selected promoter DNA and enable
NF-jB to be recaptured in the cytosol.
NF-jB signaling is generally considered to occur
through either the canonical (classical) or non-canonical (alternative pathway) pathways. Numerous and
diverse stimuli can induce the classical NF-jB
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Phytochem Rev (2014) 13:107–121
activity. Typical inducers of NF-jB include cytokines
such as tumor necrosis factor (TNF), interleukin-1
(IL-1), viral and bacterial products such as lipopolysaccharide (LPS), which can induce Toll-like receptor
(TLR) signaling and cellular stress, such as DNA
damage, reactive oxygen species (ROS) and hypoxia.
Most of these inducers converge on IKKa, b dimers
(Fig. 1). The non-canonical pathway is activated
through receptor signaling and IKKa, a dimer activation enabling the processing of protein precursors to
form the active p50/p52 dimers. This pathway is
essential for the proper development of secondary
lymphoid organs. Most inhibitors affect the canonical
pathway and some both pathways. Thus, the NF-jB
response is highly pleiotropic and the consequences of
its activation can be context dependent.
In the physiological state, an NF-jB response is
automatically self-limiting, through the induction of
negative feedback loops including the transcription of
IjBs together with the expression of proteins that
negatively regulate the signaling pathways leading to
IKK activation, such as A20. However, NF-jB
activity becomes deregulated in cancer and chronic
inflammatory diseases. This can occur either through
mutations leading to high levels of IKK- NF-jB
signaling or through continuous exposure to NF-jBactivating external stimuli, such as systemic or tissue
microenvironment cytokine release.
Crosstalk with other signaling pathways such as
PI3K, may result in activation of AKT and MAPK
signaling converging in IKK. Moreover, tumor-supressor proteins, such as p53, provide an important
mechanism for regulating NF-jB activity. These pathways combine to determine the normal physiological
role of NF-jB as well as in disease, in tumorigenesis,
resistance to apoptosis, determining response to chemotherapy and in chronic inflammation.
Inhibitors of the NF-jB activation pathways
Most of the compounds described in table 1 are either
phenolics or terpenoids (each approximately 37 %).
Quinones and alkaloids are also represented among
the inhibitors of NF-jB via various pathways. One or
two representatives of other chemical families are also
present such as phtalides, cyclohexanes, glucosides
and lignans. Active compounds have been reported in
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Phytochem Rev (2014) 13:107–121
different organs of the plant: root, tuber, rhizome, leaf,
stem, bark fruit and seed. The same activity may be
found in some organs in the same plant but not in all of
them (Table 1). The season when the plant was
harvested may also affect the level of biological
activity.
Some compounds have been thoroughly investigated and several targets and mechanisms of action
have been extensively described (i.e. curcumin, lycopene, parthenolide etc.). In contrast, the NF-jBrelated mode of action of other phytochemicals is
starting to be examined (i.e., Cudraflavone B, Plumbagin, Nimbolide etc.). Thorough investigation of the
mode of action and specificity of a compound showing
effect on NF-jB will determine if a molecule has
multiple targets or has limited specificity. Both types
of compounds should be therapeutically useful as
single agents or in combination, together with other
lines of treatment. In addition to a direct effect on
NF-jB, inhibitors may be given together with standard
anti-cancer drugs or radiotherapy, acting as ‘‘sensitizers’’ or as inhibitors of multidrug resistance (Nakanishi and Toi 2005). It is worth noting that sometimes
in purification of an active compound from a plant
extract the specific activity declines as purification
progresses. This may indicate loss of activity by losing
compounds acting synergistically or complementarily.
Therefore, we have included in this review, recently
reported mixtures of cumarins (ADEE), hesperitin
metabolites, quince polyphenols extract, sesquiterpenoid lactones and a partially purified nuphridines extract
(NUP) from Nuphar lutea. It could well be that a mixture
of derivatives of a given compound is more active than
any one specific compound in the mixture. Furthermore,
the naturally occurring derivatives can serve as lead
compounds for organic synthesis and search for new
more potent compounds.
In addition, it seems that different secondary
metabolite classes can modulate the same targets, for
example, quinones, as well as a variety of terpenoids
have been demonstrated to inhibit p65 through its
cystein 38 and IKK through cystein 179 (Table 1).
Upstream regulation of NF-jB depends on many
different molecules, which are triggered by an external
stimulus unique for the cell type involved. Thus,
upstream targets present an opportunity to detect
specific inhibitory substances of varied chemical
structures, for example, carnosic acid a phenolic
diterpenoid, blocks signaling through Syc/Src, PI3K
117
and Akt. Interestingly, citreorosein an anthroquinone
and naringenin a phenolic flavanone, both affect PI3K
and AKT signaling as well.
Gupta et al. (2010b) have thoroughly described the
different levels of regulation of NF-jB signaling by a
large number of natural products. In this review we
have focused only on recently published secondary
metabolites of plants (Table 1). In Fig. 1, we show
schematically the regulatory targets at which the
different classes of the compounds act, based on the
following categories:
Inhibition of upstream signaling Through TLR-4
(LPS induced) (isoliquiritigenin, butylidenephtalide);
modulation through reactive oxygen species (ROS)
(carnosic acid, celastrol, citreorosein, luteolin, naringenin, rosmarinic acid, sesamin); through inhibition
of TNF-a signaling (artemisinin, impressic acid,
maslinic acid, triptolide, sinomenine, NUP); through
ERK1/2 (b-caryophyllene).
IKK modulation usually by direct binding to Cys 179:
(piceatannol, wedelolactone, xanthohumol, embelin,
artemisinin, escin, impressic acid, maslinic acid, parthenolid, triptolide, sinomenine, cepharantine).
IjB modulation mainly by phosphorylation and
degradation, as well as IjB nuclear translocation
(ADEE, carnosic acid, resveratrol, embelin, artemisinin, bharangin, celastrol, santamarin, triptolide, berbamine, berberine).
NF-jB modulation anacardic acid, cardamonin,
hesperitin, isoliquiritigenin, quercetin, quince polyphenols, resveratrol, diosgenine, ginsenoside Rh2,
lupeol, nimbolide, NUP-(both classic and the alternative pathways), cryptopleurine, crotepoxide); through
Cys 38: (plumbagin, thymokinone, bharangin, parthenolide, picroliv, sesquiterpene lactones); through NFjB phosphorylation and acetylation: (carnosic acid,
curcumin, celastrol, diosgenin, triptolide).
NF-jB nuclear translocation (ADEE, carnosic
acid, carnosol, cudraflavone B, berbamine).
NF-jB DNA-binding activity (cardamonine, citreorosein, bharangin, lycopene, nimbolide, triptolide,
sinomenine).
NF-jB transcriptional activity (carnosol, cudraflavone B, kahweol, parthenolide, dauricine, c-tocotrienol, noscapine, thiocolchicoside).
NF-jB inhibition limiting cell survival (lupeol);
induction of apoptosis and caspase activation: (rosmarinic acid, NUP); sensitization of malignant cells to
anti-cancer drugs: (DEDC, NUP).
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118
Conclusions
The last 25 years have seen remarkable progress in
understanding of NF-jB structure–function relationship. Yet NF-jB as a therapeutic target has remained
largely unexploited in drug development for clinical
use. Therefore, one of the major challenges facing
researchers is to develop NF-jB inhibitors aimed at
treating different diseases based on their ability to
target specific pathways or cells. Development of
efficient NF-jB inhibitors which selectively target
core components of this pathway will also require the
careful establishment of a therapeutic correlation
between dose and target inhibition. Key points for
therapeutic intervention include targeting upstream
activators of IKK, IKK activation, IjB degradation,
NF-jB modifications, NF-jB DNA binding and
modulation of its transcriptional activity. Full realization of the therapeutic potential of the NF-jB pathway
lies within better understanding of its regulatory
complexity and the cell type and stimulus dependent
selective manipulation of its components. A comprehensive list of diseases where NF-kB is known to be
deregulated is presented in Kumar et al. (2004).
Preclinical established models for each disease should
be used to test hypotheses and pave the way to clinical
drug development.
In theory, an arsenal of therapeutic agents, natural
and synthetic, directed against well defined targets is
readily available and many more are continuously
added to the list. Phytochemicals represent an essential
source for potential drugs. Plants are the source for
complex molecules which can be on one hand
exquisitely target selective or pleiotropic, multitargets in their activity. Both, selective or pleiotropic
agents affecting NF-jB can also modulate other
pathways such as PI3K, AKT, MAPK, p53 etc.,
contributing an additional level of complexity and
therapeutic potential. The challenge ahead of us is to
choose the right combination of existing and newly
discovered molecules and determine their optimal
activity, time and concentration wise. Optimal protocols should be determined initially in vitro followed by
well established preclinical in vivo studies.
Acknowledgments The authors gratefully acknowledge
the support of the Israel Ministry of Health through the
Winkselbaum fund, the Israel Cancer Association through the
Miriam and Shlomo Hasid Memorial fund, ICA in Israel, Jacobs
foundation through BG-Negev and The Richard H. Holzer
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Phytochem Rev (2014) 13:107–121
Foundation. We thank Janet Ozer (M.Sc.) for assistance in
preparation of figure 1 and critical reading of the manuscript.
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