InsIghts Into the mechanIsm of natural terpenoIds as NF-κB InhIBItors: an overvIew on theIr antIcancer potentIal
The transcription factor, nuclear factor kappa B (NF-kB) is one of the principal inducible protein in mammals known to control the gene expression in many critical physiological responses such as oxidative stress, inflammation etc. and has been shown to play an important role in the pathogenesis of...
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
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irk-123456789-1377182018-06-18T03:06:09Z InsIghts Into the mechanIsm of natural terpenoIds as NF-κB InhIBItors: an overvIew on theIr antIcancer potentIal Jain, H. Dhingra, N. Narsinghani, T. Sharma, R. Reviews The transcription factor, nuclear factor kappa B (NF-kB) is one of the principal inducible protein in mammals known to control the gene expression in many critical physiological responses such as oxidative stress, inflammation etc. and has been shown to play an important role in the pathogenesis of cancer. Terpenoids are major constituents present in nutritionally used fruits, vegetables and different spices which possess various pharmacological action including anticancer activity. Various terpenoids, viz. monoterpenoids, sesquiterpenoids, diterpenoids, sesterterpenoids, triterpenoids, tetraterpenoids and polyterpenoids inhibit NF-kB signaling pathway through IkB phosphorylation, DNA binding, p65 translocation etc. Keeping in mind these facts, the present review revealed the anti-cancer potential of naturally occurring terpenoids highlighting their mechanism of NF-kB inhibition. This review also focuses on some of the naturally occurring terpenoids belonging to various chemical categories with potential inhibitory effects on NF-kB and their role in the treatment of cancer. 2016 Article InsIghts Into the mechanIsm of natural terpenoIds as NF-κB InhIBItors: an overvIew on theIr antIcancer potentIal / H. Jain, N. Dhingra, T. Narsinghani, R. Sharma // Experimental Oncology. — 2016 — Т. 38, № 3. — С. 158–168. — Бібліогр.: 86 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/137718 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Reviews Reviews Jain, H. Dhingra, N. Narsinghani, T. Sharma, R. InsIghts Into the mechanIsm of natural terpenoIds as NF-κB InhIBItors: an overvIew on theIr antIcancer potentIal Experimental Oncology |
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The transcription factor, nuclear factor kappa B (NF-kB) is one of the principal inducible protein in mammals known to control the gene expression in many critical physiological responses such as oxidative stress, inflammation etc. and has been shown to play an important role in the pathogenesis of cancer. Terpenoids are major constituents present in nutritionally used fruits, vegetables and different spices which possess various pharmacological action including anticancer activity. Various terpenoids, viz. monoterpenoids, sesquiterpenoids, diterpenoids, sesterterpenoids, triterpenoids, tetraterpenoids and polyterpenoids inhibit NF-kB signaling pathway through IkB phosphorylation, DNA binding, p65 translocation etc. Keeping in mind these facts, the present review revealed the anti-cancer potential of naturally occurring terpenoids highlighting their mechanism of NF-kB inhibition. This review also focuses on some of the naturally occurring terpenoids belonging to various chemical categories with potential inhibitory effects on NF-kB and their role in the treatment of cancer. |
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| author |
Jain, H. Dhingra, N. Narsinghani, T. Sharma, R. |
| author_facet |
Jain, H. Dhingra, N. Narsinghani, T. Sharma, R. |
| author_sort |
Jain, H. |
| title |
InsIghts Into the mechanIsm of natural terpenoIds as NF-κB InhIBItors: an overvIew on theIr antIcancer potentIal |
| title_short |
InsIghts Into the mechanIsm of natural terpenoIds as NF-κB InhIBItors: an overvIew on theIr antIcancer potentIal |
| title_full |
InsIghts Into the mechanIsm of natural terpenoIds as NF-κB InhIBItors: an overvIew on theIr antIcancer potentIal |
| title_fullStr |
InsIghts Into the mechanIsm of natural terpenoIds as NF-κB InhIBItors: an overvIew on theIr antIcancer potentIal |
| title_full_unstemmed |
InsIghts Into the mechanIsm of natural terpenoIds as NF-κB InhIBItors: an overvIew on theIr antIcancer potentIal |
| title_sort |
insights into the mechanism of natural terpenoids as nf-κb inhibitors: an overview on their anticancer potential |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| publishDate |
2016 |
| topic_facet |
Reviews |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/137718 |
| citation_txt |
InsIghts Into the mechanIsm of natural terpenoIds as NF-κB InhIBItors: an overvIew on theIr antIcancer potentIal / H. Jain, N. Dhingra, T. Narsinghani, R. Sharma // Experimental Oncology. — 2016 — Т. 38, № 3. — С. 158–168. — Бібліогр.: 86 назв. — англ. |
| series |
Experimental Oncology |
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2025-07-10T02:38:17Z |
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2025-07-10T02:38:17Z |
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| fulltext |
158 Experimental Oncology 38, 158–168, 2016 (September)
InsIghts Into the mechanIsm of natural terpenoIds
as nf-κB InhIBItors: an overvIew on theIr antIcancer
potentIal
H. Jain1, N. Dhingra2, T. Narsinghani1*, R. Sharma1
1School of Pharmacy, Devi Ahilya University, Takshashila Campus, Indore (Madhya Pradesh) 452001, India
2School of Life Science, Devi Ahilya University, Takshashila Campus, Indore (Madhya Pradesh) 452001, India
The transcription factor, nuclear factor kappa B (NF-kB) is one of the principal inducible protein in mammals known to control
the gene expression in many critical physiological responses such as oxidative stress, inflammation etc. and has been shown to play
an important role in the pathogenesis of cancer. Terpenoids are major constituents present in nutritionally used fruits, vegetables
and different spices which possess various pharmacological action including anticancer activity. Various terpenoids, viz. monoter-
penoids, sesquiterpenoids, diterpenoids, sesterterpenoids, triterpenoids, tetraterpenoids and polyterpenoids inhibit NF-kB signa-
ling pathway through IkB phosphorylation, DNA binding, p65 translocation etc. Keeping in mind these facts, the present review
revealed the anti-cancer potential of naturally occurring terpenoids highlighting their mechanism of NF-kB inhibition. This review
also focuses on some of the naturally occurring terpenoids belonging to various chemical categories with potential inhibitory effects
on NF-kB and their role in the treatment of cancer.
Key Words: Nuclear factor kappa B (NF-kB), terpenoids, cancer.
Nuclear factor kappa B (NF-κB) is one of the most
important transcription factors in mammals which is re-
sponsible for controlling gene expression linked with
physiological responses, viz. oxidative stress, inflam-
mation etc., and has been shown to play a pivotal role
in the mechanism of cancer development. Therefore,
the signaling pathway involving this transcriptional fac-
tor has opened a new way for pharmacologists, mainly
in the field of oncology, where this pathway could prove
to be of utmost importance in the treatment of cancer [1].
Naturally occurring plant components from tra-
ditional herbs are a significant source of potential
therapeutic compounds for cancer treatment. Today
seve ral drugs used in clinics are discovered from
natural sources. Safety and toxicity of modern drugs
are very often questionable. Because of this appre-
hension, there is tremendous increase in the interest
in natural medicines that are considered to be safe.
Active constituents such as phenolic, flavonoids, gly-
cosides and alkaloids of plants are well known for their
medicinal values [2, 3]. Plant derived natural products
provide a source for potent molecules to combat
many diseases including cancer. Several promising
molecules have been identified as anticancer agents,
but there are still hurdles to overcome before they can
be accepted as modern drugs [4].
Phenolic compounds and terpenoids are major
constituents present in nutritionally used fruits, vege-
tables and different spices which possess various
pharmacological activities including anticancer activity.
Reports revealed that terpenoids that contain variable
isoprene units have shown potential anticancer acti-
vity. Many of terpenoids which are extensively used for
medical purpose have already been studied. Previous
reports revealed that natural terpenoids were found
to have cytotoxicity against variety of tumor cells. This
observation strongly suggests that plant derived thera-
peutic ingredients modulate NF-κB signaling, which
has a major role in the pathogenesis of cancer [5–8].
The present review focuses on the anticancer
potential of natural terpenoids of varied categories,
viz. monoterpenoids, sesquiterpenoids, diterpenoids,
sesterterpenoids, triterpenoids, tetraterpenoids and
polyterpenoids as NF-κB inhibitors. The review also
deals with the activation and inhibition mechanism
of NF-κB signaling pathways.
structure, functIon
and regulatIon of nf-κB
NF-κB protein comprises of homodimers and hete-
rodimers of different subunits. NF-κB is related through
deoxyribonucleic acid (DNA) binding domain called
as Rel homology domain. NF-κB proteins belonging
to Rel family consists of five members which includes:
p65 (RelA), RelB, cRel, p50/p105 (NF-κB 1) and p52/
p100 (NF-κB 2). NF-κB 1 and NF-κB 2 are synthesized
as precursor p100 and p105. Rel or NF-κB transcrip-
tion factor binds to 9–10 base pair DNA sites known
as kB sites. All vertebrate Rel proteins can form ho-
modimers or heterodimers, except RelB that can form
only heterodimers [9–11].
Rel or NF-κB proteins can be divided into two class-
es based on the sequence C-terminal to RH domain.
Members of one class have long C-terminal which
contains multiple copies of ankyrin repeats (33 residue
protein structure) and has transrepression activity.
This class includes NF-κB proteins p105, p100, and
Drosophila Relish. The second class (the Rel proteins)
Submitted: July 21, 2016.
*Correspondence: E-mail: kashishnarsinghani@rediffmail.com
Abbreviations used: DNA — deoxyribonucleic acid; ERK — extracellular
signal regulated kinases; JNK — c-Jun N-terminal kinases; IKK — en-
zyme IκB kinase; LPS — lipopolysaccharide; NEMO — non-enzyma tic
protein NF-κB essential modulator; NF-κB — nuclear factor kappa B;
NIK — NF-κB inducing kinase; TNF-α — tumor necrosis factor α.
Exp Oncol 2016
38, 3, 158–168
Experimental Oncology 38, 158–168, 2016 (September) 159
includes c-Rel (and its retroviral homologue v-Rel),
RelB, RelA (p65). This second class of Rel proteins
contains C-terminal transcription activation domains
which is required for transport of active NF-κB complex
into the nucleus. The subunits p50 and p52 do not
contain transcription activation domain [12, 13].
The transcriptional activity of NF-κB is suppressed
by interaction with IκB family of inhibitory proteins.
Nuclear factor of kappa light polypeptide gene en-
hancer in B-cells inhibitor (IκB) proteins are family
of related proteins containing six or more ankyrin units
at their N-terminus. IκB proteins include the following
members: IκBα, IκBβ, IκBγ, IκBε, Bcl-3, Cactus, and
the precursor proteins p100, p105 which contains five
to seven ankyrin repeats [14].
sIgnalIng pathway of nf-κB
Activation of NF-κB. Two signaling pathways lead
to the activation of NF-κB, known as the classical (canoni-
cal) pathway and the alternative (non-canonical) path-
way. The common regulatory step in both of these path-
ways is activation of an enzyme IκB kinase (IKK) which
is present in complex form that consist of catalytic kinase
subunits (IKKα/IKKβ) and the regulatory non-enzymatic
protein NF-κB essential modulator (NEMO) also known
as IKKγ. Activation of NF-κB dimers due to IKK involves
phosphorylation which leads to proteasomal degrada-
tion of IκB, enabling the active NF-κB transcription factor
for cytoplasmic translocation into the nucleus, thereby
inducing target gene expression [14].
In the classical or canonical pathway proinflamma-
tory cytokine tumor necrosis factor α (TNFα) stimulates
and activates NF-κB, which in turns activates the sub-
unit of IKK complex and leads to phosphorylation and
degradation of IκB inhibitors. The canonical pathway
activates NF-κB dimers comprising of RelA, c-Rel, RelB
and p50. This pathway plays major role in the control
of innate immunity and inflammation (Fig. 1) [15, 16].
p100/Re1B complexes are activated by non-
canonical pathway and this pathway seems to involve
an IKK complex consisting of two IKKα subunits
(Fig. 2). Non-canonical pathway works on the mecha-
nism of ligand induced activation which results in the
activation of central signaling component of the path-
way, i.e., NF-κB-inducing kinase (NIK). NIK phos-
phorylates and activates a downstream kinase, IκB
kinase-α (IKKα) which further phosphorylates p100.
Phosphorylation of p100 causes the translocation
of NF-κB to the nucleus, which subsequently binds
to specific target genes for processing [17].
Inhibition of NF-κB. In inactivated form, NF-κB re-
mains in cytoplasm by family of inhibitors known as IκB
proteins. This protein contains ankyrin repeats and
masks the nuclear localization signals of NF-κB pro-
teins and makes them inactivated and remains in the
cytoplasm.
IKK complex consist of three subunits, IKKα, IKKβ,
IKKγ also known as NEMO. IKKα plays an important role
in NF-κB regulation, and also in epidermal diffe rentiation
independent of NF-κB pathway. IKKβ plays important
function in the phosphorylation. NEMO is also known
as inhibitor of IKKγ and this activates NF-κB [18, 19].
fig. 1. Canonical pathway of NF-κB signaling
fig. 2. Non-canonical pathway of NF-κB signaling
160 Experimental Oncology 38, 158–168, 2016 (September)
mechanIsm of nf-κB actIon
In malIgnant transformatIon
It was found that inactive NF-κB dimers are lo-
cated in cell cytoplasm and are unable to bind with
DNA as this inhibition of binding is associated with
IκB proteins. This IκB proteins form complex with
NF-κB. IκBα or IκBβ proteins of IκB family, selectively
bind to the p50/p65 heterodimers and masks their
nuclear localization signal, preventing nuclear trans-
location of NF-κB. Activation of NF-κB can occur
by acetylation of p65 (RelA). Acetylated NF-κB is ac-
tive and resistant from inhibitory action of IκB protein.
Activation of NF-κB requires phosphorylation of IκB
proteins by external inducers which activate enzyme
IKK. This IKK phosphorylates the IκB protein result-
ing in dissociation of NF-κB from IκB protein and
degradation of IκB by proteasome. The enzyme IKK
is composed of heterodimers of catalytic IKKα and
IKKβ and a regulatory protein NEMO. The NF-κB is then
translocated to nucleus to activate target genes. The
DNA/NF-κB complex then recruits other proteins that
transcribe DNA into mRNA and then translate into pro-
teins which result in change in cell function and may
cause cancer (Fig. 3) [1–3, 13, 14].
fig. 3. Inhibition by different terpenoids in NF-κB signaling
pathways (Ub — ubiquitination; P — phosphorylation)
terpenoIds:
chemIstry and synthesIs
Origination of term terpene came from word tur-
pentine (lat. Balsamum terebinthinae). Terpenes are
a large and varied class of natural products, produced
primarily by a wide variety of plants, insects, microor-
ganisms, and animals. More than 55,000 terpenoid
molecules have been discovered so far. Diffe rent
chemical and biological studies have proved that
terpenoids possess variety of chemical, physical and
biological activities due to their rich diversity in struc-
tural classes with varying degrees of unsaturation,
functional groups, and ring closures [20].
Chemistry of terpenoids. Terpenoids are formed
by 2-methylbutane residues, less precisely but usually
also referred to as isoprene units (C5H8) and called
as isoprenoids known to build up the carbon skeleton
of terpenes. Terpenoids are broadly classified on the
basis of the number of isoprene units present in the
molecule. Depending on the number of 2-methylbu-
tane (isoprene) subunits one differentiates between
hemi- (C5), mono- (C10), sesqui- (C15), di- (C20), sester-
(C25), tri- (C30), tetraterpenes (C40) and polyterpenes
(C5)n with n > 8 [20].
Biosynthesis of terpenoids. Terpenoids are
the secondary metabolites obtained naturally; these
terpenoids are synthesized from isopentyl pyrophos-
phate and its isomer dimethylallyl pyrophosphate.
Synthesis of terpenoids involves an enzyme known
as terpene synthase. During the synthesis, firstly
geranyl pyrophosphate, farnesyl pyrophosphate,
geranylgeranyl pyrophosphate are synthesized. The
prenyl pyrophosphate acts as precursor for different
terpenoids such as monoterpenoids, diterpenoids,
sesqueterpenoids. In triterpenoid synthesis oxido-
squalene cyclase converts oxidosqualene into cyclic
triterpene alcohols. Tetraterpenoids are synthesized
from phytoene pathway in which phytoene synthases
catalyzes the conversion of geranylgeranyl pyrophos-
phate into phytoene via condensation [21–23].
natural terpenoIds
as nf-κB sIgnalIng InhIBItors
Terpenoids of natural origin can inhibit the signa ling
of NF-κB, the major regulator in the pathogenesis of in-
flammation and cancer. Various pathways were found
to be involved in the anticancer activity of terpenoids,
including activation of apoptosis. The terpenoids from
natural sources are well known inhibitors of NF-κB sig-
naling (Fig. 3). Some therapeutic indications on various
terpenoids are described in the subsequent section.
Monoterpenoids. Monoterpenes (Table 1) are
composed of isoprene units (two in number) with
a general molecular formula of C10H16. They exist
in acyclic, monocyclic or bicyclic forms. Naturally,
monoterpenoids are found as terpene derivatives
and modifications resulting from oxidation, methyla-
tion and glycosylation and most of them are volatile
in nature [21, 22]. Some of the monoterpenoids act
as NF-κB signaling inhibitors through IκB degradation,
DNA binding or p65 translocation [24–26]. Some of the
monoterpenoids are described below.
Aucubin. The glycoside derivatives irinoids are
a class of monoterpenoids. The most common irinoid
glycoside is aucubin. According to some studies, IκBα
degradation is prevented by aucubin. Aucubin also
prevents the nuclear translocation of p65 subunit
Experimental Oncology 38, 158–168, 2016 (September) 161
of NF-κB complex in stimulated mast cells. It has been
revealed through different studies that aucubin could
be useful agent in prevention of inflammation, cancer,
and hepatotoxicity [24–26].
Limonene. Limonenes are cyclic aromatic mono-
terpenes. The derivatives of limonene are perillic
acid, perillyl alcohol and menthol. It has observed
that menthol and perillyl alcohol have ability to induce
NF-κB dependent apoptosis. In lymphoma cells, these
compounds may inhibit NF-κB signaling. Also, in some
studies the capability of limonene and perillyl alcohols
to inhibit proliferation and metastasis of gastric can-
cer has been revealed; also it has been shown that
dietary monoterpenes, limonene and perillyl alcohols
have an inhibitory effect on mammary and pancreatic
tumors in animal models [27–29].
α-Pinene. Pinene, a bicyclic monoterpene,
is a powerful inhibitor of NF-κB system and is usually
obtained from conifer trees. It has been reported that
α-pinene inhibit NF-κB/p65 protein translocation in li-
popolysaccharide (LPS) stimulated THP-1 cells. The
inhibition of NF-κB signaling increased the expression
of IκBα protein in the cells pretreated with α-pinene.
It could be inferred from the studies that NF-κB signal-
ing is inhibited by several flavoring monoterpenoids
which are found in essential oils and spices. These
flavoring monoterpenoids can also be used in inflam-
matory diseases and cancer [30].
Catalposide. Catalposide is an iridoid glycoside
that inhibit NF-κB system. Catalposide inhibit degrada-
tion of IκBα protein and also translocation of p65 sub-
unit [31].
Genipin. Genipin is a monoterpenoid that inhibit
degradation of IκBβ protein thus inhibiting NF-κB sig-
naling. Genipin is the metabolite product of genipino-
side. Genipin inhibits the expression of iNOS and
NO production in LPS stimulated cells [24, 32].
Sesquiterpene. Sesquiterpenes (Table 2) are
derived from three isoprene units. Hence, they are
C13 compounds and biosynthesized from farnesyl
pyrophosphate. They have wide occurrence in nature
and are mainly found in plants and fungi. The carbon
skeleton of sesquiterpenes is found in highly diverse
forms as compared to other terpenes. Sesquiterpene
lactones contain α-methylene, γ-lactone system. Some
of them also contain α-β-unsaturated carbonyls and
epoxides. A number of sesquiterpene lactones show
antitumor properties [32, 33].
Costunolide. Costunolide is a sesquiterpene lac-
tone and a popular folk remedy in India. The most
common source of costunolide is the root of medicinal
plant Saussurea costus and it is also isolated from
other medicinal plants such as Magnolia grandiflora.
The mechanism of inhibition of NF-κB signaling by co-
sutnolide is the prevention of phosphorylation of IκB
proteins. It also inhibits LPS induced basic inflamma-
tory signaling pathway by inhibition of NF-κB activation
and by prevention of downstream gene expression.
Though some studies have presented it as an agent
having anticancer, anti-inflammatory, anti-microbial,
anti-ulcer properties but still these effects need more
verification [34–37].
Artemisinin. Artemisinin, a sesquiterpene lac-
tone, is a traditional Chinese medicine and is also
called qinghaosu. Artemisinin is obtained from leaves
Table 1. Natural monoterpenoids as inhibitors of NF-κB pathways
Name Structure Site of NF-κB inhibition Therapeutic Indication References
Aucubin
O
OH
H
H
RO
H
HO
H
IκBα degradation Inflammation, hepatotoxic-
ity, cancer [24–26]
Limonene CH3
H2C
H3C
DNA binding Lymphoma and metastasis
of gastric cancer [27–29]
α-Pinene
H3C
H3C
CH3
P65 translocation Inflammation [30]
Catalposide
O
O
OHO
H
O
H
O
OH
HO
HO
HO
OH
H
O
IκBα degradation Inflammation [31, 32]
162 Experimental Oncology 38, 158–168, 2016 (September)
of Artemisia annua. Artemisinin is very popular for
the treatment of multidrug resistant malaria. Some
stu dies have revealed its anticancer, immunosuppres-
sive, anti-fungal and anti-angiogenesis properties.
Chemically, artemisinin is endoperoxide sesquiter-
penoid lactone containing complex polycyclic rings
which function through alkylation of protein (a typical
mechanism of sesquiterpene lactones). In cells, there
Table 2. Natural sesquiterpenes as inhibitors of NF-κB pathways
Name Structure Site of NF-κB inhibition Therapeutic Indication References
Costunolide
O
H3C
H3C
O
CH2
H
H
IκB phosphorylation Leukemia, inflammation [33–35]
Artemisinin O
O
O
O O
H
CH3
H
H
H3C
CH3
DNA binding Malaria, cancer [36–38]
Humulene
H3C
CH3
H3C
CH3
DNA binding Inflammation [40]
Parthenolide
O
O
O
CH2 Alkylation of p65 Arthiritis, lung cancer [33, 59–61]
Helenalin A
O
O CH2
O
H
H
OH
H3C
H
CH3
p65 alkylation Inflammation, infection [62, 63]
Ergolide
O
O
H H
3HC
H
O
AcO
H3C
IκB degradation Inflammation, cancer [64, 65]
Zerumbone
H3C
H3C
O
CH3
CH3
IκBα degradation Inflammation, metastasis [66, 67]
Valerenic
acid
CH3
HO O
H3C
H
CH3
Reporter assay Insomnia [68]
Experimental Oncology 38, 158–168, 2016 (September) 163
are many targets for alkylation, even NF-κB transcrip-
tion system may be one, as artemisinin inhibits acti-
vation of NF-κB signaling induced by LPS. In a study
of TNFα treated human synoviocytes, it was found that
a synthetic derivative of artemisinin, artesunate, inhi-
bited NF-κB signaling activation and proinflammatory
cytokines production. Though the exact mechanism
of artemisinin is unclear, but still it is an important
agent as DNA binding of NF-κB complex which has
been reported in some studies [38–40].
Nepalolide A. A plant of Chinese traditional medicine
Carpesium nepalense is a source of sesquiterpene
lactone nepalolide A. In C6 glioma cells, nepalolide
A is found to suppress signaling induced by LPS and
cytokine and inhibit IκB protein phosphorylation [41].
Humulene. A source of monocyclic sesquiter-
pene humulene is Humulus lupulus, which is chemi-
cally α-caryophyllene. It was observed that activa-
tion of NF-κB system by LPS and the inflammatory
response in rat paw edema assay could be effectively
reduced by humulene. Even, it is more specific in prop-
erties, in comparison to other sesquiterpenes, as there
is no modification in activation of extracellular signal
regulated kinases (ERK), c-Jun N-terminal kinases
(JNK) and p38 by humulene [42]..
Parthenolide. Parthenolide is known to be the
most powerful NF-κB signaling inhibitor. Parthenolide
inhibits nuclear translocation of p65 subunit and also
inhibit DNA binding of NF-κB complex. It is also used
in the treatment of arthritis and other inflammatory
diseases [36, 43–45].
Helenalin A. Helenalin A is a sesquiterpene that
inhibits NF-κB signaling. Helenalin alkylates p65 sub-
unit thus inhibiting the DNA binding of NF-κB complex.
Table 3. Natural diterpenoids as inhibitors of NF-κB pathways
Name Structure Site of NF-κB inhibition Therapeutic Indication References
Acanthoic
acid
CH3
COOHH3C H
H
CH3
CH2 IκB phosphorylation Inflammation [42, 43]
Oridonin
OH
O
O
H3C H
OH
OH
H
OH
CH3
DNA binding Leukemia,
immunosuppresion [44–46]
Taxol O
NHO
H3C
O
H3C
O
O
CH3
OH
O
O
OOH
CH3
CH3
O
CH3
O
O
OH
Degradation of IKK com-
plex Inflammation [47, 48]
Cornosol
CH3
O
O
HO
OH CH3
CH3H3C
H
IκBα phosphorylation Inflammation, metastasis [69, 70]
Ginkgolides
O
O
O
O
O
O
CH3
CH3
CH3
H3C
HO
OH
H
HO
O
H
DNA binding Neuroprotection,
inflammation [59, 71–73]
164 Experimental Oncology 38, 158–168, 2016 (September)
In addition to its anti-inflammatory properties, this
terpene is also potent against many infections [46, 47].
Ergolide. Ergolide comes under the category
of sesquiterpenoid isolated from Innula britannica.
Ergolide possesses anti-inflammatory and anticancer
properties exerted via apoptosis induction. It inhibits
translocation of NF-κB complex and degradation of IκB
proteins [48, 49].
Zerumbone. It is a cyclic sesquiterpene isolated
from Zingiber zerumbet. It induces phosphorylation
of IκB proteins and thus blocks the function of IKK
complex as a result of phosphorylation and degrada-
tion of IκB proteins. It leads to reduction of nuclear
translocation of NF-κB complex [50, 51].
Valerenic acid. Valerenic acid is an effective ses-
quiterpene used against cancer and inflammation.
Valerenic acid is obtained from Valeriana officinalis.
It is a powerful inhibitor of NF-κB activation and cyto-
kine activation. It is also used in sleep disorders [52].
Diterpenoids. Diterpenoids (Table 3) are C20 com-
pounds, derived from four isoprene units and generally
non-volatile in nature. They are biosynthesized from ge-
ranyl pyrophosphate. Diterpenoids may be acyclic, but
generally they appear as monocyclic, bicyclic or tetracy-
clic compounds. Usually, diterpenoids show antitumor
properties by indirectly inhibiting NF-κB signaling [22].
Some of the compounds with antitumor properties and
of therapeutic importance are as follows:
Acanthoic acid. The mechanism of action of acan-
thoic acid and its analogues is reduction in activation
of LPS induced IκBα phosphorylation along with inhibi-
tion of nuclear DNA binding of NF-κB system. Its prop-
erty to prevent cytokine synthesis and pro-inflammatory
response was also revealed. Some studies reported the
Table 4. Natural triterpenoids as inhibitors of NF-κB pathways
Name Structure Site of NF-κB inhibition Therapeutic
Indication References
Ginsen-
osides
O
O
HO
O
O
H
HO
OH
HO
OH
H3C
CH3
HO
CH3
OH
H
H
H3C
H3C
HO
OH
H
H
CH3
OH
IκBα phosphorylation,
and degradation
Neurodegenerative
diseases, cancer, inflam-
mation
[50–53]
Glycyrrhizin
O
O
O
O
COOH
CH3
CH3
H3C
H3C
H
H3C
H
HCH3
O
COOH
HO
HO
HOOC
HO
OH
OH
DNA binding Inflammation [54–56]
Betulin
HO
CH3 CH3
H
H
H CH3
CH3
H2C
OH
H
H3C
H3C
IKKα inhibition Arthritis, cancer metas-
tasis [74, 75]
Lupeol CH3
H
CH3CH3
HO
H CH3
H
3HC
CH2
CH3
3HC
IκBα phosphorylation Metastasis, skin cancer [76–78]
Experimental Oncology 38, 158–168, 2016 (September) 165
ability of acanthoic acid to prevent fibrosis and nodular
formation [53, 54].
Oridonin. Oridonin is a kaurane diterpenoid which
is obtained from Rabsodia rubescens. Oridonin af-
fects the cancerous cells proliferation by inducing
phagocytosis of apoptotic cells by macrophages and
trigger apoptotic cell death as well. In vitro and in vivo
studies have revealed immunosuppressive properties
of oridonin. Unlike other diterpenoids, which suppress
TNFα-induced IκBα protein degradation and nuclear
translocation of NF-κB complex, oridonin inhibits
NF-κB signaling by reversibly inhibiting DNA binding
of NF-κB complex [55–57].
Taxol. Taxus brevifolia, a pacific yew tree, is a source
of taxol which is chemically a complex polyoxygen-
ated diterpenoid. Paclitaxel (generic name of taxol)
is a popu lar and powerful drug used in cancer che-
motherapy. The anticancer property of taxol is due
to its binding to the β-tubulin protein present in mi-
crotubules. This results in suppression of microtu-
bular dynamics and it also raised acetylation level
of α-tubulin protein. This increase in stability of micro-
tubules inhibits mitosis and thus results in cell death
of proliferating cells. Some studies reveal the capacity
of taxol in activation of NF-κB signaling via activation
of TLR4 receptor (a receptor responsible for LPS in-
duced NF-κB signaling) by taxol. The binding of taxol
to CD18 protein also activates TLR4 system [58, 59].
Cornosol. Cornosol is a diterpenoid, obtained from
Rosmarinus officinalis that inhibits IκBα phosphoryla-
tion and iNOS and NO production. Cornosol inhibits
NF-κB signaling via its antioxidant capacity [60, 61].
Ginkgolide is biological active diterpenoid extract-
ed from Ginkgo biloba. Ginkgolides inhibits the DNA
binding of NF-κB complex and iNOS activation, and
is therapeutically efficient in variety of inflammatory
disorders [59, 62–65, 71–73].
Triterpenoids. Triterpenoids (Table 4) are formed
by six isoprene units with 30 carbon atoms, and are
structurally similar as steroidal compounds. Triterpe-
noids are present either in free state or as ester or gly-
cosides and are classified as tetracyclic and pentacyclic
triterpenoids. Various triterpenoids exhibiting NF-κB in-
hibiting properties are listed below [66].
Ginsenosides. Ginsenosides are steroids chemi-
cally similar to triterpene saponins. These compounds
are obtained from roots of Panax ginseng (Korean gin-
seng), Panax notoginseng (Chinese ginseng), Panax
quinquefolium (American ginseng) and other species
of perennial plant Panax. Ginsenosides are widely
used therapeutically as anti-inflammatory and anti-
cancer agents and are also found useful in treatment
of neurodegenerative disorders. Ginsenosides have
many targets in cells and some studies have revealed
their anti-cancer and anti-inflammatory activities via
regulating signaling pathways. Inhibition of NF-κB sig-
naling may be direct or indirect, and it is due to sup-
pression of IκBα protein degradation as well as IKKα
kinase activation. Some studies also showed the effect
of ginsenosides in the DNA binding of NF-κB system.
Ginsenosides also inhibit JNK pathway and AP-1 bind-
ing activity which shows that it can affect the upstream
components of NF-κB signaling [67–70].
Glycyrrhizin. Glycyrrhizin is chemically a triterpe-
noid saponin glycoside and is widely used in Chinese
and Egyptian medicine for treatment of cardiovascular,
gastrointestinal and respiratory disorders. Glycyrrhizin
is an active chemical constituent of licorice obtained
from roots and stolons of Glycyrrhiza glabra. Glycyrrhi-
zin is chemically composed of glycyrrhizic acid. Glycyr-
rhizic acid is widely studied and is shown to be capable
to inhibit NF-κB signaling. Studies have also revealed
the ability of glycyrrhizic acid to inhibit glutamate in-
duced excitotoxicity in primary neurons and calcium
mediated activation of NF-κB system [71–73].
Betulin is pentacyclic triterpenoid extracted from
the bark of Betula alba. Derivatives of betulin are more
therapeutically active against HIV and inflammation
and act through inhibition of IKKα and NF-κB depen-
dent gene expression [74, 75].
Lupeol is very common terpenoid found in many
fruits and vegetables. The structure of lupeol is penta-
cyclic. Lupeol exhibits anticancer property by inhibit-
ing NF-κB signaling including phosphorylation of IκB
proteins [76–78].
Avicins are the plant stress metabolites obtained
from the Acacia victoriae. Avicins inhibit DNA binding
of NF-κB complex. Avicins do not affect degradation
of IκB proteins [79].
Carotenoid tetraterpenoids. Carotenoid terpe-
noids (Table 5) are the pigmented tetrapenes contain-
ing eight isoprene units. These compounds are found
to have antioxidative activity with therapeutic effects
in cardiovascular disorders and osteoporosis; they also
exhibit anticancer activity by regulating NF-κB signal-
ing pathway.
Lycopene is an acyclic tetraterpenoid that is most
commonly found in human body. Major dietary source
include tomato and other fruits. Lycopene has powerful
antioxidant activity. Lycopene can inhibit NF-κB signal-
Table 5. Natural carotenoid tetraterpenoids as inhibitors of NF-κB pathways
Name Structure Site of NF-κB inhibition Therapeutic Indication References
Lycopene NF-kB translocation Inflammation [80–83]
β-Carotene IκBα degradation,
DNA binding Cancer, inflammation [84, 85]
Lutein
OH
HO
IκBα degradation Cataract, uveitis [86, 87]
166 Experimental Oncology 38, 158–168, 2016 (September)
ing, nuclear translocation of NF-κB complex as well
as its DNA binding [80–83].
β-Carotene. These compounds are the cyclic
carotenes. β-Carotene is stored in liver and converted
into vitamin A. β-Carotene suppresses LPS induced
NF-κB signaling. It also degrades IκB protein and inhibits
nuclear translocation of p65 subunit and DNA binding
of NF-κB complex. β-Carotene by virtue of its proxidant
characteristic inhibits cancer growth [84, 85].
Lutein is a cyclic tetraterpenoid present in fruits,
vegetables and egg yolk. It inhibits nuclear localization
of p65 subunits and IκBα protein degradation. It also
inhibits activation of NF-κB signaling. Lutein pigment
can protect from oxidative stress and cataract [86, 87].
conclusIon
Chemically diverse class of terpenoids represented
with monoterpenoids, sesquiterpenoids, diterpenoids,
sesterterpenoids, triterpenoids, tetraterpenoids and
polyterpenoids, is capable to inhibit signaling via
NF-κB pathway through different mechanisms, in par-
ticular, through IκB phosphorylation, DNA binding,
p65 translocation etc. This provides promising pos-
sibilities for the use of terpenoids as NF-κB inhibitors
from natural sources, for treatment of various human
pathologies including cancer.
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