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Bioactive
molecules of traditional Chinese medicine have been gaining great momentum in
the past few decades as treatments for many diseases. Boswellia serrata,
via its active boswellic acids, appears to have promising anti-tumor and
anti-inflammatory effects. Acetyl-11-Keto-β-Boswellic Acid
(AKBA), is a major constituent and key bioactive molecule among boswellic acids.
The potential roles of AKBA have been demonstrated in inflammatory diseases
such as arthritis, inflammatory bowel disease, asthma and many types of tumors
including glioma, leukemia, myeloma, pancreatic cancer, prostate cancer and
other diseases. In this brief review, in vitro and in vivo functions
of AKBA in inflammation diseases and tumors as well as the underlying
mechanisms are discussed.
Keywords: AKBA, Boswellic acid, Inflammation, Cancer,
Target
Abbreviations:
AKBA: Acetyl-11-Keto-β-Boswellic Acid; IKK:
IκB kinase; Akt: Protein Kinase B; TNF-α: Tumor Necrosis Factor α; NF-κB: Nuclear Factor
kappa-light-chain-enhancer of activated B cells; MCP-1: Monocyte
Chemoattractant Protein 1; VEGF: Vascular Endothelial Growth Factor; MMP-3:
Matrix Metalloproteinase-3; LTB4: Leukotriene B4; NASID: Nonsteroidal
Anti-inflammatory Drug; LPS: Lipopolysaccharides; ROS: Reactive Oxygen Species;
LDL: Low-density Lipoprotein; PGE2: Prostaglandin E2; PI3K:
Phosphatidylinositol-4,5-bisphosphate 3-kinase; COX: Cyclooxygenase; Erk: Extracellular
Signal–Regulated
Kinases; DR5: Death Receptor 5; CXCR: CXC Chemokine Receptors; CXCL: Chemokine (C-X-C
motif) Ligand
INTRODUCTION
Bowellic
acids are a series of pentacyclic triterpene molecules which exist in the Boswellia
genus. Many researchers have demonstrated that Boswellic acids exert
bioactivity both in vitro and in vivo as the main components of
frankincense, which is traditionally used for treating arthritis and wound
healing [1-4]. Boswellic acids have been revealed to act as anti-inflammatory
and anti-tumor agents partially through inhibition of 5-lipoxygense, topoisomerase
and leukocyte elastase [5, 6] and other multiple mechanisms.
Among
these Boswellic acids, AKBA is shown to be a major bioactive molecule
displaying multiple functions in anti-inflammation and anti-tumor activity.
Numerous studies focusing on AKBA have reported the beneficial and curative
effects in treating inflammatory diseases and cancer. Published literature
suggests that AKBA regulates a variety of molecular targets such as
5-lipoxygenase, NF-κB, LL-37, HIF-1 and other molecules that contribute to
inflammation and tumor progression [7-9]. In this review, the in vitro
and in vivo activity of AKBA on several inflammatory diseases and cancer
will be discussed. In addition, the putative and possible mechanisms underlying
this effective molecule may help tailor the future strategies for fighting
against cancer and refractory inflammatory diseases.
Targets
and Anti-inflammatory Mechanisms of AKBA
5-lipoxygenase
The resin
of Boswellic serrata has been used in many countries as traditional
medicine to treat inflammatory diseases. AKBA as one of the major constituents
of Boswellic serrata, has been proved to inhibit 5-lipoxygenase (5-LOX) in
vitro and in animal models [6,10-15]. Leukotrieneshas been implicated to
have proinlfammatory properties in inflammation and hypersensitivity [16,17].
5-lipoxygenase, as a key enzyme in the leukotriene synthesis, has been
developed to be a major target clinically [18]. 5-LOX product from exogenous
arachidonic acid of rat peritoneal PMNL, was inhibited by 15μM AKBA. Natural
and synthetic analogues of AKBA were tested for inhibiting 5-lipoxygenase in
intact rat neutrophils [19]. Moreover, AKBA showed efficient inhibition of
5-lipoxygenase product formation in isolated human neutrophils with IC50 of
2.8 to 8.8 μM, while failed to inhibit that of human whole blood
[20]. Upon noninhibitory pentacyclic triterpenes such as amyrin, 5-LOX product
formation was reversed [21]. As for the underlying mechanism of binding, AKBA
was shown to directly target 5-lipoxygenase via a pentacyclic
triterpene-selective binding site [11,13]. These researches indicate that AKBA
may be a potential drug for 5-lipoxygenase contributing inflammatory diseases.
Human
leukocyte elastase
As is the
case in many inflammatory diseases, levels of 5-LOX and elastase are increased
simultaneously [22]. AKBA was reported
to block the activity of human leukocyte elastase (HLE) in a
dose-dependent manner in vitro, while other leukotriene biosynthesis
inhibitors failed to inhibit HLE. In line with inhibition on 5-LOX, AKBA also
exerts non-competitive mode of HLE blocking [5,10]. This unique dual inhibition
of AKBA on both 5-LOX and HLE might provide us with better understanding about
the pathophysiology of many inflammatory disease.
LL-37
LL-37, an
antimicrobial peptide, also exerts immunomodulatory effects by induction of
cytokines production of many immune and non-immune cells [23]. Macrophage-like
cell lines produce TNF-α after LL-37 stimulation [24]. And mast cells release
IL-2, IL-4 and IL-6 when stimulated with LL-37 [25]. As the sole member of
cathelicidin with the immune modulating property, LL-37 contributes to many
autoimmune disease development such as psoriasis, atherosclerosis, systemic
lupus erythematosus and rheumatoid arthritis [26]. AKBA has been reported to
directly bind to LL-37 using an unbiased target fishing approach and exert the
inhibitory effect in a concentration dependent way [9]. Thus, AKBA may be a
suitable and potential natural chemical to treat LL-37 associated diseases.
NF-Κb
NF-κB,
due to its controlling of many pro-inflammatory and cell proliferation
associated genes transcription, is involve in a large number of diseases including
inflammatory diseases and cancers. AKBA has been reported to be a natural
inhibitor of NF-κB in many studies through several different mechanisms. In
PC-3 prostate cancer cells, AKBA was shown to directly bind to IKK,
subsequently inhibiting NF-κB signaling pathway [27]. In accordance with this,
AKBA was also reported to inhibit TNF-α induction by directly interaction with
IKK and followed inhibition of NF-κB in LPS-stimulated human monocytes [28].
AKBA potentiated apoptosis induced by TNF, suppressed TNF-induced invasion and
inhibited NF-κB ligand-induced osteoclastogenesis, all of which are considered
to require NF-κB activation. However, this inhibition on NF-κB was not observed
to act through direct binding to IKK, but through inhibition of Akt [29]. In
the case of LPS-challenged ApoE-/- mice, AKBA treatment
significantly reduced NF-κB activity and NF-κB-dependent genes such as MCP-1,
VEGF, IL-1 and TF, resulting in reduced atherosclerotic lesion size [30].
Targeting NF-κB signaling, a pivotal cause in the pathogenesis of CD18hypo
mouse model of psoriasis, with treatment of AKBA, NF-κB-dependent cytokine
production, intradermal MCP-1, IL-12 and IL-23 expression as well as the
aberrant proliferation of keratinocytes were suppressed and reduced abundantly
[31]. These reports indicate that AKBA, as a natural inhibitor of NF-κB, may
provide an effective tool for the treatment of many inflammatory diseases and
cancers.
Potential
Role of AKBA in Inflammatory Diseases
Arthritis
Osteoarthritis
(OA) is the commonest form of inflammatory joint disease, characterized by
articular cartilage degradation with an accompanying periarticular bone
response [32]. Derivatives of boswellic acid have been demonstrated to suppress
IL-β induced apoptosis of chondrocytes as well as TNFα induced production of
MMP3 by synovial fibroblasts, thus demonstrated a clear therapeutic potential
for the treatment of OA [33]. AKBA is a potent inhibitor of 5-lipoxygenase
(5-LOX), an enzyme that catalyzes the generation of leukotrienes including
LTB4, which is a molecule strongly implicated in osteoarthritis (OA)-associated
inflammation [34,35]. Huh Luo Xiao Ling Dan (HLXLD), a Chinese herbal formula
containing AKBA has been traditionally used to treat arthritis and other
chronic inflammatory diseases [36]. Boswellic acid is reported to attenuate
mouse model of osteoarthritis either orally or topically treated [37]. Based on these, several drugs which mainly
contain enriched AKBA, have been reported to have therapeutic effects on OA treatment.
In a double-blind, randomized, placebo-controlled study, patients who received
5-Loxin (containing 30% enriched AKBA) treatment, showed significantly
improvements in pain scores and physical function scores, accompanying reduced
synovial fluid matrix metalloproteinase-3 comparing to placebo group [38].
Considering the poor bioavailability of AKBA by oral administration of 5-loxin,
a novel Boswellia serrata extract Aflapin was developed [39], which
contained at least 20% of AKBA. Compared with 5-Loxin, Aflapin treatment
increased the availability of alba in systemic circulation of experimental
animals by 51.78%. Also, the inhibition of MMP-3 production was 14.83% better
than 5-Loxin [33]. These investigations reveal that AKBA is potential and
feasible to treat osteoarthritis as a alternative to NASID which exerts severe
side effects such as stomach ulcers, heartburn, headaches, etc [40].
Atherosclerosis
Atherosclerosis
is a inflammatory disease featured unresolved chronic inflammation condition
[41]. During the inflammatory process of atherosclerosis, leukocyte adhesion
and infiltration process lead to intimal arterial plaques formation, plaque
rupture, thrombosis and finally occlusion [42]. NF-κB plays an important role
in all stages of atherogenesis through genes, membrane and cellular proteins,
polypeptides, chemokines and hormonal influence [43]. In the animal experiment,
atherosclerosis lesions were induced by LPS injection in ApoE-/-
mice. AKBA treatment reduced NF-κB activity and subsequent NF-κB-dependent
genes expression such as MCP-1, MCP-3, MIP-2, VEGF and TF. Compared to LPS
injection group, AKBA treated group exerted nearly 50% reduction of
atherosclerotic lesion size. AKBA treatment did not affect the plasma
concentration of triglycerides, total cholesterol, anti oxidized LDL antibodies
and various subsets of lymphocyte-derived cytokines, indicating its
non-toxicity and safety.
Inflammatory
Bowel Disease
AKBA has
been reported to attenuate indomethacin-induced ileitis, an experimental model
of inflammatory bowel disease (IBD). Leukocyte-endothelial cell adhesive
interactions and severe tissue injury were decreased with both low and high
dose of AKBA treatment in a concentration-dependent manner [44]. A selective
5-LOX inhibitor, zileuton, was observed to significantly improve healing of
dextran sodium sulphate-induced colitis rat model of IBD, through inhibition of
neutrophil recruitment. This indicates that inhibitors of 5-LOX may
playeffective therapeutic role in treating chronic intestinal inflammation
[45]. Sphingomyelin phosphodiesterase (SMase) is regarded to contribute to
several inflammation-related diseases including IBD. As a specific inhibitor of
5-LOX, AKBA was found to inhibit and decrease SMase activity and expression in
Caco-2 cells, resulting in inhibition of cell proliferation [46]. Besides its
effectiveness, AKBA was test for its safety for influence on integrity and
function of the intestinal epithelium. 0.027 μg/ml of AKBA was administrated,
and reduced NF-κB phosphorylation as well as ROS increased by H2O2
exposure, which indicated the antioxidant activity and intestinal epithelium
barrier protection from inflammatory damage of AKBA. All together, AKBA is a
potential and safe natural product for treating intestinal inflammatory disease
including IBD [47].
Psoriasis
Psoriasis
is an immune-mediated, chronic inflammatory skin disease which affects about
2-4% of the western population [48]. It is featured by disfiguring erythematous
skin lesions covered with white silvery scales and often leads to
discrimination of the patients. The relapse and life-long accompany of this
disease also result in substantial reduction in the life quality of the patients
[49]. Thus, it is urgent to develop medicines that exert few side effects and
significant therapeutic effects against
psoriasis. In the CD18hypo mouse model of psoriasis, systematically
or locally treatment with AKBA was observed to profoundly suppress the NF-κB
signaling and the subsequent NF-κB dependent TNF-α production by macrophages.
In addition, administration of AKBA also attenuated the intradermal MCP-1,
IL-12 and IL-23 expression level in previous skin lesions, which led to
resolution of the abundant immune cell infiltrates and reduction of the
aberrant proliferation of keratinocytes. All together, AKBA treatment largely
improved the psoriasis disease activity score in the CD18hypo mice
with a nearly normal phenotype [31]. This finding demonstrates the mechanism
which might underly the effectiveness of AKBA for psoriasis treatment.
Several
drugs have been developed and even come onto market which containing AKBA as
the main effective component, for the treatment of psoriasis as a complementary
and alternative medicine. A phase Ⅲ clinical trial of Boswellia
serrata cream containing 5% of 95%AKBA revealed that 200 psoriasis patients
enrolled showed marked improvement. A significant reduction in psoriasis
activity severity index (PASI) score as well as biomarkers including TNF-α,
VEGF, LTB4 and PGE2 were also observed [50].
Antitumor
Effects
Anti-agiogenesis
Angiogenesis
is essential for tumor growth and metastasis. There are a plenty of factors
involving in the angiogenesis of tumor progression [51]. Fibroblast growth
factors are a family of growth factors that are involved in many pathways that
can contribute to carcinogenesis, and they also play a important role in
angiogenesis. It has been reported that FGF acts synergistically with VEGF to
promote angiogenesis and tumor maturation. Thus, targeting FGF is a potential
strategy for inhibiting tumor angiogenesis [52]. AKBA was found to inhibit
bFGF-induced angiogenesis in a Matrigel Plug Assay. Subcutaneous administration
of AKBA for 10mg/kg/d inhibited Matrgel + bFGF-induced angiogenesis
significantly comparing with indomethacin and cyclophosphamide at the same
dose. Histological examination also revealed inhibition of blood vessels growth
in comparison with the controlled group [7]. Besides, AKBA has also been
reported to reduce and inhibit angiogenesis in prostate tumor growth and a
mouse model of oxygen-induced retinopathy [53,54].
HIF-1
Hypoxia-inducible
factor 1 (HIF-1), is a transcriptional activator that is highly involved in
cancer pathogenesis and inflammatory disorders. Aberrant upregulation of HIF-1
is associated with aggressive tumor growth angiogenesis and metastasis, which
makes it a feature of solid tumors [55]. Therefore, HIF-1 has been validated as
a therapeutic target and inhibitors of HIF-1 have been considered to be a
potential strategy against cancer [56]. In the screening of HIF-1 inhibitors
from frankincense, molecularly imprinted polymer (MIP) was used. With
quercetin, a known inhibitor of HIF-1, as the imprinted polymer, AKBA was then
retained by solid phase extraction on MIP. AKBA effectively inhibited HIF-1
transcriptional activity and HIF-1α induction at concentration larger than 10Μm
[57].
mi-RNA
AKBA has
been reported to modulate miRNAs both in vitro and in vivo. In
HCT116, HT29, SW480, and SW620 CRC cell lines, expression levels of let-7 and
miR-200 families, which are putative tumor-suppressive mi-RNAs, were
significantly up-regulated when treated with AKBA. Downstream targets of let-7
and miR-200, such as CDK6, vimentin and E-cadherin, were
subsequently regulated. As in the case of orthotpoic CRC mouse model, the
regulations of let-7, miR-200 and their target genes were identical with that
in vitro [58]. In spite of let-7 and miR-200, AKBA has been reported to
regulate miR-34a and miR-27a as well. In CRC cell lines including HCT116, RKO,
SW480, SW620, HT29 and Caco2, AKBA inhibited cell proliferation, induced
apoptosis and cell cycle arrest. Using gene expression array and in-silico
analysis, miR-34a and miR-27a and their target genes were found to be regulated
by AKBA. Furthermore, in a mouse xenograft model, AKBA showed tumor growth
inhibition, which was consistent with in vitro findings [59]. These
novel evidences of AKBA’s anti-tumor effects via epigenetic machinery
modulation provide a new insight into the application of AKBA.
Topoisomerase
In HL-60
AND CCRF-CEM cell lines, AKBA significantly reduced cell counts and thymidine
incorporation in a concentration-dependent way, with its IC50 being
30μM. Then, in a DNA relaxation assay, AKBA was found to inhibit topoisomerase
I at the concentration of from 10μM, suggesting that induction of apoptosis in
these two leukemia cell lines by AKBA may be due to inhibition of topoimerase I
[60].
AKBA has
been reported as well to inhibit STAT-3 activation in human multiple myeloma
cells [8].
AKBA
Functions as an Anti-Tumor Agent
Glioma
AKBA has
been demonstrated to exert the cytotoxic effect against malignant glioma cell
lines including both long-term and glioma initiating cell lines by inducing
apoptosis at low concentrations with approximate EC50 value being
20μM. This toxicity was obtained by inducing p53-dependent p21 expression,
supporting by ectopic expression of p53. Nevertheless, treatment with AKBA of
subtoxic concentration didn’t interfere with the toxicity of other anti-cancer
drugs toward glioma cells in acute cytotoxicity or clonogenic cell death
assays. This indicates the effectiveness and safety of AKBA on human malignant
glioma cells and makes AKBA a possible adjunct for the treatment of human
malignant glioma [61]. In recent days, AKBA has been considered a useful
adjunct agent for treating brain metastasis [62] and glioblastoma [63].
Colorectal
cancer (CRC)
Colorectal
cancer is the third most common cancer and the fourth most common cancer cause
of death globally, accounting for roughly 1.2 million new cases and 600,000
deaths per year. The therapy for CRC patients with stage III/IV and high-risk
stage II colon cancer are adjuvant
chemotherapy [64]. AKBA has been reported to have chemoprevention effects on
colorectal cancer both in vitro and in vivo. In the cases of CRC
cell lines, AKBA induced HT-29 apoptosis slightly at the concentration of 30μM.
It was observed that AKBA treated cells showed Akt activation by Ser473 and
Thr308 phosphorylation. Inhibitors of PI3K pathway sharply enhanced AKBA
induced HT-29 apoptosis, indicating that AKBA might induce CRC cell apoptosis
through PI3K/Akt pathway [65]. Besides, AKBA was found to largely up-regulate let-7
and miR-200 expression in CRC cell lines, accompanied by modulated downstream
target genes expression such as CDK6, vimentin and E-adherin.
This was supported by the orthotopic CRC mouse model where AKBA modulated
downstream target genes of let-7 and miR-200, suggesting that AKBA might
modulate epigenetic machinery to achieve its anti-cancer activity [58].
AKBA was
also demonstrated to inhibit colorectal cancer progression or intestinal
adenomatous polypsis in animal models. Orthotropic human CRC mouse model orally
administrated with AKBA exhibited decreased tumor volumes without significant
body weight loss compared to vehicle treated group. In addition, AKBA
suppressed ascites and metastasis of tumors to the liver, lung and spleen.
Biomarkers of tumor including Ki-67, CD31, NF-κB, COX-2, cyclinD1, MMP-9 and
VEGF were also inhibited by ABKA [66]. In APCmin/+ mice which
is another human CRC mouse model, gavage administration of AKBA decreased
polyps by approximately 50% both in the small intestine and colon, along with
prevention of malignant progression of these polyps [67]. There is considerable
evidence that aspirin is potential for prevention of colorectal cancer. Also,
broader clinical recommendations for aspirin-based chemoprevention strategy have
been recently established [68]. However, in the APCmin/+ mouse
model, AKBA exerted more potential prevention of small intestinal and colonic
polyps than aspirin. And this efficacy of AKBA might contribute to its
modulation of Wnt/β-catenin and NF-κB/COX-2 pathways [69].
Leukemia
AKBA has
been reported to inhibit the proliferation and induce the apoptosis of several
leukemia cell lines including HL-60 cells and CCRF-CEM cells [70-72]. DNA, RNA
and protein synthesis were significantly inhibited by AKBA with IC50 values
of 0.6, 0.5 and 4.1μM respectively [70]. AKBA induced HL-60 and CCRF-CEM cells
apoptosis in a dose-dependent manner, which might be due to topoisomerase Ⅰ
inhibition [60,73]. These suggest that AKBA might be a promising approach for
acute myeloid leukemia, though still needsmore investigations.
Hepatocellular
carcinoma
In liver
cancer HepG2 cells, AKBA decreased cell viability as well as [3H] thymidine
incorporation, and strongly induced apoptosis accompanied by activation of
caspase-3, caspase-8 and caspase-9 [74]. Dose-dependent increase in caspase-3
activity, TNF-α level and IL-6 level was observed in HepG2 cells. Besides, AKBA
protected anti-cancer drug Doxorubicin induced hepatic toxicity in Wistar rats
[75].
Meningioma
Meningioma
cells established from surgically removed meningioma specimens, when treated
with AKBA, exhibited decrease in viable cells and inhibition of Erk-1/2 pathway
[76].
Prostate
cancer
Prostate
cancer is the most common malignancy in men and a major cause of cancer deaths
contributing to 1-2% deaths in men [77]. Since reduction of androgen
stimulation in prostatic cells is one of the main treatment strategies for
prostate cancer and expensive drugs for this disease, new agents targeting this
disease in a different mechanism are needed to be developed.
AKBA has
been reported to inhibit chemoresistant androgen-independent PC-3 prostate
cancer cells proliferation and elicit cell death in vitro by
specifically inhibiting IKK activity and NF-κB signaling pathway. Topical
application of AKBA on PC-3 tumors xenograft and nude mice implanted with PC-3
tumors inhibited tumor growth without systemic toxicity [27]. As androgen
receptor-mediated signaling is crucial for the progression and development of
prostate cancer, AKBA was demonstrated to inhibit androgen receptor by
interruption on Sp1(specificity protein 1) binding activity in prostate cancer
cells [78]. Sp1 was suggested to be a possible target for treatment of prostate
cancer for use of natural and synthetic compounds used to inhibit Sp1in
prostate cancer [79]. In addition, human prostate tumor xenograft mice treated
with AKBA shoed reduced tumor growth, which was well correlated with
suppression of angiogenesis. In vitro experiment showed that AKBA
inhibited VEGFR-2 phosphorylation and downstream protein kinases, indicating
that AKBA might inhibit prostate tumor growth via intercepting VEGFR2 signaling
pathway [53].
A novel
mechanism of AKBA inhibition of prostate cancer cell lines was demonstrated as
well. AKBA elicited apoptosis of LNCaP and PC-3 cells at concentrations above
10μg/ml. Caspase-8 was activated in AKBA treatment, which correlated with DR5
increase. Knocking down of DR5 by its shRNA inhibited AKBA-induced prostate
cancer cell apoptosis and caspase-8 activation, suggesting that AKBA may induce
apoptosis in prostate cancer cells through a DR-5-mediated pathway [80].
The
anti-prostate cancer effect of AKBA through multiple targets and pathways
demonstrates that AKBA has a large potential in strategies for treating
prostate cancer.
Pancreatic
cancer
Targeting CXCR4/CXCL12 pathway has been
considered a promising strategy for treating tumor growth and metastasis of
many types of cancers [81]. AKBA has been reported to suppress CXCR4 expression in PANC-28 cells in vitro
and in orthotopic pancreatic cancer mouse model, with reduced tumor growth and
metastasis [82,83]. Besides, pancreatic cancer cell lines including AsPC-1,
PANC-28, MIA PaCa-2 cells proliferation were inhibited by AKBA treatment, which
correlated with NF-κB and its modulating target genes suppression. In the
orthotopic human pancreatic animal model, AKBA also down-regulated Ki-67, CD31,
COX-2, MMP-9 and VEGF expression [82].
CONCLUSIONS
This
reviewed data suggest that AKBA can target and regulate multiple cell signaling
pathways which contribute to the pathogenesis and development of inflammatory
diseases and various types of tumors. These functions of AKBA make it a
potential and useful natural molecule for treatment of many diseases including
arthritis, inflammatory bowel disease, psoriasis, colorectal cancer, glioma,
leukemia, prostate cancer and also as a alternative to NASID. In spite of the
efforts that have been made through different methods including nanomicelles
loaded with AKBA and transdermal microemulsions, there remains improvement for
higher bioavailability of AKBA in vivo. Although the
anti-inflammatory and anti-cancer effect of AKBA have been demonstrated in
vitro and in vivo, resolving the problem of AKBA’s bioavailability
and enhancing its bioactivity in human patients will endow AKBA with more
applications clinically in the future.
ACKNOWLEDGEMENT
This work
is supported by grants from National Natural Science Foundation of China (Key
Program, 31330026), National Natural Science Foundation of China (General
Program, 31570922).
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