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International Reviews of Immunology, 27:293–319, 2008
Copyright © Informa Healthcare USA, Inc.
ISSN: 0883-0185 print / 1563-5244 online
DOI: 10.1080/08830180802276179
Special Topic: NF-κB, Immunity and Cancer
NF-κB Signaling Pathway and Its Therapeutic
Implications in Human Diseases
Fazlul H. Sarkar, Yiwei Li, Zhiwei Wang, and
Dejuan Kong
Department of Pathology, Barbara Ann Karmanos Cancer Institute,
Wayne State University School of Medicine, Detroit, Michigan, USA
The nuclear factor-κB (NF-κB) pathway is one of the most important cellular signal transduction pathways involved in both physiologic processes and disease
conditions. It plays important roles in the control of immune function, inflammation, stress response, differentiation, apoptosis, and cell survival. Moreover,
NF-κB is critically involved in the processes of development and progression of
cancers. More importantly, recent studies have shown that NF-κB signaling also
plays critical roles in the epithelial-mesenchymal transition (EMT) and cancer
stem cells. Therefore, targeting of NF-κB signaling pathway could be a potent
strategy for the prevention and/or treatment of human cancers and inflammatory
diseases.
Keywords NF-κB, immune, inflammation, cancer, EMT
NUCLEAR FACTOR-κB (NF-κB) PATHWAY
NF-κB was firstly discovered as a factor bound to the κ light-chain immunoglobulin enhancer in the nuclei of B lymphoid lineage [1]. Shortly
after, NF-κB was found in PMA-treated Jurkat and HeLa cells, suggesting that NF-κB is non–cell-type-specific and inducible [2]. With the
discovery of its activators and downstream targets, NF-κB pathway
has become one of the most intensely studied signaling pathways in
the past three decades. Emerging evidence demonstrates that NF-κB
signaling pathway plays important roles in the control of cell growth,
differentiation, apoptosis, immune, inflammation, stress response, and
Address correspondence to Fazlul H. Sarkar, Department of Pathology, Barbara Ann
Karmanos Cancer Institute, Wayne State University School of Medicine, 740 Hudson Webber Cancer Research Center, 4100 John R, Detroit, MI 48201, USA. E-mail:
[email protected]
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many other physiologic processes [3, 4]. The NF-κB family has five proteins: RelA (p65), RelB, Rel, NF-κB1 (p50), and NF-κB2 (p52), each of
which may form homo- or heterodimers. The activated NF-κB is a heterodimer, which usually consists of p65 and p50 or contains p52 and
RelB. In human cells without specific extracellular signal, NF-κB is sequestered in the cytoplasm through tight association with its inhibitors:
IκBα, which acts as a NF-κB inhibitor, and p100 proteins, which serve
as both inhibitor and precursor of NF-κB DNA-binding subunits. NF-κB
can be activated by many types of stimuli such as cytokines, oxidants,
viruses, immune stimuli, and so forth [4]. The activation of NF-κB occurs through phosphorylation of IκBα by IKKβ and/or phosphorylation
of p100 by IKKα, leading to the degradation of IκBα and/or the processing of p100 into smaller form (p52). This process allows two forms of
activated NF-κB (p50-p65 and p52-RelB) to become free, resulting in
the translocation of the activated NF-κB into the nucleus for binding to
NF-κB–specific DNA-binding sites, which, in turn, regulates the transcription of target genes (Fig. 1) [3]. In addition, IKKα also regulates the
activation of NF-κB–directed gene expression through phosphorylation
of histone H3 [5].
By binding to the promoters of target genes, NF-κB controls the
expression of many genes that are involved in the processes of immunity, inflammation, cell survival, and apoptosis. The activated NF-κB
frequently functions together with other transcription factors such
as AP-1 to regulate the expression of immune and inflammatory
genes[6,7]. NF-κB has been found to promote the expression of cytokines, chemokines, and receptors including IL-2, IL-6, IL-8, TNF-α,
IL-2R, TCR, and so forth [4, 6, 7]. These proteins regulated by NF-κB
also cause the activation of NF-κB, forming a positive regulatory loop
to amplify inflammatory responses [4]. NF-κB also transcriptionally
upregulates 5-lipoxygenase, cyclooxygenase-2 (COX-2), and nitric oxide synthase (NOS) [8–10], which are inflammatory enzymes and play
important roles in the processes of inflammation. It has been reported
that overexpression of NF-κB protects cells from apoptosis whereas
inhibition or absence of NF-κB induces apoptosis or sensitizes cells
to apoptosis-inducing agents including TNF-α, ionizing radiation cancer therapeutic agents, and so forth [11, 12]. NF-κB can also bind to
the promoters and enhancers of some target genes (i.e., MMP-9, IL8, uPA, VEGF, CXCR4, osteopontin, etc.) that control cancer cell invasion, metastasis, and angiogenesis [13–15]. These findings suggest
that NF-κB is a critical transcription factor for the control of immunity, inflammation, cell survival, apoptosis, and cancer cell invasion
and metastasis (Fig. 1).
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FIGURE 1 NF-κB pathway and its role in human diseases.
OXIDATIVE STRESS AND NF-κB ACTIVATION
It is well-known that NF-κB is critically involved in the processes of
oxidative stress response. Oxidative stress is defined as an increase in
intracellular reactive oxygen species (ROS) such as H2 O2 , superoxide,
hydroxyl radical, and so forth. We and other investigators have found
that direct addition of H2 O2 to cell culture medium activates NF-κB in
several types of cell lines [16, 17]. In addition, ROS in cells are increased
in response to agents that also activate NF-κB [18]. These results suggest that oxidative stress activates NF-κB activity in the cells.
Oxidative stress is frequently observed as part of aging, immune disorders, inflammatory diseases, metabolic diseases, and cancers. When
ROS are intracellularly formed, the activity of NF-κB is upregulated,
leading to the expression of cytokines, chemokines, cellular adhesion
molecules, and inflammatory enzymes that activate the immune and
inflammatory system. Therefore, the inflammatory reactions and altered immune responses occurring in inflammatory diseases are often
associated with an increase in ROS production, activation of NF-κB,
and expression of NF-κB driven proteins. In addition to the induction of inflammatory factors, ROS also induce DNA damage and alter
cellular signal transduction pathways among which NF-κB signaling
is the most important. Because DNA damage plays a central role in
carcinogenesis, it is conceivable that oxidative stress could be carcinogenic [19]. Hence, DNA repair is an important process in preventing
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mutagenesis. However, under oxidative stress, the repair of DNA damage can be inhibited by several redox-dependent metals, resulting in
carcinogenesis [19]. Moreover, the activation of NF-κB has been known
as a key event in carcinogenesis [20], suggesting the importance of
NF-κB activation in the development of cancer.
ACTIVATION OF NF-κB IN AGING AND METABOLIC DISEASES
Because human beings live in an aerobic environment, exposure to
ROS is continuous and unavoidable with aging. Although a number
of defense systems have evolved to combat the accumulation of ROS,
these defense systems are not always adequate to counteract the productions of ROS, resulting in oxidative stress. Oxidative stress and
NF-κB activation have been linked to the normal aging and a variety
of chronic metabolic diseases including diabetes, pulmonary fibrosis,
neurodegenerative diseases, and so forth [21].
There is growing evidence implicating NF-κB activation and oxidative damage to DNA, protein, and lipid in the pathogenesis of various chronic diseases. Type I diabetes, or insulin-dependent diabetes,
is characterized by the severe destruction of insulin-producing β cells,
and ROS are believed to play a central role in β-cell death and disease
progression [22]. In diabetes, pancreas-specific ROS production plays a
critical role in signal transduction response by activating NF-κB. Both
c-Rel and NF-κB1 are essential for the development of type I diabetes
[23,24]. Alzheimer’s disease is the most common neurodegenerative
disease and shows progressive memory loss and dementia. Growing
evidence shows that there is a linkage between Alzheimer’s disease
and oxidative damage with activated NF-κB [25, 26]. Administration
of vitamin E leads to a slowing of disease progression, and the patients
taking antioxidant vitamins and anti-inflammatory compounds have a
lower incidence of Alzheimer’s disease [25], suggesting the importance
of NF-κB activity in the disease process. Parkinson’s disease is the second most common neurodegenerative disease and causes a progressive
movement disorder. The oxidative damage to protein, the protein oxidation, and the activated NF-κB have been found in Parkinson’s disease,
suggesting the involvement of NF-κB signaling pathway in neurodegenerative disease [25, 27], and active research is ongoing in these areas.
ACTIVATION OF NF-κB IN INFLAMMATORY DISEASES
NF-κB has been involved in the differentiation of macrophages, osteoclasts, granulocytes, and T and B cells, all of which play important roles
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in immunity and inflammation. During the development of the adaptive
immune system, NF-κB signaling is constitutively activated via an autocrine loop induced by chemokines, cytokines and their respective receptors, leading to the differentiation of macrophages, granulocytes, T
and B cells, as well as for the maintenance of their homeostasis. Because these cells are critically involved in the processes of inflammation, NF-κB is known as a primary regulator of inflammatory response.
The activation of NF-κB has been found in human inflammatory diseases such as rheumatoid arthritis [28], atherosclerosis [29], gastritis
[30], inflammatory bowel disease [31], sepsis [32], systemic lupus erythematosus [33], and so forth. It has been reported that ROS contribute
significantly to tissue injury in rheumatoid arthritis, and that the control of inflammation in arthritic patients by antioxidants could become
a relevant strategy for antirheumatic therapy [34]. The increase in ROS
generation has also been related to the risk for cardiovascular diseases
such as atherosclerosis, angina pectoris, and myocardial infarction [35],
suggesting the activation of NF-κB in these diseases. The activity of
NF-κB and the expression of proinflammatory cytokines are increased
in most of the inflammatory diseases and further causes deregulation
of the immune response [30–32].
Inhibition of NF-κB activation is now widely recognized as a valid
drug-target strategy to combat inflammatory disease [36]. However,
it has become obvious that the inhibition of NF-κB activity is not
only desirable for the treatment of inflammation but also in cancer
therapy [37]. It is hypothesized that chronic inflammation generates a
microenvironment that contributes to malignant transformation in human organs [38]. Examination of the inflammatory microenvironment
in neoplastic tissues has supported the hypothesis that inflammation is
a cofactor in oncogenesis for a variety of cancers. Moreover, the inflammatory mediators such as cytokines, prostaglandins, and growth factors, which are regulated by NF-κB, can induce genetic and epigenetic
changes including mutations in tumor suppressor genes, DNA methylation, and post-translational modifications, leading to the development
and progression of cancer [39]. Many anti-inflammatory drugs and antioxidants can inhibit NF-κB activity and induce apoptosis; therefore,
they may also be desirable for the treatment of cancers.
ACTIVATION OF NF-κB IN CANCERS
NF-κB has been described as a major culprit in cancer because it is constitutively activated in most human cancers, especially in the poorly
differentiated cancers, but not in normal tissues and immortalized cells
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[20]. It has been reported that NF-κB is activated in Hodgkin’s tumor
[40] and multiple myeloma cells [41]. The activation of NF-κB is also
frequently observed in breast and prostate cancer cells [42, 43]. Studies have also shown that NF-κB is upregulated in pancreatic cancer
[44, 45], gastric carcinoma [46], and squamous cell carcinoma of the
head and neck [47]. In cancer cells, NF-κB is activated through constitutive activation of IKK followed by the phosphorylation and degradation
of IκBα. Inhibition of NF-κB by a super-inhibitor of NF-κB (δ-N-IκBα)
results in impaired proliferation and induction of apoptosis [48], suggesting that NF-κB is a target for the treatment of cancer.
Moreover, evidence has shown that NF-κB participates in the processes of cancer metastasis. It was found that inhibition of constitutive
NF-κB activity by a mutant IκBα (S32A, S36A) completely suppressed the liver metastasis of pancreatic cancer cells [49]. The inhibition of NF-κB activity also inhibited the tumorigenic phenotype
of a nonmetastatic pancreatic cancer cell, suggesting that constitutive NF-κB activity plays a key role in cancer metastasis and tumor
progression [50]. Constitutive NF-κB activation also increases the expression of its downstream genes, uPA and MMP-9, both of which
are the critical proteases involved in tumor invasion and metastasis [51]. These results suggest that constitutively activated NF-κB is
tightly related to the invasion and metastatic processes during tumor
progression.
De novo and acquired resistance to chemotherapeutic agents is a
major cause of treatment failure in cancer. It has been found that
chemotherapeutic agents can activate NF-κB in cancer cells, leading
to cancer cell resistance to chemotherapy [52–54]. Other molecules
such as IL-1 and E3-ubiquitin ligase receptor could also induce NF-κB
activation and lead to the chemoresistance in human cancer cells,
suggesting that NF-κB plays important roles in the development of
chemoresistance in cancers [55,56]. Therefore, it is becoming obvious
that inhibition of NF-κB activity is highly desirable for the treatment
of chemoresistant cancer.
NF-κB ACTIVATION AND EPITHELIAL-MESENCHYMAL
TRANSITION (EMT)
EMT was recognized as a critical feature of embryogenesis several
decades ago; however, more recently it has also been implicated in
cancer progression. During EMT of cancer cells, expression of proteins that promote cell-cell contact such as E-cadherin and γ-catenin
is lost, and there is gain in the expression of mesenchymal markers
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such as vimentin, fibronectin, N-cadherin, MMP-2, and MMP-9, which
leads to enhanced ability of cancer cell migration and invasion [57].
The epithelial cancer cells undergo remarkable morphologic changes
characterized by a transition from epithelial cobblestone phenotype to
elongated fibroblastic phenotype with the loss of epithelial cell-cell junction and actin cytoskeleton reorganization. For most epithelial tumors,
progression toward malignancy is accompanied by a loss of epithelial
differentiation and a shift toward mesenchymal phenotype [57]. Moreover, studies have shown that primary cancers and their corresponding
metastatic tumors exhibited mixed epithelial-mesenchymal phenotype
[58]. Cells in the tumor center remain positive for the expression of Ecadherin and cytoplasmic β-catenin, and the tumor cells in the periphery display loss of surface E-cadherin and upregulation of vimentin,
the typical characteristics of EMT phenotype [58]. The alteration of
molecules during EMT has been observed in association with dysregulated cellular signal transduction pathways. The downregulation and
relocation of E-cadherin and zonula occludens-1 (ZO-1), the translocation of β-catenin from cell membrane to nucleus, and the activation of
Snail, Twist, and ZEB1 transcription factors results in the induction of
EMT phenotype [59–64].
Importantly, increasing evidence has shown that NF-κB activation is
required for the induction and maintenance of EMT (Fig. 1) [65,66]. It
has been found that NF-κB suppresses the expression of epithelial specific genes, E-cadherin and desmoplakin, and induces the expression of
the mesenchymal specific gene vimentin [67]. Repression of E-cadherin
expression by the transcription factor Snail is a central event during
the loss of epithelial phenotype. NF-κB has been found to induce the
expression of Snail, leading to the downregulation of E-cadherin [68].
NF-κB also upregulates transcription factor ZEB1 and ZEB2, resulting
in the inhibition of E-cadherin expression during EMT [67]. Furthermore, studies have shown that NF-κB could induce Bcl-2 expression
and promote invasion of breast cancer cells, which are associated with
EMT [69]. Recently, we have found that overexpression of PDGF-D
could activate NF-κB and thereby upregulates Bcl-2, which may contribute to EMT phenotype and invasive behavior of PC-3 prostate cancer cells [70]. In addition, gene expression profile analysis has shown
that the genes involved in EMT and NF-κB signaling deregulation are
the most prominent molecular characteristics of the high-risk head and
neck squamous cell carcinoma [71], suggesting that NF-κB signaling
plays important roles in EMT. Therefore, inhibition of NF-κB could
stop the progression, invasion, and metastasis of cancer in part due to
deregulation of the processes of EMT.
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TARGETING NF-κB FOR THE TREATMENT OF HUMAN
DISEASES
Because NF-κB is constitutively activated in many human cancers,
immune disorders, inflammation, and metabolic diseases, targeting
NF-κB signaling is an important strategy for the treatment of many
human diseases. Experimental studies have shown that natural antioxidant compounds including isoflavones, curcumin, green tea catechins, and so forth, inhibit the activity of NF-κB and induce apoptotic
cell death in cancers and inflammatory diseases. Moreover, synthetic
NF-κB inhibitors also suppress inflammatory diseases and tumor
growth through inhibition of NF-κB activity. Thus, natural or synthetic
antioxidants that inactivate NF-κB activity could serve as molecularly
targeted agents against human diseases.
Natural Antioxidant Compounds
Isoflavones
Isoflavones are a subclass of flavonoids. Genistein, daidzein, and
glycitein are three main isoflavones found in soybeans. Evidence from
epidemiologic and in vivo studies has shown a decreased risk of cancer
with soy consumption [72,73]. Experimental studies have revealed that
isoflavones, particularly genistein, exert antioxidant and anti-NF-κB
effects on human inflammatory and cancer cells.
In lipopolysaccharide-induced inflammation, isoflavones including
genistein, kaempferol, quercetin, and daidzein have been found to inhibit the activation of NF-κB with downregulation of iNOS expression
and NO production in activated macrophages [74], suggesting their
anti-inflammatory effect. Isoflavone genistein also prevents NF-κB
activation and acute lung injury induced by lipopolysaccharide in
Sprague-Dawley rats [75]. Dietary supplementation with soy isoflavone
also reduces the exhaled NO level, the inflammatory mediators in the
exhaled breath condensate, and the ability of eosinophils to release inflammatory molecules in asthma [76, 77]. These results provide some
evidence demonstrating the inhibitory effects of isoflavones on inflammation.
We have investigated the effects of genistein on NF-κB DNA binding
activity in prostate, breast, and pancreatic cancer cells. We found that
genistein treatment significantly inhibited NF-κB DNA-binding activity in all cell lines we tested [53, 78, 79]. We also found that genistein
significantly inhibited cancer cell growth and induced apoptotic cell
death through the downregulation of NF-κB [53, 78, 79]. More importantly, we and other investigators have found that isoflavone could
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enhance the therapeutic effects of chemotherapy and radiotherapy
through the inhibition of NF-κB [53,80]. These results suggest that
isoflavone functions as an antioxidant, which could be a potent agent
for the inhibition of cancer cell growth.
By in vivo studies, we found that isoflavone supplementation inhibited NF-κB DNA binding activity and abrogated TNF-α–induced
NF-κB activity in lymphocytes harvested from human subjects receiving soy isoflavone supplements [17]. We also found that isoflavone is
very effective in reducing the level of 5-OhmdU, a modified DNA base
that represents the endogenous status of cellular oxidative stress [17].
These results demonstrated that isoflavone inhibits NF-κB activation
and decreases oxidative damage, suggesting its inhibitory effects on
carcinogenesis. Several phase I and II clinical trials using isoflavone as
supplement in the treatment of prostate, breast, and bladder cancers
have also been or are being conducted [81] (www.clinicaltrials.gov). The
results of clinical trials will hopefully guide us to design novel strategy
for the treatment of cancer.
Curcumin
Curcumin is a compound from Curcuma longa (tumeric).It has recently received considerable attention due to its pronounced antiinflammatory, antioxidative, immunomodulating, antiatherogenic, and
anticarcinogenic activities [82,83]. It has been found that curcumin
inhibits IKK, suppresses both constitutive and inducible NF-κB activation, and potentiates TNF-α–induced apoptosis [84]. Curcumin also
showed strong antioxidant and anticancer properties through regulating the expression of genes that require the activation of NF-κB [85],
suggesting that curcumin is a strong inhibitor of NF-κB.
Curcumin has been shown to inhibit diethylnitrosamine-induced
liver inflammation and trinitrobenzene sulfonic acid–induced colitis
through the inhibition of NF-κB in rats and mice [86, 87]. Curcumin
also inhibits NF-κB activation and reduces the severity of experimental
steatohepatitis in mice [88]. It has been found that curcumin attenuates inflammatory responses of TNF-α–stimulated human endothelial
cells [89] and protects against acute liver damage by inhibiting NF-κB,
proinflammatory cytokines production, and oxidative stress [90]. Obesity is a major risk factor for the development of type 2 diabetes. Dietary
curcumin significantly improves obesity-associated inflammation and
diabetes in mouse models of diabetes [91]. These findings suggest the
inhibitory effects of curcumin on inflammatory and metabolic diseases.
Curcumin also showed strong anticancer properties mediated
through the regulation of the expression of genes that require the
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activation NF-κB [92]. We have also found that curcumin inhibited
cell growth and induced apoptosis in pancreatic cancer cells in part
due to downregulation of Notch-1, Hes-1, and NF-κB [93]. Moreover,
curcumin downregulates the inflammatory cytokines CXCL-1 and -2
in breast cancer cells via NF-κB [94]. Curcumin also inhibits tumor
growth in ovarian carcinoma, head and neck squamous cell carcinoma,
and colon cancer by targeting the NF-κB pathway [95–97]. Importantly,
curcumin has been found to significantly inhibit chemotherapeutic
agent–induced NF-κB activation and enhance the antitumor activities
of chemotherapeutics through inhibition of NF-κB in different types of
cancers [52,98]. These results suggest that curcumin could inhibit cancer cell growth and sensitize cancer cells to chemotherapeutic agents
through the inhibition of the NF-κB pathway.
Two phase I trials using curcumin have been conducted to test the
safety, biomarkers, and activity of curcumin. The results demonstrated
that PGE2 production in blood and target tissue could indicate the biological activity of curcumin [99] and that curcumin showed a biologic
effect on the chemoprevention of cancer [100]. Recently, oral curcumin
has been used for a phase II clinical trial in patients with pancreatic
cancer [101]. The authors have found that curcumin has potent NF-κB
inhibitory effects, and it has shown activity to inhibit NF-κB in peripheral blood mononuclear cells (PBMCs). The authors also showed
that 2 of 49 patients had benefit and another patient had more than
2 years of stable disease [101]. Because oral curcumin showed some
activity, further studies have been done using liposome-encapsulated
formulation of curcumin. This formulation showed significant antitumor, antiangiogenesis, and NF-κB inhibitory effects in pancreatic cancer in mouse xenograft model [102,103]. In addition, a phase III clinical
trial using combination of gemcitabine, curcumin, and celebrex in patients with advance or inoperable pancreatic cancer is being conducted.
This trial will be able to demonstrate whether the combination effect
could be correlated with synergistic augmentation of apoptosis involving downregulation of COX-2 protein. Another clinical trial is being
conducted to determine whether supplementation of curcumin could
decrease oral mucositis in children undergoing doxorubicin-containing
chemotherapy (www.clinicaltrials.gov). In addition, a pilot study of curcumin and ginkgo for treating Alzheimer’s disease is being conducted
(www.clinicaltrials.gov).
Indole-3-carbinol and 3,3’-Diindolylmethane
Indole-3-carbinol (I3C) is produced from naturally occurring glucosinolates contained in a wide variety of plants including members of the
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family Brassica. I3C is biologically active and is easily converted in vivo
to its dimeric product 3,3 -diindolylmethane (DIM). I3C and DIM have
been shown to reduce oxidative stress and stimulate antioxidant response element–driven gene expression as antioxidants [104, 105].
DIM has been found to suppress the inflammatory response to
lipopolysaccharide (LPS) in murine macrophages. DIM suppresses
LPS-induced NF-κB transcriptional activity by inhibiting degradation
of IκBα, translocation of NF-κB to the nucleus, and NF-κB DNA-binding
activity [106]. DIM also significantly decreases the release of NO,
PGE2, COX-2, TNF-α, IL-6, and IL-1β by RAW264.7 cells treated with
LPS [106]. Downregulation of NF-κB could be one of the mechanisms
by which DIM inhibits inflammatory responses. NO, PGE2, and COX-2
play pivotal roles as mediators of inflammation involved in early steps
of carcinogenesis. Therefore, the inhibition of these molecules by DIM,
through inhibition of NF-κB, could also suppress the onset of cancer.
Indeed, rats fed with I3C, precursor of DIM, show decreasing tendency
in multiplicities of colonic adenomatous polyps [107].
We have found that both I3C and DIM significantly inhibited
NF-κB DNA binding activity in cancer cells, corresponding with the
inhibition of cell proliferation and the induction of apoptosis [108,
109]. Importantly, it has been found that the combinations of I3C
and cisplatin or tamoxifen cooperate to inhibit the growth of PC-3
prostate and MCF-7 breast cancer cells more effectively than does
either agent alone [110, 111], suggesting that inhibition of NF-κB
activity by I3C and DIM may contribute to the enhanced antitumor
activity of chemotherapeutic agents.
Several clinical trials using I3C and DIM in the treatment
of various cancers have been or are being conducted [112, 113]
(www.clinicaltrials.gov). Our institute is also conducting a phase I trial
studying the side effects and best dose of DIM toward eventual treatment of prostate cancer (www.clinicaltrials.gov).
Epigallocatechin-3-gallate
Epigallocatechin-3-gallate (EGCG) is believed to be the most potent
catechin from green tea for the inhibition of oncogenesis and reduction
of oxidative stress [114]. EGCG shows strong antioxidant and anti-NFκB activity. It has been reported that EGCG treatment inhibits activation of IKK, phosphorylation of IκBα, and translocation of NF-κB to the
nucleus [115], demonstrating that EGCG is a potent inhibitor of NF-κB.
In rodent models of polymicrobial sepsis, EGCG improves hypotension and survival by inhibiting activation of NF-κB and subsequent
NOS gene expression in aortic smooth muscle cells, suggesting that
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EGCG is a potential nutritional supplement or pharmacologic agent in
patients with sepsis [116]. By the inhibition of NF-κB, EGCG also regulates inflammatory response in autoimmune encephalomyelitis [117]
and colitis [118]. Moreover, EGCG has beneficial effects on diabetes
[119]. Dietary supplementation with EGCG elevates levels of circulating adiponectin in a model of type II diabetes [120]. EGCG also prevents
autoimmune diabetes induced by multiple low doses of streptozotocin
in mice [121].
Growing evidence shows that EGCG inhibits the proliferation of
various cancer cells and induces apoptotic processes in cancer cells
through inhibition of NF-κB [114,122]. Moreover, EGCG has been found
to reduce the levels of matrix metalloproteinases, suppress angiogenesis, and inhibit invasion and metastasis. Furthermore, it has been
reported that EGCG and tamoxifen synergistically induced apoptosis
and growth inhibition in cancer cells [123] and this effect of EGCG
could be mediated through inhibition of NF-κB. These findings suggest
that EGCG is a potent antioxidant that is likely to be useful for cancer
prevention and treatment.
An NCI-sponsored phase I/II trial of decaffeinated green tea extracts
for patients with asymptomatic, early stage of chronic lymphocytic
leukemia has been conducted at the Mayo Clinic to define the optimal
dosing, schedule, toxicities, and clinical efficacy [124]. Several phase
II trials using green tea in preventing breast, prostate, lung, cervical,
and esophageal cancers are being conducted (www.clinicaltrials.gov). A
phase II trial of erlotinib and green tea extract in preventing cancer
recurrence in former smokers who have undergone surgery for bladder
cancer is also being conducted (www.clinicaltrials.gov). In addition, a
phase II trial to examine the effect of green tea extract on type II diabetes and to explore the relationship between green tea extract and
related hormone peptides is being conducted (www.clinicaltrials.gov).
Resveratrol
Resveratrol (3,5,4 -trihydroxystilbene) is a phytoalexin present in a
wide variety of plant species including grapes. Resveratrol has been
shown to have beneficial effects on the reduction of oxidative stress
and the prevention of heart disease, degenerative diseases, and cancer
[125].
Resveratrol has been found to inhibit NF-κB activation, downregulate COX-2, and decrease synthesis and release of proinflammatory
mediators, leading to the suppression of inflammatory responses. In
this way, resveratrol inhibits Serratia marcescens–induced acute pneumonia in rats [126], experimental autoimmune myocarditis [127], inflammatory arthritis [128], and lung injury caused by sepsis in rats
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[129]. By regulation of NF-κB, resveratrol also protects against vascular alterations, aging, and Alzheimer’s disease [130, 131].
Experimental studies have shown that resveratrol inhibits the
growth of various cancer cells and induces apoptotic cell death [132,
133]. Resveratrol shows its inhibitory effects on the activation of NF-κB
[134], suggesting its role as NF-κB inhibitor that could sensitize cancer
cells to chemotherapeutic agents. It has been reported that resveratrol could sensitize TRAIL-induced apoptosis in pancreatic cancer cells
[135], suggesting that use of resveratrol may be a novel approach to
enhance the efficacy of chemotherapy for cancer treatment.
Several clinical trials using resveratrol in preventing colorectal cancer, follicular lymphoma, and Alzheimer’s disease are being conducted
(www.clinicaltrials.gov).
Inhibition of NF-κB by Synthetic NF-κB Inhibitors
Dehydroxymethylepoxyquinomicin (DHMEQ)
DHMEQ is a novel synthesized NF-κB inhibitor. It has been found
that DHMEQ inhibited NF-κB translocation to the nucleus and induced apoptotic cell death [136]. DHMED has been reported to suppress
diabetes-induced retinal inflammation by inhibiting the angiotensin II
type 1 receptor and NF-κB [137]. DHMEQ also suppresses osteoclastogenesis and expression of NFATc1 in mouse arthritis through the
inhibition of NF-κB [138].
It has been found that DHMEQ inhibited the growth and infiltration
of cancer cells transplanted in SCID mice [136,139]. More importantly,
DHMEQ could inhibit constitutively activated NF-κB and exhibited
synergistically inhibitory effect on cancer cell growth with cisplatin
[140]. In cancer cells, DHMEQ decreased the level of activated nuclear
NF-κB and attenuated NF-κB activation induced by cisplatin. The combination of DHMEQ with cisplatin also decreased the levels of IL-6 and
Bcl-xL mRNA, suggesting that DHMEQ could inhibit expression of
NF-κB target genes [140]. The effect of DHMEQ combined with TNF-α
were evaluated in PK-8 pancreatic cancer cells [141]. The addition of
DHMEQ to TNF-α markedly induced apoptosis with downregulation of
antiapoptotic c-FLIP and survivin in PK-8 cells [141]. These findings
suggest that DHMEQ in combination with chemotherapeutic agents
may be a promising strategy for the treatment of cancer.
Cyclooxygenase-2 (COX-2) Inhibitors
Aspirin has been used in inflammatory diseases for a long time.
In atherosclerosis, low-dose aspirin suppresses vascular inflammation
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and increases the stability of atherosclerotic plaques, both of which
contribute to its antiatherogenic effect [142]. Experimental studies
have shown that aspirin inhibits constitutively activated NF-κB in
cell culture and, in turn, decreases the expression of the NF-κB downstream gene, especially COX-2 [143]. Recently, aspirin is also considered as a cancer prevention drug because of its ability to downregulate NF-κB and COX-2. Another COX-2 inhibitor, SC236, has been
shown to suppress NF-κB DNA binding activity and NF-κB–mediated
gene transcription [144]. It is believed that SC236 directly targets
proteins that facilitate the nuclear translocation of NF-κB, thereby
suppressing the nuclear translocation of NF-κB [144] by inhibiting
COX-2.
Celecoxib, one of the COX-2 inhibitors, has been found to abrogate
TNF-α–induced NF-κB activation through inhibition of IKK and Akt in
human non–small cell lung carcinoma [145]. We have found that celecoxib significantly inhibited NF-κB activation and COX-2 expression in
pancreatic cancer cells [146, 147]. We and others have also found that
celecoxib combined with erlotinib (EGFR blocker) or curcumin synergistically potentiate the growth inhibitory and proapoptotic effects in
pancreatic cancer cells [146, 148], suggesting that celecoxib could be a
potent agent for combination treatment of cancers together with inhibition of NF-κB and EGFR.
Several phase II and III clinical trials using celecoxib in combination treatment of pancreatic, prostate, lung, and colon cancers are being
conducted (www.clinicaltrials.gov). For inflammation, a phase IV trial
is being conducted to determine if celecoxib can reduce the blood vessel inflammation associated with high cholesterol and heart disease
(www.clinicaltrials.gov). Another phase IV trial is being conducted to
determine whether the anti-inflammatory drug celecoxib can delay the
onset of Alzheimer’s disease in people with age-associated memory impairment (www.clinicaltrials.gov).
Parthenolide
Parthenolide is a synthesized small molecule that suppresses NF-κB
activation. It has been found that parthenolide inhibits the activity of IKK and NF-κB and suppresses the inflammatory response
in cystic fibrosis cells [149]. Parthenolide also modulates the NFκB–mediated inflammatory responses in experimental atherosclerosis
[150]. Importantly, parthenolide also sensitizes cancer cells to TNF-α–
induced apoptosis by inhibition of NF-κB in human cancer cells [151].
In pancreatic cancer cell lines (BxPC-3, PANC-1, and MIA PaCa-2),
parthenolide treatment dose-dependently increased the amount of
NF-κB as a Target for Human Diseases
307
IκBα and decreased NF-κB DNA binding activity [152]. By the inhibition of NF-κB pathway, parthenolide sensitized pancreatic cancer
cells to as NSAID. The combination treatment with parthenolide and
NSAID sulindac synergistically inhibited cell growth and induced apoptosis, suggesting that combination treatment with NF-κB inhibitor
and NSAIDs could be a novel strategy for the treatment of cancer
[152].
Sulfasalazine
Sulfasalazine is commonly used as an anti-inflammatory agent
and is known as a potent inhibitor of NF-κB. Sulfasalazine interferes with IKK/NF-κB pathway to regulate the release of proinflammatory cytokines from human adipose tissue and skeletal muscle [153]. Muerkoster et al. have investigated whether blockade of
NF-κB activity with sulfasalazine is suitable for overcoming NF-κB–
induced chemoresistance in vivo in a mouse model of pancreatic cancer [154]. They found that treatment with chemotherapeutic agent
etoposide alone moderately reduced tumor size (32–35% reduction)
compared with untreated tumors. Sulfasalazine alone only temporarily decreased the tumor sizes. However, sulfasalazine in combination
with etoposide significantly reduced tumor size (80% reduction) in all
experiments. TUNEL staining showed higher numbers of apoptotic
cells in tumors from the combination group. Immunohistochemical
staining showed that sulfasalazine treatment abolished the basal NFκB activity in tumor xenografts, suggesting that sulfasalazine sensitizes cancer cells to chemotherapeutic agents by inhibition of NF-κB
[154].
Several clinical trials are being conducted to investigate the effects of sulfasalazine on pediatric juvenile idiopathic arthritis, rheumatoid arthritis, spondylitis, atherosclerosis, and coronary artery disease
(www.clinicaltrials.gov).
Proteasome Inhibitor: PS-341 and MG-132
Proteasome inhibitors PS-341 (bortezomib, Velcade, Millennium
Pharmaceuticals, Cambridge, MA) and MG-132 have been known to
block intracellular degradation of IκBα proteins and, in turn, inhibit activation of NF-κB. These proteasome inhibitors have been used as antiinflammatory drugs [155]. However, these drugs have also been used for
cancer treatment. PS-341 has been found to completely abolish NF-κB
DNA binding activity through inhibition of IκBα degradation and to inhibit expression of Bcl-xL in pancreatic cancer cells [156]. Moreover, PS341 could also sensitize cancer cells to apoptosis induced by paclitaxel
308
F. H. Sarkar et al.
through the inhibition of NF-κB. In addition to PS-341, MG-132 has
also been found to inhibit NF-κB activation by downregulation of IκBα
degradation. It has been found that MG-132 also downregulates expression of MMP-9, one of the NF-κB downstream target genes, through inhibition of NF-κB [157]. These findings suggest that combination treatment with proteasome inhibitors could enhance the efficacy of cancer
therapies.
Several clinical trials using PS-341 (bortezomib) are being conducted
for the combination treatment of pancreatic, breast, prostate, lung,
colorectal, and head and neck cancers (www.clinicaltrials.gov).
BAY 11-7082
BAY 11-7082 is a synthetic NF-κB inhibitor that downregulates
IκBα phosphorylation and leads to the inhibition of NF-κB activation.
BAY 11-7082 interferes with NF-κB pathway to regulate the release of
proinflammatory cytokines from human adipose and skeletal muscle
cells [153]. BAY 11-7082 also downregulates NF-κB–inducible genes
such as IL-10, IL-15, Bcl-xL, TNF-α, and TGF-β [158], suggesting its
anti-inflammatory effect. Importantly, BAY 11-7082 inhibits constitutive NF-κB activity, leading to cell cycle arrest in G1 phase and rapid
induction of apoptosis in multidrug-resistant cancers [159], suggesting that suppression of constitutive NF-κB activity by BAY 11-7082
could be a useful treatment strategy for multidrug-resistant cancers.
Moreover, BAY 11-7082 has been found to sensitize cancer cells to
TPA-induced growth inhibition and apoptosis through inhibition of
NF-κB activation induced by TPA [160], suggesting that BAY 11-7082
could be used to enhance the efficacy of chemotherapy in combination
treatment.
CONCLUSION
NF-κB is an important transcription factor that plays central roles in
oxidative stress, inflammation, and carcinogenesis. It regulates the expression of genes critically involved in the processes of aging, metabolic
diseases, inflammatory diseases, carcinogenesis, cancer cell EMT, invasion, and metastasis. Targeting NF-κB may be a novel and important
preventive or therapeutic strategy against human cancers and chronic
diseases that are caused in part due to induction of oxidative stress.
Therefore, the strategies focused on reducing the activity of NF-κB by
natural or synthetic NF-κB inhibitors could become a novel and potent
approach for enhancing the therapeutic efficacy of conventional agents
for the treatment of human cancers and inflammatory diseases.
NF-κB as a Target for Human Diseases
309
REFERENCES
[1] R. Sen and D. Baltimore, Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell 46: 705–716, 1986.
[2] R. Sen and D. Baltimore, Inducibility of kappa immunoglobulin enhancer-binding
protein Nf-kappa B by a posttranslational mechanism. Cell 47: 921–928, 1986.
[3] M. Karin and F.R. Greten, NF-kappaB: linking inflammation and immunity to
cancer development and progression. Nat Rev Immunol 5: 749–759, 2005.
[4] P.J. Barnes and M. Karin, Nuclear factor-kappaB: a pivotal transcription factor in
chronic inflammatory diseases. N Engl J Med 336: 1066–1071, 1997.
[5] V. Anest, J.L. Hanson, P.C. Cogswell, K.A. Steinbrecher, B.D. Strahl, and A.S. Baldwin, A nucleosomal function for IkappaB kinase-alpha in NF-kappaB-dependent
gene expression. Nature 423: 659–663, 2003.
[6] C. Granet, W. Maslinski, and P. Miossec, Increased AP-1 and NF-kappaB activation
and recruitment with the combination of the proinflammatory cytokines IL-1beta,
tumor necrosis factor alpha and IL-17 in rheumatoid synoviocytes. Arthritis Res
Ther 6: R190–R198, 2004.
[7] Y.M. Zhu, D.A. Bradbury, L. Pang, and A.J. Knox, Transcriptional regulation
of interleukin (IL)-8 by bradykinin in human airway smooth muscle cells involves prostanoid-dependent activation of AP-1 and nuclear factor (NF)-IL-6 and
prostanoid-independent activation of NF-kappaB. J Biol Chem 278: 29366–29375,
2003.
[8] Y.C. Hseu, F.Y. Wu, J.J. Wu, J.Y. Chen, W.H. Chang, F.J. Lu, Y.C. Lai, and H.L.
Yang, Anti-inflammatory potential of Antrodia camphorata through inhibition of
iNOS, COX-2 and cytokines via the NF-kappaB pathway. Int Immunopharmacol
5: 1914–1925, 2005.
[9] A.K. Kiemer, T. Hartung, C. Huber, and A.M. Vollmar, Phyllanthus amarus has
anti-inflammatory potential by inhibition of iNOS, COX-2, and cytokines via the
NF-kappaB pathway. J Hepatol 38: 289–297, 2003.
[10] C. Jobin, O. Morteau, D.S. Han, and S.R. Balfour, Specific NF-kappaB blockade selectively inhibits tumour necrosis factor-alpha-induced COX-2 but not constitutive
COX-1 gene expression in HT-29 cells. Immunology 95: 537–543, 1998.
[11] D.J. Van Antwerp, S.J. Martin, T. Kafri, D.R. Green, and I.M. Verma, Suppression
of TNF-alpha-induced apoptosis by NF-kappaB. Science 274: 787–789, 1996.
[12] M. Wu, H. Lee, R.E. Bellas, S.L. Schauer, M. Arsura, D. Katz, M.J. FitzGerald, T.L.
Rothstein, D.H. Sherr, and G.E. Sonenshein, Inhibition of NF-kappaB/Rel induces
apoptosis of murine B cells. EMBO J 15: 4682–4690, 1996.
[13] G. Helbig, K.W. Christopherson, P. Bhat-Nakshatri, S. Kumar, H. Kishimoto, K.D.
Miller, H.E. Broxmeyer, and H. Nakshatri, NF-kappaB promotes breast cancer cell
migration and metastasis by inducing the expression of the chemokine receptor
CXCR4. J Biol Chem 278: 21631–21638, 2003.
[14] S. Huang, C.A. Pettaway, H. Uehara, C.D. Bucana, and I.J. Fidler, Blockade of
NF-kappaB activity in human prostate cancer cells is associated with suppression
of angiogenesis, invasion, and metastasis. Oncogene 20: 4188–4197, 2001.
[15] R.S. Samant, D.W. Clark, R.A. Fillmore, M. Cicek, B.J. Metge, K.H. Chandramouli,
A.F. Chambers, G. Casey, D.R. Welch, and L.A. Shevde, Breast cancer metastasis suppressor 1 (BRMS1) inhibits osteopontin transcription by abrogating NFkappaB activation. Mol Cancer 6: 6, 2007.
[16] B.R. van den, G.R. Haenen, B.H. van, den, and A. Bast, Transcription factor NFkappaB as a potential biomarker for oxidative stress. Br J Nutr 86 (Suppl 1):
S121–S127, 2001.
310
F. H. Sarkar et al.
[17] J.N. Davis, O. Kucuk, Z. Djuric, and F.H. Sarkar, Soy isoflavone supplementation in
healthy men prevents NF-kappa B activation by TNF-alpha in blood lymphocytes.
Free Radic Biol Med 30: 1293–1302, 2001.
[18] L. Deng, Y.C. Lin-Lee, F.X. Claret, and M.T. Kuo, 2-acetylaminofluorene upregulates rat mdr1b expression through generating reactive oxygen species that
activate NF-kappa B pathway. J Biol Chem 276: 413–420, 2001.
[19] D. Galaris and A. Evangelou, The role of oxidative stress in mechanisms of metal-induced carcinogenesis. Crit Rev Oncol Hematol 42: 93–103,
2002.
[20] M. Karin, Nuclear factor-kappaB in cancer development and progression. Nature
441: 431–436, 2006.
[21] T. Finkel and N.J. Holbrook, Oxidants, oxidative stress and the biology of ageing.
Nature 408: 239–247, 2000.
[22] E. Ho and T.M. Bray, Antioxidants, NFkappaB activation, and diabetogenesis. Proc
Soc Exp Biol Med 222: 205–213, 1999.
[23] S.E. Lamhamedi-Cherradi, S. Zheng, B.A. Hilliard, L. Xu, J. Sun, S. Alsheadat,
H.C. Liou, and Y.H. Chen, Transcriptional regulation of type I diabetes by NFkappa B. J. Immunol 171: 4886–4892, 2003.
[24] Z.U. Mollah, S. Pai, C. Moore, B.J. O’Sullivan, M.J. Harrison, J. Peng, K. Phillips,
J.B. Prins, J. Cardinal, and R. Thomas, Abnormal NF-{kappa}B function characterizes human type 1 diabetes dendritic cells and monocytes. J Immunol 180:
3166–3175, 2008.
[25] M.F. Beal, Oxidatively modified proteins in aging and disease. Free Radic Biol Med
32: 797–803, 2002.
[26] B. Kaltschmidt, M. Uherek, B. Volk, P.A. Baeuerle, and C. Kaltschmidt, Transcription factor NF-kappaB is activated in primary neurons by amyloid beta peptides
and in neurons surrounding early plaques from patients with Alzheimer disease.
Proc Natl Acad Sci U. S. A 94: 2642–2647, 1997.
[27] S. Hunot, B. Brugg, D. Ricard, P.P. Michel, M.P. Muriel, M. Ruberg, B.A. Faucheux,
Y. Agid, and E.C. Hirsch, Nuclear translocation of NF-kappaB is increased in
dopaminergic neurons of patients with parkinson disease. Proc Natl Acad Sci U.
S. A 94: 7531–7536, 1997.
[28] R.E. Simmonds and B.M. Foxwell, Signalling, inflammation and arthritis: NFkappaB and its relevance to arthritis and inflammation. Rheumatology (Oxford)
47: 584–590, 2008.
[29] L. Hajra, A.I. Evans, M. Chen, S.J. Hyduk, T. Collins and M.I. Cybulsky. The
NF-kappa B signal transduction pathway in aortic endothelial cells is primed for
activation in regions predisposed to atherosclerotic lesion formation. Proc Natl
Acad Sci U. S. A. 97: 9052–9057, 2000.
[30] H. Isomoto, Y. Mizuta, M. Miyazaki, F. Takeshima, K. Omagari, K. Murase,
T. Nishiyama, K. Inoue, I. Murata, and S. Kohno, Implication of NF-kappaB
in Helicobacter pylori-associated gastritis. Am. J. Gastroenterol 95: 2768–2776,
2000.
[31] S. Schreiber, S. Nikolaus, and J. Hampe, Activation of nuclear factor kappa B
inflammatory bowel disease. Gut 42: 477–484, 1998.
[32] M.A. Brown and W.K. Jones, NF-kappaB action in sepsis: the innate immune
system and the heart. Front. Biosci 9: 1201–1217, 2004.
[33] P. Burgos, C. Metz, P. Bull, R. Pincheira, L. Massardo, C. Errazuriz, M.R. Bono, S.
Jacobelli, and A. Gonzalez, Increased expression of c-rel, from the NF-kappaB/Rel
family, in T cells from patients with systemic lupus erythematosus. J Rheumatol
27: 116–127, 2000.
NF-κB as a Target for Human Diseases
311
[34] K. Bauerova and A. Bezek, Role of reactive oxygen and nitrogen species in
etiopathogenesis of rheumatoid arthritis. Gen Physiol Biophys 18 (Spec No): 15–
20, 1999.
[35] M. Yoshizumi, K. Tsuchiya, and T.Tamaki, Signal transduction of reactive oxygen
species and mitogen-activated protein kinases in cardiovascular disease. J Med
Invest 48: 11–24, 2001.
[36] Y. Yamamoto and R.B. Gaynor, Therapeutic potential of inhibition of the NFkappaB pathway in the treatment of inflammation and cancer. J Clin Invest 107:
135–142, 2001.
[37] A.C. Bharti and B.B. Aggarwal, Nuclear factor-kappa B and cancer: its role in
prevention and therapy. Biochem Pharmacol 64: 883–888, 2002.
[38] H. Algul, M. Treiber, M. Lesina, and R.M. Schmid, Mechanisms of disease: chronic inflammation and cancer in the pancreas—a potential role for
pancreatic stellate cells? Nat Clin Pract Gastroenterol Hepatol 4: 454–462,
2007.
[39] H.S. Perwez and C.C. Harris, Inflammation and cancer: an ancient link with novel
potentials. Int J Cancer 121: 2373–2380, 2007.
[40] R.C. Bargou, F. Emmerich, D. Krappmann, K. Bommert, M.Y. Mapara, W.
Arnold, H.D. Royer, E. Grinstein, A. Greiner, C. Scheidereit, and B. Dorken,
Constitutive nuclear factor-kappaB-RelA activation is required for proliferation
and survival of Hodgkin’s disease tumor cells. J Clin Invest 100: 2961–2969,
1997.
[41] T. Hideshima, D. Chauhan, P. Richardson, C. Mitsiades, N. Mitsiades, T. Hayashi,
N. Munshi, L. Dang, A. Castro, V. Palombella, J. Adams, and K.C. Anderson, NFkappa B as a therapeutic target in multiple myeloma, J Biol Chem 277: 1663916647, 2002.
[42] H. Nakshatri, P. Bhat-Nakshatri, D.A. Martin, R.J. Goulet, Jr., and G.W.Sledge,
Jr., Constitutive activation of NF-kappaB during progression of breast cancer to
hormone-independent growth. Mol Cell Biol 17: 3629–3639, 1997.
[43] S. Shukla, G.T. MacLennan, P. Fu, J. Patel, S.R. Marengo, M.I. Resnick, and
S.Gupta, Nuclear factor-kappaB/p65 (Rel A) is constitutively activated in human
prostate adenocarcinoma and correlates with disease progression. Neoplasia 6:
390–400, 2004.
[44] L. Li, B.B. Aggarwal, S. Shishodia, J. Abbruzzese, and R.Kurzrock, Nuclear factorkappaB and IkappaB kinase are constitutively active in human pancreatic cells,
and their down-regulation by curcumin (diferuloylmethane) is associated with the
suppression of proliferation and the induction of apoptosis. Cancer 101: 2351–
2362, 2004.
[45] B. Holcomb, M. Yip-Schneider, and C.M.Schmidt, The role of nuclear factor kappaB
in pancreatic cancer and the clinical applications of targeted therapy. Pancreas 36:
225–235, 2008.
[46] G. Levidou, P. Korkolopoulou, N. Nikiteas, N. Tzanakis, I. Thymara, A.A. Saetta,
C. Tsigris, G. Rallis, K. Vlasis, and E.Patsouris, Expression of nuclear factor kappaB in human gastric carcinoma: relationship with I kappaB a and prognostic
significance. Virchows Arch 450: 519–527, 2007.
[47] C.T. Allen, J.L. Ricker, Z. Chen, and W.C.Van, Role of activated nuclear factorkappaB in the pathogenesis and therapy of squamous cell carcinoma of the head
and neck Head Neck 29: 959–971, 2007.
[48] S. Liptay, C.K. Weber, L. Ludwig, M. Wagner, G. Adler, and R.M. Schmid, Mitogenic
and antiapoptotic role of constitutive NF-kappaB/Rel activity in pancreatic cancer.
Int J Cancer 105: 735–746, 2003.
312
F. H. Sarkar et al.
[49] S. Fujioka, G. M.Sclabas, C. Schmidt, W.A. Frederick, Q.G. Dong, J.L. Abbruzzese,
D.B. Evans, C. Baker, and P.J. Chiao, Function of nuclear factor kappaB in pancreatic cancer metastasis. Clin Cancer Res 9: 346–354, 2003.
[50] S. Fujioka, G.M. Sclabas, C. Schmidt, J. Niu, W.A. Frederick, Q.G. Dong, J.L.
Abbruzzese, D.B. Evans, C. Baker, and P.J. Chiao, Inhibition of constitutive NFkappa B activity by I kappa B alpha M suppresses tumorigenesis. Oncogene 22:
1365–1370, 2003.
[51] W. Wang, J.L. Abbruzzese, D.B. Evans, and P.J. Chiao, Overexpression of
urokinase-type plasminogen activator in pancreatic adenocarcinoma is regulated
by constitutively activated RelA. Oncogene 18: 4554–4563, 1999.
[52] S.E. Chuang, P.Y. Yeh, Y.S. Lu, G.M. Lai, C.M. Liao, M. Gao, and A.L. Cheng, Basal
levels and patterns of anticancer drug-induced activation of nuclear factor-kappaB
(NF-kappaB), and its attenuation by tamoxifen, dexamethasone, and curcumin in
carcinoma cells. Biochem Pharmacol 63: 1709–1716, 2002.
[53] Y. Li, F. Ahmed, S. Ali, P.A. Philip, O. Kucuk, and F.H. Sarkar, Inactivation of
nuclear factor kappaB by soy isoflavone genistein contributes to increased apoptosis induced by chemotherapeutic agents in human cancer cells. Cancer Res 65:
6934–6942, 2005.
[54] P.Y. Yeh, S.E. Chuang, K.H. Yeh, Y.C. Song, C.K. Ea, and A.L. Cheng, Increase of the resistance of human cervical carcinoma cells to cisplatin by inhibition of the MEK to ERK signaling pathway partly via enhancement of anticancer drug-induced NF kappa B activation. Biochem Pharmacol 63: 1423–1430,
2002.
[55] A. Arlt, J. Vorndamm, S. Muerkoster, H. Yu, W.E. Schmidt, U.R. Folsch, and
H.Schafer, Autocrine production of interleukin 1beta confers constitutive nuclear
factor kappaB activity and chemoresistance in pancreatic carcinoma cell lines.
Cancer Res 62: 910–916, 2002.
[56] S. Muerkoster, A. Arlt, B. Sipos, M. Witt, M. Grossmann, G. Kloppel, H. Kalthoff,
U.R. Folsch, and H.Schafer, Increased expression of the E3-ubiquitin ligase receptor subunit betaTRCP1 relates to constitutive nuclear factor-kappaB activation
and chemoresistance in pancreatic carcinoma cells. Cancer Res 65: 1316–1324,
2005.
[57] J.P. Thiery, Epithelial-mesenchymal transitions in tumour progression. Nat. Rev.
Cancer 2: 442–454, 2002.
[58] T. Brabletz, A. Jung, S. Reu, M. Porzner, F. Hlubek, L.A. Kunz-Schughart, R.
Knuechel, and T. Kirchner, Variable beta-catenin expression in colorectal cancers
indicates tumor progression driven by the tumor environment. Proc Natl Acad Sci
U. S. A 98: 10356–10361, 2001.
[59] V. Stemmer, C.B. de, G. Berx, and J.Behrens, Snail promotes Wnt target gene
expression and interacts with beta-catenin. Oncogene 2008.
[60] T.R. Graham, H.E. Zhau, V.A. Odero-Marah, A.O. Osunkoya, K.S. Kimbro, M.
Tighiouart, T. Liu, J.W. Simons, and R.M. O’Regan, Insulin-like growth factor-Idependent up-regulation of ZEB1 drives epithelial-to-mesenchymal transition in
human prostate cancer cells. Cancer Res 68: 2479–2488, 2008.
[61] M.H. Yang, M.Z. Wu, S.H. Chiou, P.M. Chen, S.Y. Chang, C.J. Liu, S.C. Teng, and
K.J.Wu, Direct regulation of TWIST by HIF-1alpha promotes metastasis. Nat Cell
Biol 10: 295–305, 2008.
[62] S. Spaderna, O. Schmalhofer, M. Wahlbuhl, A. Dimmler, K. Bauer, A. Sultan, F.
Hlubek, A. Jung, D. Strand, A. Eger, T. Kirchner, J. Behrens, and T.Brabletz, The
transcriptional repressor ZEB1 promotes metastasis and loss of cell polarity in
cancer. Cancer Res 68: 537–544, 2008.
NF-κB as a Target for Human Diseases
313
[63] J. Yang, S.A. Mani, J.L. Donaher, S. Ramaswamy, R.A. Itzykson, C. Come, P. Savagner, I. Gitelman, A. Richardson, and R.A. Weinberg. Twist, a master regulator
of morphogenesis, plays an essential role in tumor metastasis. Cell 117: 927–939,
2004.
[64] T. Muller, G. Bain, X. Wang, and J. Papkoff, Regulation of epithelial cell migration
and tumor formation by beta-catenin signaling. Exp Cell Res 280: 119–133, 2002.
[65] C. Min, S.F. Eddy, D.H. Sherr, and G.E. Sonenshein, NF-kappaB and epithelial to
mesenchymal transition of cancer. J Cell Biochem 2008.
[66] D.C. Radisky and M.J. Bissell, NF-kappaB links oestrogen receptor signalling and
EMT. Nat Cell Biol 9: 361–363, 2007.
[67] H.L. Chua, P. Bhat-Nakshatri, S.E. Clare, A. Morimiya, S. Badve, and H. Nakshatri, NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1
and ZEB-2. Oncogene 26: 711–724, 2007.
[68] S. Julien, I. Puig, E. Caretti, J. Bonaventure, L. Nelles, R.F. van, C. Dargemont,
A.G. de Herreros, A. Bellacosa, and L.Larue, Activation of NF-kappaB by Akt upregulates Snail expression and induces epithelium mesenchyme transition. Oncogene 26: 7445–7456, 2007.
[69] X. Wang, K. Belguise, N. Kersual, K.H. Kirsch, N.D. Mineva, F. Galtier, D. Chalbos, and G.E. Sonenshein, Oestrogen signalling inhibits invasive phenotype by
repressing RelB and its target BCL2. Nat Cell Biol 9: 470–478, 2007.
[70] D. Kong, Z. Wang, S.H. Sarkar, Y. Li, S. Banerjee, A. Saliganan, H.R. Kim,
M.L. Cher, and F.H. Sarkar, PDGF-D over-expression contributes to epithelialmesenchymal transition of PC3 prostate cancer cells. Stem Cells 26: 1425–1435,
2008.
[71] C.H. Chung, J.S. Parker, K. Ely, J. Carter, Y. Yi, B.A. Murphy, K.K. Ang, A.K.
El-Naggar, A.M. Zanation, A.J. Cmelak, S. Levy, R.J. Slebos, and W.G. Yarbrough,
Gene expression profiles identify epithelial-to-mesenchymal transition and activation of nuclear factor-kappaB signaling as characteristics of a high-risk head
and neck squamous cell carcinoma. Cancer Res 66: 8210–8218, 2006.
[72] M. Zhang, X. Xie, A.H. Lee, and C.W. Binns, Soy and isoflavone intake are associated with reduced risk of ovarian cancer in southeast China. Nutr Cancer 49:
125–130, 2004.
[73] A.H. Wu, M.C. Yu, C.C. Tseng, N.C. Twaddle, and D.R. Doerge, Plasma isoflavone
levels versus self-reported soy isoflavone levels in Asian-American women in Los
Angeles County. Carcinogenesis 25: 77–81, 2004.
[74] M. Hamalainen, R. Nieminen, P. Vuorela, M. Heinonen and E. Moilanen. Antiinflammatory effects of flavonoids: genistein, kaempferol, quercetin, and daidzein
inhibit STAT-1 and NF-kappaB activations, whereas flavone, isorhamnetin, naringenin, and pelargonidin inhibit only NF-kappaB activation along with their inhibitory effect on iNOS expression and NO production in activated macrophages.
Mediators Inflamm 2007: 45673, 2007.
[75] J.L. Kang, H.W. Lee, H.S. Lee, I.S. Pack, Y. Chong, V. Castranova, and Y. Koh,
Genistein prevents nuclear factor-kappa B activation and acute lung injury induced by lipopolysaccharide. Am J Respir Crit Care Med 164: 2206–2212, 2001.
[76] R. Kalhan, L.J. Smith, M.C. Nlend, A. Nair, J.L. Hixon, and P.H. Sporn, A mechanism of benefit of soy genistein in asthma: inhibition of eosinophil p38-dependent
leukotriene synthesis. Clin Exp Allergy 38: 103–112, 2008.
[77] L.J. Smith, J.T. Holbrook, R. Wise, M. Blumenthal, A.J. Dozor, J. Mastronarde,
and L. Williams, Dietary intake of soy genistein is associated with lung function
in patients with asthma. J Asthma 41: 833–843, 2004.
314
F. H. Sarkar et al.
[78] S. Banerjee, Y. Zhang, S. Ali, M. Bhuiyan, Z. Wang, P.J. Chiao, P.A. Philip, J.
Abbruzzese, and F.H. Sarkar, Molecular evidence for increased antitumor activity
of gemcitabine by genistein in vitro and in vivo using an orthotopic model of
pancreatic cancer. Cancer Res 65: 9064–9072, 2005.
[79] Y. Li and F.H. Sarkar, Inhibition of nuclear factor kappaB activation in PC3 cells
by genistein is mediated via Akt signaling pathway. Clin Cancer Res 8: 2369–2377,
2002.
[80] J.J. Raffoul, S. Banerjee, V. Singh-Gupta, Z.E. Knoll, A. Fite, H. Zhang, J. Abrams,
F.H. Sarkar, and G.G. Hillman, Down-regulation of apurinic/apyrimidinic endonuclease 1/redox factor-1 expression by soy isoflavones enhances prostate cancer
radiotherapy in vitro and in vivo. Cancer Res 67: 2141–2149, 2007.
[81] C.H. Takimoto, K. Glover, X. Huang, S.A. Hayes, L. Gallot, M. Quinn, B.D. Jovanovic, A. Shapiro, L. Hernandez, A. Goetz, V. Llorens, R. Lieberman, J.A. Crowell, B.A. Poisson, and R.C. Bergan, Phase I pharmacokinetic and pharmacodynamic
analysis of unconjugated soy isoflavones administered to individuals with cancer.
Cancer Epidemiol Biomarkers Prev 12: 1213–1221, 2003.
[82] M. Banerjee, L.M. Tripathi, V.M. Srivastava, A. Puri, and R. Shukla, Modulation
of inflammatory mediators by ibuprofen and curcumin treatment during chronic
inflammation in rat. Immunopharmacol Immunotoxicol 25: 213–224, 2003.
[83] C.V. Rao, A. Rivenson, B. Simi, and B.S. Reddy, Chemoprevention of colon carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound.
Cancer Res 55: 259–266, 1995.
[84] A.C. Bharti, N. Donato, S. Singh, and B.B. Aggarwal. Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-kappa B
and IkappaBalpha kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis. Blood 101: 1053–1062, 2003.
[85] B.B. Aggarwal and S. Shishodia, Molecular targets of dietary agents for prevention
and therapy of cancer. Biochem Pharmacol 71: 1397–1421, 2006.
[86] S.E. Chuang, A.L. Cheng, J.K. Lin, and M.L. Kuo, Inhibition by curcumin
of diethylnitrosamine-induced hepatic hyperplasia, inflammation, cellular gene
products and cell-cycle-related proteins in rats. Food Chem Toxicol 38: 991–995,
2000.
[87] K. Sugimoto, H. Hanai, K. Tozawa, T. Aoshi, M. Uchijima, T. Nagata, and Y. Koide,
Curcumin prevents and ameliorates trinitrobenzene sulfonic acid-induced colitis
in mice. Gastroenterology 123: 1912–1922, 2002.
[88] I.A. Leclercq, G.C. Farrell, C. Sempoux, P.A. dela, and Y. Horsmans, Curcumin
inhibits NF-kappaB activation and reduces the severity of experimental steatohepatitis in mice. J Hepatol 41: 926–934, 2004.
[89] Y.S. Kim, Y. Ahn, M.H. Hong, S.Y. Joo, K.H. Kim, I.S. Sohn, H.W. Park, Y.J. Hong,
J.H. Kim, W. Kim, M.H. Jeong, J.G. Cho, J.C. Park, and J.C. Kang, Curcumin
attenuates inflammatory responses of TNF-alpha-stimulated human endothelial
cells. J Cardiovasc Pharmacol 50: 41–49, 2007.
[90] K. Reyes-Gordillo, J. Segovia, M. Shibayama, P. Vergara, M.G. Moreno, and P.
Muriel, Curcumin protects against acute liver damage in the rat by inhibiting
NF-kappaB, proinflammatory cytokines production and oxidative stress. Biochim
Biophys Acta 1770: 989–996, 2007.
[91] S.P. Weisberg, R. Leibel, and D.V. Tortoriello. Dietary curcumin significantly improves obesity-associated inflammation and diabetes in mouse models of diabesity.
Endocrinology 149: 3549–3558, 2008.
[92] A. Duvoix, F. Morceau, S. Delhalle, M. Schmitz, M. Schnekenburger, M.M. Galteau,
M. Dicato, and M. Diederich, Induction of apoptosis by curcumin: mediation by
NF-κB as a Target for Human Diseases
[93]
[94]
[95]
[96]
[97]
[98]
[99]
[100]
[101]
[102]
[103]
[104]
315
glutathione S-transferase P1-1 inhibition. Biochem Pharmacol 66: 1475–1483,
2003.
Z. Wang, Y. Zhang, S. Banerjee, Y. Li, and F.H. Sarkar, Notch-1 downregulation by curcumin is associated with the inhibition of cell growth and
the induction of apoptosis in pancreatic cancer cells. Cancer 106: 2503–2513,
2006.
B.E. Bachmeier, I.V. Mohrenz, V. Mirisola, E. Schleicher, F. Romeo, C. Hohneke, M.
Jochum, A.G. Nerlich, and U. Pfeffer, Curcumin downregulates the inflammatory
cytokines CXCL1 and -2 in breast cancer cells via NFkappaB. Carcinogenesis 29:
779–789, 2008.
Y.G. Lin, A.B. Kunnumakkara, A. Nair, W.M. Merritt, L.Y. Han, G.N. rmaiz-Pena,
A.A. Kamat, W.A. Spannuth, D.M. Gershenson, S.K. Lutgendorf, B.B. Aggarwal,
and A.K. Sood, Curcumin inhibits tumor growth and angiogenesis in ovarian carcinoma by targeting the nuclear factor-kappaB pathway. Clin Cancer Res 13: 3423–
3430, 2007.
S. Aggarwal, Y. Takada, S. Singh, J.N. Myers, and B.B. Aggarwal. Inhibition of
growth and survival of human head and neck squamous cell carcinoma cells by
curcumin via modulation of nuclear factor-kappaB signaling. Int J Cancer 111:
679–692, 2004.
S.M. Plummer, K.A. Holloway, M.M. Manson, R.J. Munks, A. Kaptein, S. Farrow,
and L.Howells, Inhibition of cyclo-oxygenase 2 expression in colon cells by the
chemopreventive agent curcumin involves inhibition of NF-kappaB activation via
the NIK/IKK signalling complex. Oncogene 18: 6013–6020, 1999.
B.B. Aggarwal, S. Shishodia, Y. Takada, S. Banerjee, R.A. Newman, C.E. BuesoRamos, and J.E. Price, Curcumin suppresses the paclitaxel-induced nuclear factorkappaB pathway in breast cancer cells and inhibits lung metastasis of human
breast cancer in nude mice. Clin Cancer Res 11: 7490–7498, 2005.
R.A. Sharma, S.A. Euden, S.L. Platton, D.N. Cooke, A. Shafayat, H.R. Hewitt, T.H. Marczylo, B. Morgan, D. Hemingway, S.M. Plummer, M. Pirmohamed, A.J. Gescher, and W.P. Steward, Phase I clinical trial of oral curcumin:
biomarkers of systemic activity and compliance. Clin Cancer Res 10: 6847–6854,
2004.
A.L. Cheng, C.H. Hsu, J.K. Lin, M.M. Hsu, Y.F. Ho, T.S. Shen, J.Y. Ko, J.T. Lin, B.R.
Lin, W. Ming-Shiang, H.S. Yu, S.H. Jee, G.S. Chen, T.M. Chen, C.A. Chen, M.K.
Lai, Y.S. Pu, M.H. Pan, Y.J. Wang, C.C. Tsai, and C.Y. Hsieh, Phase I clinical trial
of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant
lesions. Anticancer Res 21: 2895–2900, 2001.
N. Dhillon, B.B. Aggarwal, R.A. Newman, R.A. Wolff, A.B. Kunnumakkara,
J.L. Abbruzzese, C.S. Ng, V. Badmaev, R. Kurzrock, Phase II trial of curcumin
in patients with advanced pancreatic cancer. Clin Cancer Res 14: 4491–4499,
2008.
L. Li, B. Ahmed, K. Mehta, and R. Kurzrock, Liposomal curcumin with and without
oxaliplatin: effects on cell growth, apoptosis, and angiogenesis in colorectal cancer.
Mol Cancer Ther 6: 1276–1282, 2007.
L. Li, F.S. Braiteh, and R.Kurzrock, Liposome-encapsulated curcumin: in vitro and
in vivo effects on proliferation, apoptosis, signaling, and angiogenesis. Cancer 104:
1322–1331, 2005.
C.W. Nho and E.Jeffery, Crambene, a bioactive nitrile derived from glucosinolate
hydrolysis, acts via the antioxidant response element to upregulate quinone reductase alone or synergistically with indole-3-carbinol. Toxicol Appl Pharmacol
198: 40–48, 2004.
316
F. H. Sarkar et al.
[105] S.H. Benabadji, R. Wen, J.B. Zheng, X.C. Dong, and S.G. Yuan, Anticarcinogenic
and antioxidant activity of diindolylmethane derivatives. Acta Pharmacol Sin 25:
666–671, 2004.
[106] H.J. Cho, M.R. Seon, Y.M. Lee, J. Kim, J.K. Kim, S.G. Kim, and J.H. Park, 3,3 Diindolylmethane suppresses the inflammatory response to lipopolysaccharide in
murine macrophages. J Nutr 138: 17–23, 2008.
[107] D.J. Kim, D.H. Shin, B. Ahn, J.S. Kang, K.T. Nam, C.B. Park, C.K. Kim, J.T. Hong,
Y.B. Kim, Y.W. Yun, D.D. Jang, and K.H. Yang, Chemoprevention of colon cancer
by Korean food plant components. Mutat Res 523–524: 99–107, 2003.
[108] Y. Li, S.R. Chinni, and F.H. Sarkar, Selective growth regulatory and pro-apoptotic
effects of DIM is mediated by AKT and NF-kappaB pathways in prostate cancer
cells. Front Biosci 10: 236–243, 2005.
[109] K.W. Rahman and F.H. Sarkar, Inhibition of nuclear translocation of nuclear factorkappaB contributes to 3,3’-diindolylmethane-induced apoptosis in breast cancer
cells. Cancer Res 65: 364–371, 2005.
[110] C.M. Cover, S.J. Hsieh, E.J. Cram, C. Hong, J.E. Riby, L.F. Bjeldanes, and G.L.
Firestone, Indole-3-carbinol and tamoxifen cooperate to arrest the cell cycle of
MCF-7 human breast cancer cells. Cancer Res 59: 1244–1251, 1999.
[111] F.H. Sarkar and Y. Li. Indole-3-carbinol and prostate cancer. J Nutr 134: 3493S3498S, 2004.
[112] R. Naik, S. Nixon, A. Lopes, K. Godfrey, M.H. Hatem, and J.M. Monaghan, A
randomized phase II trial of indole-3-carbinol in the treatment of vulvar intraepithelial neoplasia. Int J Gynecol Cancer 16: 786–790, 2006.
[113] G.A. Reed, K.S. Peterson, H.J. Smith, J.C. Gray, D.K. Sullivan, M.S. Mayo,
J.A. Crowell, and A. Hurwitz, A phase I study of indole-3-carbinol in women:
tolerability and effects. Cancer Epidemiol Biomarkers Prev 14: 1953–1960,
2005.
[114] H. Mukhtar and N. Ahmad. Green tea in chemoprevention of cancer. Toxicol Sci
52: 111–117, 1999.
[115] F. Afaq, V.M. Adhami, N. Ahmad, and H. Mukhtar, Inhibition of ultraviolet Bmediated activation of nuclear factor kappaB in normal human epidermal keratinocytes by green tea Constituent (-)-epigallocatechin-3-gallate. Oncogene 22:
1035–1044, 2003.
[116] D.S. Wheeler, P.M. Lahni, P.W. Hake, A.G. Denenberg, H.R. Wong, C. Snead, J.D.
Catravas, and B. Zingarelli, The green tea polyphenol epigallocatechin-3-gallate
improves systemic hemodynamics and survival in rodent models of polymicrobial
sepsis. Shock 28: 353–359, 2007.
[117] O. Aktas, T. Prozorovski, A. Smorodchenko, N.E. Savaskan, R. Lauster, P.M. Kloetzel, C. Infante-Duarte, S. Brocke, and F.Zipp, Green tea epigallocatechin-3-gallate
mediates T cellular NF-kappa B inhibition and exerts neuroprotection in autoimmune encephalomyelitis. J Immunol 173: 5794–5800, 2004.
[118] P.A. Abboud, P.W. Hake, T.J. Burroughs, K. Odoms, M. O’Connor, P. Mangeshkar,
H.R. Wong, and B. Zingarelli, Therapeutic effect of epigallocatechin-3-gallate in a
mouse model of colitis. Eur J Pharmacol 579: 411–417, 2008.
[119] S.I. Rizvi, M.A. Zaid, R. Anis, and N. Mishra, Protective role of tea catechins
against oxidation-induced damage of type 2 diabetic erythrocytes. Clin. Exp. Pharmacol. Physiol 32: 70–75, 2005.
[120] M. Shimada, K. Mochizuki, N. Sakurai, and T. Goda, Dietary supplementation
with epigallocatechin gallate elevates levels of circulating adiponectin in nonobese type-2 diabetic Goto-Kakizaki rats. Biosci Biotechnol Biochem 71: 2079–
2082, 2007.
NF-κB as a Target for Human Diseases
317
[121] E.K. Song, H. Hur, and M.K. Han, Epigallocatechin gallate prevents autoimmune
diabetes induced by multiple low doses of streptozotocin in mice. Arch Pharm Res
26: 559–563, 2003.
[122] K. Hastak, S. Gupta, N. Ahmad, M.K. Agarwal, M.L. Agarwal, and H. Mukhtar,
Role of p53 and NF-kappaB in epigallocatechin-3-gallate-induced apoptosis of
LNCaP cells. Oncogene 22: 4851–4859, 2003.
[123] Q. Zhang, D. Wei, and J. Liu, In vivo reversal of doxorubicin resistance by (−)epigallocatechin gallate in a solid human carcinoma xenograft. Cancer Lett 208:
179–186, 2004.
[124] T.D. Shanafelt, Y.K. Lee, T.G. Call, G.S. Nowakowski, D. Dingli, C.S. Zent, and
N.E. Kay, Clinical effects of oral green tea extracts in four patients with low grade
B-cell malignancies. Leuk Res 30: 707–712, 2006.
[125] B. Olas, B. Wachowicz, J. Saluk-Juszczak, and T. Zielinski, Effect of resveratrol,
a natural polyphenolic compound, on platelet activation induced by endotoxin or
thrombin. Thromb Res 107: 141–145, 2002.
[126] C.C. Lu, H.C. Lai, S.C. Hsieh, and J.K. Chen, Resveratrol ameliorates Serratia
marcescens-induced acute pneumonia in rats. J Leukoc Biol 83: 1028–1037, 2008.
[127] Y. Yoshida, T. Shioi, and T. Izumi, Resveratrol ameliorates experimental autoimmune myocarditis. Circ J 71: 397–404, 2007.
[128] N. Elmali, O. Baysal, A. Harma, I. Esenkaya, and B. Mizrak, Effects of resveratrol
in inflammatory arthritis. Inflammation 30: 1–6, 2007.
[129] M. Kolgazi, G. Sener, S. Cetinel, N. Gedik, and I. Alican, Resveratrol reduces renal
and lung injury caused by sepsis in rats. J Surg Res 134: 315–321, 2006.
[130] D. Delmas, B. Jannin, and N.Latruffe, Resveratrol: preventing properties against
vascular alterations and ageing. Mol Nutr Food Res 49: 377–395, 2005.
[131] L. Rossi, S. Mazzitelli, M. Arciello, C.R. Capo, and G. Rotilio, Benefits from
dietary polyphenols for brain aging and alzheimer’s disease. Neurochem. Res,
2008.
[132] F. Scarlatti, G. Sala, G. Somenzi, P. Signorelli, N. Sacchi, and R. Ghidoni, Resveratrol induces growth inhibition and apoptosis in metastatic breast cancer cells via
de novo ceramide signaling. FASEB J 17: 2339–2341, 2003.
[133] D. Delmas, C. Rebe, S. Lacour, R. Filomenko, A. Athias, P. Gambert, M. CherkaouiMalki, B. Jannin, L. Dubrez-Daloz, N. Latruffe, and E. Solary, Resveratrol-induced
apoptosis is associated with Fas redistribution in the rafts and the formation of a
death-inducing signaling complex in colon cancer cells. J Biol Chem 278: 41482–
41490, 2003.
[134] Z. Estrov, S. Shishodia, S. Faderl, D. Harris, Q. Van, H.M. Kantarjian, M. Talpaz,
and B.B. Aggarwal, Resveratrol blocks interleukin-1beta-induced activation of the
nuclear transcription factor NF-kappaB, inhibits proliferation, causes S-phase
arrest, and induces apoptosis of acute myeloid leukemia cells. Blood 102: 987–
995, 2003.
[135] S. Fulda and K.M. Debatin, Sensitization for tumor necrosis factor-related
apoptosis-inducing ligand-induced apoptosis by the chemopreventive agent resveratrol. Cancer Res 64: 337–346, 2004.
[136] T. Ohsugi, T. Kumasaka, A. Ishida, T. Ishida, R. Horie, T. Watanabe, K. Umezawa,
and K. Yamaguchi, In vitro and in vivo antitumor activity of the NF-kappaB
inhibitor DHMEQ in the human T-cell leukemia virus type I-infected cell line,
HUT-102. Leuk Res 30: 90–97, 2006.
[137] N. Nagai, K. Izumi-Nagai, Y. Oike, T. Koto, S. Satofuka, Y. Ozawa, K. Yamashiro,
M. Inoue, K. Tsubota, K. Umezawa, and S. Ishida, Suppression of diabetesinduced retinal inflammation by blocking the angiotensin II type 1 receptor or
318
[138]
[139]
[140]
[141]
[142]
[143]
[144]
[145]
[146]
[147]
[148]
[149]
F. H. Sarkar et al.
its downstream nuclear factor-kappaB pathway. Invest Ophthalmol Vis Sci 48:
4342–4350, 2007.
T. Kubota, M. Hoshino, K. Aoki, K. Ohya, Y. Komano, T. Nanki, N. Miyasaka, and
K.Umezawa, NF-kappaB inhibitor dehydroxymethylepoxyquinomicin suppresses
osteoclastogenesis and expression of NFATc1 in mouse arthritis without affecting
expression of RANKL, osteoprotegerin or macrophage colony-stimulating factor.
Arthritis Res Ther 9: R97, 2007.
M. Watanabe, T. Ohsugi, M. Shoda, T. Ishida, S. Aizawa, M. Maruyama-Nagai,
A. Utsunomiya, S. Koga, Y. Yamada, S. Kamihira, A. Okayama, H. Kikuchi, K.
Uozumi, K. Yamaguchi, M. Higashihara, K. Umezawa, T. Watanabe, and R. Horie,
Dual targeting of transformed and untransformed HTLV-1-infected T cells by
DHMEQ, a potent and selective inhibitor of NF-kappaB, as a strategy for chemoprevention and therapy of adult T-cell leukemia. Blood 106: 2462–2471, 2005.
P. Poma, M. Notarbartolo, M. Labbozzetta, R. Sanguedolce, A. Alaimo, V. Carina,
A. Maurici, A. Cusimano, M. Cervello, and N. D’Alessandro, Antitumor effects
of the novel NF-kappaB inhibitor dehydroxymethyl-epoxyquinomicin on human
hepatic cancer cells: analysis of synergy with cisplatin and of possible correlation
with inhibition of pro-survival genes and IL-6 production. Int J Oncol 28: 923–930,
2006.
G. Matsumoto, M. Muta, K. Umezawa, T. Suzuki, K. Misumi, K. Tsuruta, A.
Okamoto, and M. Toi, Enhancement of the caspase-independent apoptotic sensitivity of pancreatic cancer cells by DHMEQ, an NF-kappaB inhibitor. Int J Oncol
27: 1247–1255, 2005.
T. Cyrus, S. Sung, L. Zhao, C.D. Funk, S. Tang, and D. Pratico, Effect of lowdose aspirin on vascular inflammation, plaque stability, and atherogenesis in lowdensity lipoprotein receptor-deficient mice. Circulation 106: 1282–1287, 2002.
G.M. Sclabas, T. Uwagawa, C. Schmidt, K.R. Hess, D.B. Evans, J.L. Abbruzzese,
and P.J. Chiao, Nuclear factor kappa B activation is a potential target for preventing pancreatic carcinoma by aspirin. Cancer 103: 2485–2490, 2005.
B.C. Wong, X. Jiang, X.M. Fan, M.C. Lin, S.H. Jiang, S.K. Lam, and H.F. Kung, Suppression of RelA/p65 nuclear translocation independent of IkappaB-alpha degradation by cyclooxygenase-2 inhibitor in gastric cancer. Oncogene 22: 1189–1197,
2003.
S. Shishodia, D. Koul, and B.B. Aggarwal, Cyclooxygenase (COX)-2 inhibitor celecoxib abrogates TNF-induced NF-kappa B activation through inhibition of activation of I kappa B alpha kinase and Akt in human non-small cell lung carcinoma:
correlation with suppression of COX-2 synthesis. J Immunol 173; 2011–2022,
2004.
S. Ali, B.F. El-Rayes, F.H. Sarkar, and P.A. Philip, Simultaneous targeting of the
epidermal growth factor receptor and cyclooxygenase-2 pathways for pancreatic
cancer therapy. Mol Cancer Ther 4: 1943–1951, 2005.
B.F. El-Rayes, S. Ali, F.H. Sarkar, and P.A. Philip, Cyclooxygenase-2-dependent
and -independent effects of celecoxib in pancreatic cancer cell lines. Mol Cancer
Ther 3: 1421–1426, 2004.
S. Lev-Ari, H. Zinger, D. Kazanov, D. Yona, R. Ben-Yosef, A. Starr, A. Figer, and
N. Arber, Curcumin synergistically potentiates the growth inhibitory and proapoptotic effects of celecoxib in pancreatic adenocarcinoma cells. Biomed. Pharmacother 59 (Suppl 2): S276–S280, 2005.
A. Saadane, S. Masters, J. DiDonato, J. Li, and M. Berger, Parthenolide inhibits
IkappaB kinase, NF-kappaB activation, and inflammatory response in cystic fibrosis cells and mice. Am J Respir Cell Mol Biol 36: 728–736, 2007.
NF-κB as a Target for Human Diseases
319
[150] O. Lopez-Franco, P. Hernandez-Vargas, G. Ortiz-Munoz, G. Sanjuan, Y. Suzuki,
L. Ortega, J. Blanco, J. Egido, and C.Gomez-Guerrero, Parthenolide modulates
the NF-kappaB-mediated inflammatory responses in experimental atherosclerosis. Arterioscler Thromb Vasc Biol 26: 1864–1870, 2006.
[151] S. Zhang, Z.N. Lin, C.F. Yang, X. Shi, C.N. Ong, and H.M. Shen, Suppressed NFkappaB and sustained JNK activation contribute to the sensitization effect of
parthenolide to TNF-alpha-induced apoptosis in human cancer cells. Carcinogenesis 25: 2191–2199, 2004.
[152] M.T. Yip-Schneider, H. Nakshatri, C.J. Sweeney, M.S. Marshall, E.A. Wiebke, and
C.M. Schmidt, Parthenolide and sulindac cooperate to mediate growth suppression
and inhibit the nuclear factor-kappa B pathway in pancreatic carcinoma cells. Mol
Cancer Ther 4: 587–594, 2005.
[153] M. Lappas, K. Yee, M. Permezel, and G.E. Rice, Sulfasalazine and BAY 11–7082
interfere with the nuclear factor-kappa B and I kappa B kinase pathway to regulate
the release of proinflammatory cytokines from human adipose tissue and skeletal
muscle in vitro. Endocrinology 146: 1491–1497, 2005.
[154] S. Muerkoster, A. Arlt, M. Witt, A. Gehrz, S. Haye, C. March, F. Grohmann, K.
Wegehenkel, H. Kalthoff, U.R. Folsch, and H. Schafer, Usage of the NF-kappaB inhibitor sulfasalazine as sensitizing agent in combined chemotherapy of pancreatic
cancer. Int J Cancer 104: 469–476, 2003.
[155] P.J. Elliott, T.M. Zollner, and W.H. Boehncke, Proteasome inhibition: a new antiinflammatory strategy. J Mol Med 81: 235–245, 2003.
[156] Q.G. Dong, G.M. Sclabas, S. Fujioka, C. Schmidt, B. Peng, T. Wu, M.S. Tsao, D.B.
Evans, J.L. Abbruzzese, T.J. McDonnell, and P.J. Chiao, The function of multiple
IkappaB : NF-kappaB complexes in the resistance of cancer cells to Taxol-induced
apoptosis. Oncogene 21: 6510–6519, 2002.
[157] Y. Lu and L.M. Wahl, Production of matrix metalloproteinase-9 by activated
human monocytes involves a phosphatidylinositol-3 kinase/Akt/IKKalpha/NFkappaB pathway. J Leukoc Biol 78: 259–265, 2005.
[158] K. Kim, K. Ryu, Y. Ko and C. Park, Effects of nuclear factor-kappaB inhibitors and
its implication on natural killer T-cell lymphoma cells. Br J Haematol 131: 59–66,
2005.
[159] M.G. Garcia, L. Alaniz, E.C. Lopes, G. Blanco, S.E. Hajos, and E. Alvarez, Inhibition
of NF-kappaB activity by BAY 11-7082 increases apoptosis in multidrug resistant
leukemic T-cell lines Leuk Res 29: 1425–1434, 2005.
[160] A. Hansson, Y.E. Marin, J. Suh, A.B. Rabson, S. Chen, E. Huberman, R.L. Chang,
A.H. Conney, and X. Zheng, Enhancement of TPA-induced growth inhibition and
apoptosis in myeloid leukemia cells by BAY 11-7082, an NF-kappaB inhibitor. Int
J Oncol 27: 941–948, 2005.