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Evidence gathering
methods
1. Curcuminoids from
Curcuma longa in the
fight against cancer
and age related
disorders |
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ACUTE VERSUS CHRONIC
INFLAMMATION |
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Prevalent thinking toward inflammation,
and the subsequent efforts to
immediately quell it, is associated with a
first aid type approach where pain is
manifest by the dysfunctioning of the
affected part of the body. However it is
inflammation as a lingering, rather than
an acute, process that is increasingly
attracting our attention as the root-cause
of many disease conditions which are still
poorly understood and treated.
Cardiovascular disease, a leading cause
of mortality in the world, is no longer
considered a disorder of lipid
accumulation, but rather a disease
process characterized by low-grade
inflammation of the vascular lining
(endothelial cells) and an inappropriate
'wound healing response' of the blood
vessels. Cancer is another example of a
chronic degenerative disease which is
initiated and promoted by the lingering
inflammation often triggered by an
environmental or nutritional factor, i.e.
carcinogen. In a similar way Alzheimer's
Disease (AD), a devastating
neurodegenerative disease, is
hypothesized as being a dysfunction of
the immune system reacting to enduring
inflammation of the central nervous
system.
Epidemiological and laboratory
studies have demonstrated the increased
risk of the above cited diseases in
individuals with elevated serum levels of
cytokines such as nuclear factor kappa
beta (NF-kB), interleukin-6 (IL-6) and
tumor necrosis factor-alpha (TNF-alpha),
cell adhesion molecules such as
intercellular adhesion molecule-1 and
P-selectin, and acute-phase proteins such
as C-reactive protein, fibrinogen and
serum amyloid and the over-expression
of cyclooxygenase enzymes (COX-1 and
COX-2). The above mentioned indices
signify a chronic inflammatory process
that may predispose one to a multitude
of degenerative disorders, diseases and
cancer.
Although synthetic drugs can
effectively reduce inflammation and pain
in acute and chronic inflammatory
conditions, they work in a very selective
way which may be counterproductive to
the purpose of treatment. Recent
research reveals that selective COX-2
inhibitors (pharmaceutical) may induce
metabolic imbalances that can result in
the overproduction of two toxic cytokines;
TNF-alpha and certain interleukins that
are involved in the progression of
inflammation.
Although synthetic drugs can
effectively reduce inflammation and pain
in acute and chronic inflammatory
conditions, they work in a very selective
way which may be counterproductive to
the purpose of treatment. Recent
research reveals that selective COX-2
inhibitors (pharmaceutical) may induce
metabolic imbalances that can result in
the overproduction of two toxic cytokines;
TNF-alpha and certain interleukins that
are involved in the progression of
inflammation.
In the emerging trend to search for
natural alternatives, turmeric root, ginger
root, rosemary leaves, green tea leaves
and their active phytochemical
constituents are reported to be effective
COX-2 inhibitors that also inhibit the
formation of inflammatory leukotrienes
and toxic cytokines. In addition, they do
not irritate the gastrointestinal lining (mucosa). These materials have a safe
record of medicinal and food use
spanning centuries. Furthermore, no
adverse effects have been reported in
clinical studies performed to validate
various therapeutic properties of these
herbs. In fact, many of these compounds
are included on the so-called GRAS list
(generally recognized as safe) – which
means that they are safe to use in daily
nutrition.
However, if the question were to be
asked: what is the most promising food
derived compound(s) to fight
inflammation and related diseases? -the
answer, based on the current body of
scientific evidence, would have to be
turmeric's curcuminoids.
Curcumin (chemically
diferuloylmethane), and its derivatives
demethoxycurcumin and
bisdemethoxycurcumin, collectively
known as curcuminoids, are responsible
for the yellow pigment derived from the
roots of the perennial herb turmeric
(Curcuma longa L.).
The same ground, dried roots of
turmeric, which have been used for
centuries as a spice (curry), food
preservative and a coloring agent, have
been found to be a rich source of
phenolic compounds (curcuminoids)
with versatile biological mechanisms. In
dietary supplement practice and in a
growing body of scientific research, an
extract of turmeric roots is being utilized
that is standardized for a high purity of
curcuminoids, e.g. 95% curcuminoids. |
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CURCUMINOIDS IN PREVENTION
AND TREATMENT OF CANCER |
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In the last three years alone there have
been several pioneering IND
(Investigational New Drug) studies
granted by the FDA and other NIH
funded studies for the investigation of
curcumin and its derivatives in the
treatment of patients with cancer and
Alzheimer's Disease. Some of the leading
clinical research centers in the US,
including MD Anderson Hospital in
Houston, TX, are involved in pre-clinical
and clinical research of the anti-cancer
mechanism and application of
curcuminoids in conditions including
multiple myeloma, colon cancer,
pancreatic, breast, prostate, head and
neck and respiratory tract cancers. These
cancer conditions are either currently
being studied in clinical experiments or
considered next in line for systematic
evaluation with curcuminoids therapy.
Curcuminoids inhibit several
processes that contribute to the survival,
proliferation, invasion and metastasis of
tumor cells. These processes with which
curcuminoids interfere include signaling
mechanisms (critical for tumor growth),
regulation of apoptosis (cell death), and
tumor angiogenesis (new blood vessel
formation which feeds tumors). Current
research is designed to determine which
of these fundamental processes in
cancer development account for the
clinical effects of curcumin and its
derivatives.
Curcuminoids have significant
immunomodulating and antiinflammatory
effects, in part due to the
inhibition of cyclooxygenase type 2
enzyme (COX-2) and its subsequent
arachidonic acid metabolism. Like several
other immunomodulators, curcuminoids
inhibit the activation of the nuclear factor
kappa-B (NF-kB) family of transcription
factors, which are known to be activated
in a wide variety of solid tumors and
leukemias. The activation of NF-kB may
shield tumor cells from apoptosis, or
programmed cell death, promote tumor
growth factors and those factors that
facilitate invasion and metastasis of
tumors. Curcuminoids block the NF-kB
mediated gene expression responsible
for the chain of events leading to tumor
development, progression and expansion.
A probable mechanism of curcuminoids
seems to be blocking the degradation of
the inhibitors of NF-kB. In vitro,
curcuminoids induce apoptosis, and thus
inhibit tumor growth in a broad range of
tumor cells, including cell lines from
colon, breast, prostate, squamous cell,
renal cell, hepatocellular carcinomas, B
and T-cell lymphomas, leukemias,
melanoma and sarcoma cells.
Curcuminoids also affect a signaling
mechanism that involves expression and
activation of certain receptors of growth
factors that promote tumor growth. For
example, HER-2/neu is a member of the
Epidermal Growth Factor Receptor family,
which is overexpressed in approximately
30% of breast cancer patients.
HER-2/neu breast cancer cells, when
exposed to curcumin, inhibited the
expression of the HER-2 receptor.
Curcuminoids also affect a signaling
mechanism that involves expression and
activation of certain receptors of growth
factors that promote tumor growth. For
example, HER-2/neu is a member of the
Epidermal Growth Factor Receptor family,
which is overexpressed in approximately
30% of breast cancer patients.
HER-2/neu breast cancer cells, when
exposed to curcumin, inhibited the
expression of the HER-2 receptor.
This ability makes curcumin a
promising agent for combination with
paclitaxel (Taxol). Taxol is an alkaloid derived from the Pacific yew tree, and is
used as first line chemotherapy in breast
cancer. It induces the apoptosis
(programmed cell death) of various
breast tumor cell lines, but overexpression
of HER-2/neu may block
these apoptotic effects and induce
resistance to Taxol. Further, HER-2/neu
and Taxol can activate anti-apoptotic
pathways through activation of NF-kB.
Thus, agents such as curcuminoids that
can down-regulate NF-kB activation and
decrease HER-2/neu overexpression and
other markers of tumorigenesis augment
the therapeutic effects of Taxol against
breast cancer.
Interestingly, curcuminoids may have
a comparable mechanism of action to
the drug therapy involving Herceptin for
breast cancer patients with HER-2
receptor positive cancer cells. Herceptin
is an antibody against HER-2 receptors;
binding, blocking and inactivating those
receptors. In addition, in vitro, the growth
of breast cancer cells with multi-drug
resistance (MDR) characteristics is
inhibited by these turmeric phenolics; the
stimulation of estrogen receptor (ER)
positive cell lines by estrogenic pesticides
is also inhibited by curcuminoids.
Curcuminoids have also been found to
inhibit epidermal growth factor receptor
expression and/or activation in skin
cancer cell lines as well as in androgen
sensitive and androgen insensitive
prostate cancer cell lines.
An important anti-cancer mechanism
of curcuminoids is due to constriction of
vital blood supply to the rapidly growing
tumor. These compounds inhibit in vitro
the vessel endothelial and smooth
muscle cell growth and proliferation,
which is the basis for inhibition of
angiogenesis (new blood vessel
formation). Curcuminoids also inhibit
new vessel formation induced by growth
factors, such as fibroblast growth factor-2
(FGF-2). Furthermore, curcuminoids
inhibit the production of vascular
endothelial growth factor (VEGF) in
human melanoma cells. The antiangiogenic
effect of turmeric compounds
can be explained due to the
aforementioned selective COX-2
inhibition with curcuminoids. COX-2
enzyme activity may actually contribute
to tumor growth (inhibition of apoptosis)
along with increased production of the
new vessel growth factors (VEGF, FGF)
and the formation of new blood vessels.
An in vivo study showed tumor regression in response to cyclooxygenase
inhibitors in experimental models of
human colon, prostate, gastric, lung and
certain types of head and neck tumors.
In in vitro experiments cyclooxygenase
inhibitors inhibited the growth of human
pancreatic, liver and breast cancer cell
lines.
While there are still limited human
trials involving curcuminoids, in animal
models curcuminoids prevent tumor
formation in genetically predisposed
animals, i.e. animals prone to develop
precancerous multiple intestinal
adenomas, a model for the human
condition known as Familial
Adenomatous Polyposis (FAP). Dietary
enrichment with curcuminoids inhibited
polyp growth in these animals by over
60%. A study with human subjects is
currently underway evaluating the effects
of curcuminoids on Aberrant Crypt Foci
(ACF) development in the colon.
Curcuminoids were also successfully
tested in several other intervention trials.
In one experiment mice inoculated with
melanoma cells responded to dietary
curcumin intervention with a reduction in
the number of lung tumor nodules by
90%, as compared to sham fed controls.
In a dose-escalation study 15 patients
with advanced colorectal cancer
refractory to standard chemotherapy
received curcuminoids in doses between
0.45 and 3.6 g daily for up to 4 months.
Three biomarkers of the potential activity
of curcuminoids were translated from
preclinical models and measured in
patient blood leukocytes: glutathione
S-transferase activity (GST), levels of
DNA adduct (M1G), and prostaglandin
E2 (PGE2) production induced ex vivo.
Dose-limiting toxicity was not observed. A
daily dose of 3.6 g curcuminoids resulted
in a significant decrease in PGE2
production in the blood samples, while
showing no effect on GST and M1G
formation. In conclusion of this study,
a daily oral dose of 3.6 g of
curcuminoids is advocated for Phase II
evaluation in the prevention or
treatment of cancer. PGE2 production
in blood and target tissue may
indicate biological activity. It should be
noted that other studies indicate the
anti-cancer mechanism of
curcuminoids as related to induction
of GST enzymes, inhibition of PGE2
production, or suppression of oxidative
genetic material damage (DNA adduct
(M1G) formation). |
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CURCUMINOIDS IN PREVENTION
AND TREATMENT OF
NEURODEGENERATIVE
CONDITIONS |
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Aging can be described as a decline in
function and performance of body organs
and systems, which enhances the
likelihood of wear-and-tear damage,
inflammation and pain of affected organs
or systems in the body. One of the most
challenging fields in anti-aging medicine is
the management and treatment of
chronic degenerative conditions as
exemplified by Alzheimer's Disease. This
disease is increasingly seen as a defective
response to the aging immune system.
The aging immune system becomes
progressively less efficient in dealing with
inflammation. This is because both innate
and adaptive (acquired during life-time)
immune responses show age-related
changes that could be decisive for healthy
aging and survival. Natural or innate
immunity is particularly important in the
aging process and is based on foot
soldier-type cells called macrophages,
which are crucial for defense against
microbes and removal of cellular and
metabolic debris. Innate immunity is our
first line of defense. It functions due to a
macrophages' ability to recognize a
pattern of a pathogenic (harmful)
molecule through a code system called
pathogen-associated molecular patterns
(PAMPs). These potentially harmful
molecules, e.g. amyloid protein, when
recognized by macrophages, trigger
responses which also guide an
appropriate adaptive immune response.
The interaction between the innate and
adaptive immune systems is critical for
the clinical outcome of a pathogen
molecule challenge to an organism. A
harmonious response to the challenge of
a pathogen molecule changes with aging
and may lead to a defective or misguided
response of macrophages - a difference
between macrophages contributing to the
body injury or to the healing process.
In Alzheimer’s Disease (AD), there is
increasing evidence supporting a role for
macrophages and the dependent innate
immunity system in disease origins and
progression. Brain amyloidosis is
hypothesized to be a crucial pathogenic
mechanism in the AD brain and many
investigators of AD pathogenesis believe
that accumulation of amyloid-β (Aβ) is
toxic to neurons. The immune system of
patients with AD is generally poorly
responsive to Aβ. The amyloid hypothesis
of AD has increased interest in developing
therapies that promote clearance of brain amyloidosis by macrophages leading
to a novel strategy of immunotherapy
with Aβ vaccine, or antibodies against
the amyloid protein. It was
established that the anti-Aβ
antibodies were sufficient for
reducing Aβ in the brain, and that
these reductions were accompanied
by improvement in cognitive function
in animal models of AD. Importantly,
since the 1990’s macrophages have
been considered as perpetrators of
inflammatory damage in
neurodegenerative diseases, in
parallel with cardiovascular disorders.
Consequently, anti-inflammatory therapies
with different drugs have been tested with
positive, but also negative results. |
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Figure 1 - Phagocytosis of E. coli (green) and S. aureus (red) by AD macrophages is
excellent (1) |
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Figure 2 – Phagocytosis of amyloid-β by AD macrophages is defective in comparison to control
macrophages (1).
FITC-Aβ (green), DP11 camera on Bmax Olympus |
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Figure 3 – Phagocytosis of FITC-Aβ by AD macrophages is increased by treatment with
curcuminoids (1).
0.1 μM curcuminoids overnight, 6 macrophages each, DP11 camera on Bmax Olympus microscope |
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Figure 4 – Phagocytosis of Aβ by AD macrophages is increased by curcuminoid
treatment (1).
Confocal microscopy, FITC-Aβ (green), phalloidin-FITC (red), colocalization (yellow)
Note surface binding in A vs. intracellular uptake in B |
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Recently a group of researchers from
UCLA have tested a hypothesis that
curcuminoids, which have epidemiologic
and experimental rationale for use in AD,
may improve the innate immune system
and increase amyloid clearance from the
brain of patients with sporadic Alzheimer's
Disease. Macrophages of a majority of AD
patients do not ingest (phagocitize), and
do not efficiently clear amyloid from the
brain, although they phagocytize bacteria.
In contrast, macrophages of normal
subjects phagocytize amyloid
(Figures 1, 2). Upon amyloid stimulation,
macrophages of normal subjects
accelerate synthesis of molecules which
participate in the previously discussed
system of pathogen recognition,
specifically MGAT3 (beta-1,4-mannosylglycoprotein
4-N-acetylglucosaminyltransferase) and
Toll like receptors (TLRs), whereas
mononuclear cells of AD patients
generally down-regulate these genes.
Defective phagocytosis of the amyloid
may be related to suppression of these
pathogen recognition molecules. In
mononuclear (macrophage-like) cells
isolated from peripheral blood in AD
patients, curcuminoids, especially
bisdemethoxycurcumin, may enhance
defective phagocytosis of amyloid
(Figures 3, 4) while restoring synthesis
critical for phagocytic function molecules,
MGAT3 and TLRs. Therefore curcuminoids
may provide a novel approach to AD
immunotherapy which is safer than the
recently suggested vaccine therapy. |
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CURCUMINOIDS CLINICAL USE,
SAFETY AND PHARMACOKINETICS |
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Current clinical experience indicates that
oral supplementation of curcuminoids is
tolerated without toxicity at doses of up to
8 g daily for up to 12 months.
Curcuminoids are poorly absorbed from
the gastrointestinal tract, with low
nanogram levels of circulating
curcuminoids detected in the plasma.
Nonetheless, biological activity is beyond
question, with indices of inflammation like
NF-kB and COX-2 suppressed by oral
administration of curcuminoids as well as
clinical improvement of the treated
condition. On the other hand, preclinical
data suggests that curcumin can be more
effective if higher levels of exposure are
achieved. As hydrophobic and lypophilic
compounds, curcuminoids cannot be
given directly intravenously but can be
encapsulated in a liposome for
intravenous administration. This method
would theoretically achieve higher
circulating levels of curcuminoids. Another
possibility under consideration involves a
nano-emulsion form of curcuminoids to
bypass the gastrointestinal barrier to
achieve higher plasma concentrations.
It is now well established that
curcumin exists in rodent and human
plasma largely in conjugated forms with
the glucuronide conjugate present in
much greater abundance than the sulfate
conjugate. However, even plasma
concentrations of curcumin released from
conjugated forms are surprisingly low.
Interestingly there is little evidence of the
biological activity of curcumin glucuronide,
e.g. against malignant cell growth. Possibly
there are other forms of conjugated
curcuminoids or derivatives of
curcuminoids which can better explain
their biological activity and provide future
formulae for more effective clinical
application. |
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REFERENCE |
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1) ZHANG L, FIALA M, CASHMAN J, SAYRE J,
ESPINOSA A, MAHANIAN M, ZAGHI J, BADMAEV
V, GRAVES MC, BERNARD G, ROSENTHAL M.
"Curcuminoids enhance amyloid-β uptake by
macrophages of Alzheimer's disease patients"
J. Alzheimers Dis. 2006, 10 (1), 1-7 |
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