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Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa. A preclinical and clinical research

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Curcuma longa (turmeric) has a long history of use in Ayurvedic medicine as a treatment for inflammatory conditions. Turmeric constituents include the three curcuminoids: curcumin (diferuloylmethane; the primary constituent and the one responsible for its vibrant yellow color), demethoxycurcumin, and bisdemethoxycurcumin, as well as volatile oils (tumerone, atlantone, and zingiberone), sugars, proteins, and resins. While numerous pharmacological activities, including antioxidant and antimicrobial properties, have been attributed to curcumin, this article focuses on curcumin's anti-inflammatory properties and its use for inflammatory conditions. Curcumin's effect on cancer (from an anti-inflammatory perspective) will also be discussed; however, an exhaustive review of its many anticancer mechanisms is outside the scope of this article. Research has shown curcumin to be a highly pleiotropic molecule capable of interacting with numerous molecular targets involved in inflammation. Based on early cell culture and animal research, clinical trials indicate curcumin may have potential as a therapeutic agent in diseases such as inflammatory bowel disease, pancreatitis, arthritis, and chronic anterior uveitis, as well as certain types of cancer. Because of curcumin's rapid plasma clearance and conjugation, its therapeutic usefulness has been somewhat limited, leading researchers to investigate the benefits of complexing curcumin with other substances to increase systemic bioavailability. Numerous in-progress clinical trials should provide an even deeper understanding of the mechanisms and therapeutic potential of curcumin.
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Alternative Medicine Review Volume 14, Number 2 2009
Page 141
Review Article
Abstract
Curcuma longa (turmeric) has a long history of use in Ayurvedic
medicine as a treatment for inflammatory conditions. Turmeric
constituents include the three curcuminoids: curcumin
(diferuloylmethane; the primary constituent and the one
responsible for its vibrant yellow color), demethoxycurcumin,
and bisdemethoxycurcumin, as well as volatile oils (tumerone,
atlantone, and zingiberone), sugars, proteins, and resins. While
numerous pharmacological activities, including antioxidant and
antimicrobial properties, have been attributed to curcumin,
this article focuses on curcumin’s anti-inflammatory properties
and its use for inflammatory conditions. Curcumin’s effect on
cancer (from an anti-inflammatory perspective) will also be
discussed; however, an exhaustive review of its many anticancer
mechanisms is outside the scope of this article. Research has
shown curcumin to be a highly pleiotropic molecule capable
of interacting with numerous molecular targets involved
in inflammation. Based on early cell culture and animal
research, clinical trials indicate curcumin may have potential
as a therapeutic agent in diseases such as inflammatory bowel
disease, pancreatitis, arthritis, and chronic anterior uveitis, as
well as certain types of cancer. Because of curcumin’s rapid
plasma clearance and conjugation, its therapeutic usefulness
has been somewhat limited, leading researchers to investigate
the benefits of complexing curcumin with other substances
to increase systemic bioavailability. Numerous in-progress
clinical trials should provide an even deeper understanding
of the mechanisms and therapeutic potential of curcumin.
(Altern Med Rev 2009;14(2):141-153)
Introduction
Turmeric (the common name for Curcuma
longa) is an Indian spice derived from the rhizomes of
the plant and has a long history of use in Ayurvedic
medicine as a treatment for inflammatory conditions. C.
longa is a perennial member of the Zingiberaceae family
and is cultivated in India and other parts of Southeast
Asia.1 e primary active constituent of turmeric and
the one responsible for its vibrant yellow color is cur-
cumin, first identified in 1910 by Lampe and Milobed-
zka.2 While curcumin has been attributed numerous
pharmacological activities, including antioxidant3 and
antimicrobial properties,4 this article focuses on one of
the best-explored actions, the anti-inflammatory effects
of curcumin. Curcumin’s effect on cancer (from an anti-
inflammatory perspective) is also discussed; however, an
exhaustive review of its many anticancer mechanisms is
outside the scope of this article. Based on early research
conducted with cell cultures and animal models, pilot
and clinical trials indicate curcumin may have potential
as a therapeutic agent in diseases such as inflammatory
bowel disease, pancreatitis, arthritis, and chronic ante-
rior uveitis, as well as certain types of cancer. Numerous
clinical trials are currently in progress that, over the next
few years, will provide an even deeper understanding of
the therapeutic potential of curcumin.
Anti-inflammatory Properties of
Curcumin, a Major Constituent
of Curcuma longa: A Review of
Preclinical and Clinical Research
Julie S. Jurenka, MT(ASCP)
Julie Jurenka, MT (ASCP) – Associate Editor, Alternative Medicine Review;
technical assistant, Thorne Research, Inc. – the manufacturer of Meriva
Curcumin Phytosome
Correspondence address: Thorne Research, Inc, PO Box 25, Dover, ID 83825
Email: juliej@thorne.com
Copyright © 2009 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission.
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Alternative Medicine Review Volume 14, Number 2 2009
Curcumin
Page 142
Active Constituents
Turmeric is comprised of a group of three cur-
cuminoids: curcumin (diferuloylmethane), demethoxy-
curcumin, and bisdemethoxycurcumin (Figure 1), as
well as volatile oils (tumerone, atlantone, and zingib-
erone), sugars, proteins, and resins. e curcuminoid
complex is also known as Indian saffron.5 Curcumin is
a lipophilic polyphenol that is nearly insoluble in water6
but is quite stable in the acidic pH of the stomach.7
Absorption of Curcumin
Animal studies have shown curcumin is rapidly
metabolized, conjugated in the liver, and excreted in the
feces, therefore having limited systemic bioavailability.
A 40 mg/kg intravenous dose of curcumin given to rats
resulted in complete plasma clearance at one hour post-
dose. An oral dose of 500 mg/kg given to rats resulted
in a peak plasma concentration of only 1.8 ng/mL, with
the major metabolites identified being curcumin sulfate
and curcumin glucuronide.8
Data on the pharmacokinetics, metabolites,
and systemic bioavailability of curcumin in humans,
mainly conducted on cancer patients, are inconclusive.
A phase I clinical trial conducted on 25 patients with
various precancerous lesions demonstrated oral doses
of 4, 6, and 8 g curcumin daily for three months yielded
serum curcumin concentrations of only 0.51 ± 0.11,
0.63 ± 0.06, and 1.77 ± 1.87 μM, respectively, indicat-
ing curcumin is poorly absorbed and may have limited
systemic bioavailability. Serum levels peaked between
one and two hours post-dose and declined rapidly. is
study did not identify curcumin metabolites and urinary
excretion of curcumin was undetectable.9
Another phase I trial, involving 15
patients with advanced colorectal cancer, used cur-
cumin at doses between 0.45 and 3.6 g daily for four
months. In three of six patients given the 3.6 g dose,
mean plasma curcumin measured after one hour on day
1 was 11.1 ± 0.6 nmol/L. is measurement remained
relatively consistent at all time points measured during
the first month of curcumin therapy. Curcumin was not
detected in the plasma of patients taking lower doses.
Glucuronide and sulfate metabolites of curcumin were
detected in plasma of all six patients in the high-dose
group at all measurement points in the study.10 Cur-
cumin levels reported in this study are approximately
1/45 of the levels reported by Cheng et al, who used
a similar dose of curcumin (4 g).9 e reason for the
discrepancy is unclear.
While systemic distribution of curcumin tends
to be low, Garcea et al demonstrated that 3.6 g curcu-
min given to 12 patients with varying stages of colorec-
tal cancer for seven days resulted in pharmacologically
efficacious levels of curcumin (12.7 ± 5.7 nmol/g) in
both malignant colorectal tissue and normal colorectal
tissue (7.7 ± 1.8 nmol/g), perhaps accounting for the
anti-inflammatory benefits of curcumin observed in
diseases of the gastrointestinal tract.11
Although research on curcumin pharmacoki-
netics in healthy subjects is limited, one study using high
doses (10 and 12 g in a single oral dose) in 12 healthy
subjects measured serum curcumin as well as its sulfate
and glucuronide metabolites at various time points up
to 72 hours post-dose. As in previous studies, curcumin
was rapidly cleared (only one subject had detectable
free curcumin in the serum) and subsequently conju-
gated in the gastrointestinal tract and liver. Area under
CH3O
CH=CHCOCH2COCH=CH
CH=CHCOCH2COCH=CH
CH=CHCOCH2COCH=CH
HO
HO
HO
OCH3
OCH3
OH
OH
OH
Curcumin
Demethoxycurcumin
Figure 1. Structures of Curcumin
(Diferuloylmethane), Demethoxycurcumin, and
Bisdemethoxycurcumin
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Alternative Medicine Review Volume 14, Number 2 2009
Review Article
Page 143
the curve (AUC) for curcumin conjugates was surpris-
ingly higher (35.33 ± 3.78 μg/mL) for the 10-g dose
than for the 12-g dose (26.57 ± 2.97 μg/mL), perhaps
indicating saturation of the transport mechanism in
the gut for free curcumin. Maximum serum concentra-
tion (Cmax) for the 10-g dose was 2.30 ± 0.26 μg/mL
compared to 1.73 ± 0.19 μg/mL for the 12-g dose.12
Because of curcumin’s rapid plasma clearance
and conjugation, its therapeutic usefulness has been
somewhat limited, leading researchers to investigate the
benefits of complexing curcumin with other substances
to increase systemic bioavaility. One substance that has
been studied is the alkaloid piperine, a constituent from
black pepper and long pepper (Piper nigrum and Piper
longum, respectively). In humans 20 mg piperine given
concomitantly with 2 g curcumin increased serum cur-
cumin bioavailability 20-fold, which was attributed to
piperine’s inhibition of hepatic glucuronidation and in-
testinal metabolism.13
Another method currently being investigated
is complexing curcumin with a phospholipid, known
as a phytosome. e phosphatidylcholine-curcumin
complex (Meriva) is more readily incorporated into
lipophilic cell membranes, making it significantly
more bioavailable than unbound curcumin. In rats,
peak plasma concentration and AUC were five times
higher for Meriva than for unbound curcumin.14 One
small unpublished, single-dose trial demonstrated
450 mg of Meriva curcuminoids complexed with
phosphatidylcholine was absorbed as efficiently as 4 g
unbound Curcuma longa (95% curcumin), re-
flecting a significant increase in bioavailability for
Meriva complex (Figure 2).15
Anti-inflammatory Mechanisms
Research shows curcumin is a highly pleiotropic
molecule capable of interacting with numerous molecu-
lar targets involved in inflammation. Curcumin modu-
lates the inflammatory response by down-regulating the
activity of cyclooxygenase-2 (COX-2), lipoxygenase,
and inducible nitric oxide synthase (iNOS) enzymes;
inhibits the production of the inflammatory cytokines
tumor necrosis factor-alpha (TNF-a), interleukin
(IL) -1, -2, -6, -8, and -12, monocyte chemoattractant
protein (MCP), and migration inhibitory
protein; and down-regulates mitogen-activated and
Janus kinases.16,17
0.00
5.00
10.00
15.00
20.00
25.00
30.00
35.00
40.00
45.00
0 2 4 6 8 10 12 14 16 18 20 22 24
Total Curcumin [ng/ml]
Time after supplementation [hours]
450mg MERIVA curcuminoids vs 4g curcuminoids
450mg MERIVA curcuminoids
4.0g non-complexed curcuminoids
Figure 2. Absorption of Curcumin Phytosome (Meriva) Compared to Non-complex
Curcumin in Humans
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Alternative Medicine Review Volume 14, Number 2 2009
Curcumin
Page 144
COX-2 and iNOS inhibition are likely accom-
plished via curcumin’s suppression of nuclear factor-
kappa B (NF-κB) activation.18 NF-κB, a ubiquitous
eukaryotic transcription factor, is involved in regulation
of inflammation, cellular proliferation, transformation,
and tumorigenesis. Curcumin is thought to suppress
NF-κB activation and proinflammatory gene expres-
sion by blocking phosphorylation of inhibitory factor
I-kappa B kinase (IκB). Suppression of NF-κB activa-
tion subsequently down-regulates COX-2 and iNOS
expression, inhibiting the inflammatory process and
tumorigenesis.18,19 In an animal model of inflammation,
curcumin also inhibited arachidonic acid metabolism
and inflammation in mouse skin epidermis via down-
regulation of the cyclooxygenase and lipoxygenase
pathways.20
Curcumin’s inhibition of inflammatory
cytokines is achieved through a number of mechanisms.
In vitro studies indicate curcumin regulates activa-
tion of certain transcription factors such as activating
protein-1 (AP-1) and NF-κB in stimulated monocytes
and alveolar macrophages, thereby blocking expres-
sion of cytokine gene expression. Down-regulation of
intercellular signaling proteins, such as protein kinase
C, may be another way in which curcumin inhibits
cytokine production.
Curcumins Anti-inflammatory
Properties and Carcinogenesis
It is well understood that proinflammatory
states are linked to tumor promotion.21,22 Consequently,
phytochemicals like curcumin that exert a strong anti-
inflammatory effect are anticipated to have some degree
of chemopreventive activity. Preclinical cancer research
using curcumin has shown it inhibits carcinogenesis in a
number of cancer types, including colorectal, pancreatic,
gastric, prostate, hepatic, breast, and oral cancers, and
leukemia, and at various stages of carcinogenesis.6 Anti-
inflammatory mechanisms implicated in the anticarci-
nogenic potential of curcumin include: (1) inhibition
of NF-κB and COX-2 (increased levels of COX-2 are
associated with many cancer types);18,20 (2) inhibition
of arachidonic acid metabolism via lipoxygenase and
scavenging of free radicals generated in this pathway;20
(3) decreased expression of inflammatory cytokines IL-
1b, IL-6, and TNF-a, resulting in growth inhibition of
cancer cell lines;23 and (4) down-regulation of enzymes,
such as protein kinase C, that mediate inflammation
and tumor-cell proliferation.24
Animal Research on Curcumin and
Inflammation
Inflammation and Edema
Several animal studies have investigated the
anti-inflammatory effects of curcumin. Early work by
Srimal et al demonstrated curcumin’s anti-inflamma-
tory action in a mouse and rat model of carrageenan-
induced paw edema. In mice, curcumin inhibited edema
at doses between 50-200 mg/kg. A 50-percent reduc-
tion in edema was achieved with a dose of 48 mg/kg
body weight, with curcumin nearly as effective as cor-
tisone and phenylbutazone at similar doses. In rats, a
lower dose of 20-80 mg/kg decreased paw edema and
inflammation. Curcumin also inhibited formaldehyde-
induced arthritis in rats at a dose of 40 mg/kg, had a
lower ulcerogenic index (0.60) than phenylbutazone
(1.70) (an anti-inflammatory drug often used to treat
arthritis and gout), and demonstrated no acute toxicity
at doses up to 2 g/kg body weight.25
Ulcerative Colitis
Curcumin has also been shown to reduce mu-
cosal injury in mice with experimentally-induced colitis.
A dose of 50 mg/kg curcumin for 10 days prior to in-
duction of colitis with 1,4,6-trinitrobenzene sulphonic
acid resulted in a significant amelioration of diarrhea,
improved colonic architecture, and significantly reduced
neutrophil infiltration and lipid peroxidation in colonic
tissue. Reduced levels of nitric oxide and O2 radicals
and suppressed NF-κB activation in colonic mucosa,
all indicators of reduced inflammation and symptom
improvement, were also reported.26
Rheumatoid Arthritis
In an animal model of streptococcal cell
wall-induced rheumatoid arthritis, a turmeric extract
devoid of essential oils was given to Wistar female
rats. Intraperitoneal injection of an extract containing
4 mg total curcuminoids/kg/day for four days prior to
arthritis induction significantly inhibited joint inflam-
mation in both the acute (75%) and chronic (68%)
phases. To test efficacy of an oral preparation, a 30-fold
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Alternative Medicine Review Volume 14, Number 2 2009
Review Article
Page 145
higher dose (to allow for possible low gastrointestinal
absorption) of the curcuminoid preparation, given to
rats four days prior to arthritis induction, significantly
reduced joint inflammation by 48 percent on the third
day of administration.27
Pancreatitis
In two rat models of experimentally-induced
pancreatitis, curcumin decreased inflammation by
markedly decreasing activation of NF-κB and AP-1 as
well as inhibiting mRNA induction of IL-6, TNF-a, and
iNOS in the pancreas. In both cerulein- and ethanol-in-
duced pancreatitis, curcumin’s inhibitory effect on inflam-
matory mediators resulted in improvement in disease se-
verity as measured by histology, serum amylase, pancreatic
trypsin, and neutrophil infiltration.
28
Cancer
Numerous animal studies have explored cur-
cumin’s anti-inflammatory mechanisms and their influ-
ence on carcinogenesis; however, discussion of these
studies in detail is beyond the scope of this paper.
Table 1 lists animal studies in which oral or dietary cur-
cumin inhibited carcinogenesis via anti-inflammatory
mechanisms.
Clinical Trials Exploring Curcumin’s Anti-
inflammatory Benefits
Curcumin’s potent anti-inflammatory properties
have lead to active research on its use for a variety of inflam-
matory conditions, including postoperative inflammation,
arthritis, uveitis, inflammatory pseudotumors, dyspepsia,
irritable bowel syndrome, inflammatory bowel disease,
pancreatitis, and Helicobacter pylori infection. Most studies
are promising and further exploration of curcumin’s thera-
peutic value for inflammatory conditions is warranted.
Post-surgery
Satoskar et al examined the effects of curcumin
compared to phenylbutazone or placebo for spermatic
cord edema after surgery for inguinal hernia or hydrocele.
Forty-five patients (ages 15-68) received 400 mg curcumin
(Group A), 250 mg lactose powder placebo (Group B), or
100 mg phenylbutazone (Group C) three times daily for six
days postoperatively. Parameters measured were spermatic
cord edema, spermatic cord tenderness, operative site pain,
and operative site tenderness (0: absent, 1: mild, 2: mod-
erate, 3: severe) and reflected by intensity score (TIS) of
0-12. TIS on day 6 decreased in Group A (curcumin) by
84.2 percent, by 61.8 percent in Group B (placebo), and by
86 percent in Group C (phenylbutazone). Although TIS
scores for curcumin and phenylbutazone were similar on
day 6, curcumin proved to be superior by reducing all four
parameters of inflammation. Phenylbutazone did not re-
duce tenderness at the operative site.
41
Rheumatoid Arthritis
In a preliminary double-blind, randomized,
controlled trial (RCT), curcumin was compared to phe-
nylbutazone in patients with rheumatoid arthritis. Cur-
cumin given at 1200 mg daily was effective in improv-
ing joint swelling, morning stiffness, and walking time.
Although phenylbutazone provided an even great-
er benefit, dosages, study size, and details were not
available in English full text.42
Osteoarthritis
A crossover RCT examined the effect of tur-
meric extract (50 mg/capsule) in combination with zinc
complex (50 mg/capsule) and other botanicals – With-
ania somnifera (450 mg/capsule) and Boswellia serrata
(100 mg/capsule) in 42 patients with osteoarthritis.
Patients were given 2 capsules of test formula or pla-
cebo three times daily for three months; then, after a
two-week washout period, switched to the opposite
treatment for another three months. Assessment every
two weeks during the study demonstrated significant
improvements in pain severity (p<0.001) and disability
scores (p<0.05), but no statistically significant changes
in other parameters. Curcumin’s role in this improve-
ment cannot be confirmed due to the other botanicals
and zinc in the treatment compound.43
Ocular Conditions
Anterior uveitis is a condition characterized by
inflammation of the uveal tract of the eye (including the
iris) and if untreated can result in blurred vision and
permanent damage. Although the exact cause of ante-
rior uveitis is not certain, it has been known to occur
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Alternative Medicine Review Volume 14, Number 2 2009
Curcumin
Page 146
with trauma to the eye, other eye diseases, tuberculosis,
rheumatoid arthritis, measles, or mumps. Treatment is
usually aimed at decreasing inflammation.44
In a clinical trial involving 32 patients (ages
19-70) with anterior uveitis, 375 mg curcumin was
administered alone or with antitubercular therapy (to
those patients demonstrating a positive PPD skin prick
test) three times daily for 12 weeks. Of those in the
curcumin-only group (n=18), 100 percent reported
marked improvement after two weeks of therapy,
compared to 86 percent in the curcumin/antitubercular
therapy group (n=14). Improvements were observed in
visual acuity and aqueous flare and were accompanied
by a decrease in keratic precipitates.45
Curcumin has been used for idiopathic orbital
inflammatory pseudotumors (IOIP). Orbital pseudo-
tumors include ocular lesions that are non-neoplastic in
nature for which there is no clearly defined cause. e
condition is an immunological inflammatory condi-
tion characterized by a hard mass in the orbit, inflam-
mation of the conjunctiva, and decreased visual acuity.
Author Animal Model Route of Curcumin
Administration
Dose
Chan et al 199829 Murine (liver) iNOS production Oral by gavage, Intravenous 0.5 mL of 10µM solution
0.5 µg/g body weight
Rao et al 199930 Rat colonic aberrant crypt foci Oral (diet), Subcutaneous 50-2,000 ppm
15 mg/kg body weight
Rao et al 199531 Rat colon cancer Oral (diet) 2,000 ppm
Perkins et al 200232 Murine familial adenomatous
polyposis
Oral (diet), Intraperitoneal 0.1-, 0.2-, 0.5-% diet
100 mg/kg body weight
Shpitz et al 200633 Rat colonic aberrant crypt foci Oral (diet) 0.6-% diet
Kwon et al 200934 Rat colonic apoptosis Oral 0.6-% diet
Dujic et al 200935 Murine xenograft tumor Intraperitoneal 200 µL of 0.2-1.0 µg/mL-
curcumin suspension
Garg et al 200836 Murine liver, lung tumor initiation Oral (diet) 0.01- or 0.0-% diet
Kawamori et al 199937 Rat colonic apoptosis Oral 0.2- or 0.6-% diet
Huang et al 199838 Murine lymphomas/leukemias Oral (diet) 2-% diet
Aggarwal et al 200539 Murine breast cancer
with lung metastasis
Oral (diet) 2-% diet
Tomita et al 200640 Murine T-cell leukemia Oral (gavage) 300 mg/kg body weight
Table 1. Animal Studies Investigating the Anti-inflammatory Effects of Curcumin
in Cancer Models29-40
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Alternative Medicine Review Volume 14, Number 2 2009
Review Article
Page 147
Conventional treatment consisting of corticosteroids is
often ineffective.46 In a small study of eight patients with
IOIP, 375 mg curcumin three times daily was given for
6-22 months, until complete regression of symptomol-
ogy was achieved. Patients were followed for two years
and assessed at three-month intervals. Only five pa-
tients completed the study, but four completely recov-
ered on curcumin therapy. One patient was asymptom-
atic but continued to have some restriction of ocular
movement.47
Gastrointestinal Conditions
Curcumin’s anti-inflammatory properties and
therapeutic benefit have been demonstrated for a vari-
ety of gastrointestinal conditions, including dyspepsia,
Helicobacter pylori infection, peptic ulcer, irritable bowel
syndrome, Crohn’s disease, and ulcerative colitis.
Dyspepsia and Gastric Ulcer
In a phase II clinical trial involving 45 sub-
jects (24 males, 21 females, ages 16-60 years), 25 with
endoscopically diagnosed peptic ulcers were given 600
mg curcumin five times daily 30-60 minutes before
meals, at 4:00 pm, and at bedtime for 12 weeks. Ulcers
were absent in 12 patients (48%) after four weeks, in
18 patients after eight weeks, and in 19 patients (76%)
after 12 weeks. e remaining 20 patients, also given
curcumin, had no detectable ulcerations at the start of
the study, but were symptomatic – erosions, gastritis,
and dyspepsia. Within 1-2 weeks abdominal pain and
other symptoms had decreased significantly.48
Irritable Bowel Syndrome
In patients with irritable bowel syndrome
(IBS) the most common symptoms are abdominal pain,
bloating, altered bowel habits, and increased stool fre-
quency.49 It is thought that low-grade inflammation of
the intestinal mucosa is responsible for some sympto-
mology.50 In an eight-week pilot study of IBS patients,
either 72 mg or 144 mg of a standardized turmeric
extract was administered to a group of 102 or 105 sub-
jects, respectively. After four weeks, those in the 72-mg
group experienced a 53-percent reduction in IBS preva-
lence, while the 144-mg group experienced a 60-percent
decrease. In post-study analysis, abdominal pain and
discomfort scores were reduced by 22 percent in the 72-
mg group and 25 percent in the 144-mg group.51
Inflammatory Bowel Disease
Crohn’s disease (CD) and ulcerative colitis
(UC) are the two primary forms of inflammatory bowel
disease (IBD). e primary difference between the two
is nature and location of inflammatory changes in the
gastrointestinal tract. CD can affect any part of the gas-
trointestinal tract and affects the entire bowel wall. In
contrast, UC is restricted to the colon and the rectum
and disease is confined to the intestinal epithelium.
Although very different in scope, both diseases may
present with abdominal pain, vomiting, diarrhea, bloody
stools, weight loss, and secondary sequelae such as
arthritis, pyoderma gangrenosum, and primary scleros-
ing cholangitis.52
Holt et al conducted a pilot study to examine
the effect of curcumin therapy in 10 patients with IBD
(five with CD and five with UC, ages 28-54) who had
previously received standard UC or CD therapy. Five
patients with proctitis (UC of the rectal area) received
550 mg curcumin twice daily for one month and then
were given the same dose three times daily for an ad-
ditional month. Hematological and biochemical blood
analysis, erythrocyte sedimentation rate (ESR), C-reac-
tive protein (CRP) (the latter two inflammatory indica-
tors), sigmoidoscopy, and biopsy were all performed at
baseline and at the study end. Symptoms were assessed
by questionnaire and daily symptom diary. e other
five patients, with Crohn’s disease, received 360 mg three
times daily for one month and then four times daily for a
second month. Crohn’s Disease Activity Index (CDAI),
CRP, ESR, hematological blood analysis, and kidney
function was assessed in all patients at baseline and end
of study. In the proctitis group all five patients improved
by study’s end as indicated by a global score, two elimi-
nated prestudy medications, two decreased their medi-
cations, and all five subjects demonstrated normal ESR,
CRP, and serologic indices of inflammation after two
months. In the CD group, CDAI scores decreased by
an average of 55 points, and CRP and ESR decreased
in four of five patients.53
Another clinical trial was conducted to assess
the efficacy of curcumin as a maintenance therapy in 82
patients with quiescent UC. Subjects were randomized
to receive 1 g curcumin twice daily plus sulfasalazine
or mesalamine (n=43), or placebo plus sulfasalazine
or mesalamine (n=39) for six months. Subjects were
assessed at baseline, every two months for six months,
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Alternative Medicine Review Volume 14, Number 2 2009
Curcumin
Page 148
and again at the end of a six-month follow-up period
via the Clinical Activity Index (CAI) and Endoscopic
Index (EI). Only two of 43 patients (4.7%) receiving
curcumin plus sulfasalazine/mesalamine experienced a
relapse during the six-month study, compared to eight
of 39 subjects (20.5%) in the placebo plus sulfasalazine/
mesalamine group. Subjects in the curcumin group
also demonstrated significant improvement in CAI
(p=0.038) and EI scores (p=0.001), indicating a de-
crease in UC-associated morbidity. Interestingly, at the
end of the six-month follow-up period, during which
all patients took only sulfasalazine or mesalamine, eight
additional patients from the curcumin group relapsed
(total of 23.3%) compared to six additional patients in
the placebo group (total of 35.9%). e authors con-
cluded that curcumin plus standard therapy was more
effective in maintaining remission than placebo plus
standard UC treatment.54
Pancreatitis
Clinical research on curcumin’s therapeutic
benefit for pancreatitis is limited and has primarily fo-
cused on its antioxidant properties. However, research
indicates the inflammatory response plays a critical
role in development of pancreatitis and subsequent tis-
sue damage.28,55 For this reason, it seems likely an anti-
inflammatory agent like curcumin, effective against a
variety of inflammatory molecular targets and shown to
decrease inflammatory markers in an animal model of
pancreatitis,28 might prove to be effective in humans.
One pilot study examined the effect of cur-
cumin for tropical pancreatitis in 15 patients. Subjects
received 500 mg curcumin with 5 mg of piperine to en-
hance absorption (n=8) or placebo (n=7) for six weeks.
Treatment effect on pain patterns as well as erythrocyte
malonylaldehyde (MDA; an indicator of lipid peroxida-
tion) and glutathione (GSH) were assessed at baseline
and after six weeks. In the curcumin group there was
a significant reduction in MDA levels (from 14.80 ±
1.19 to 6.02 ± 0.95). ere was no significant change in
either GSH or pain value scores between the curcu-
min and placebo groups. Further research is needed to
determine the role of lipid peroxidation in pain and
other symptomology associated with pancreatitis.56
Renal Graft Rejection
An RCT investigated the effect of a com-
bination of 480 mg curcumin and 20 mg quercetin
(per capsule) on delayed graft rejection (DGR) in 43
kidney transplant patients. Subjects were randomized
to low-dose (one capsule), high-dose (two capsules), or
placebo (one capsule twice daily) groups for one month
post-surgery. Of 39 participants who completed the
study, two of 14 in the control group experienced DGR
compared to zero in either treatment group. Early func-
tion (significantly decreased serum creatinine 48 hours
post-transplant) was achieved in 43 percent of subjects
in the control group, 71 percent of those in the low-
dose treatment group, and 93 percent in the high-dose
group. Since the amount of quercetin in the compound
was minimal, the majority of benefit is thought to be
due to curcumin’s anti-inflammatory and antioxidant
activity.57
Likely mechanisms for improved early func-
tion of transplanted kidneys include induction of the
hemeoxygenase enzyme, inhibition of NF-κB and pro-
inflammatory cytokines, and scavenging of free radicals
associated with tissue damage.57
In addition to the research presented here,
there are a number of ongoing clinical trials explor-
ing the effects of curcumin in various inflammatory
conditions (Table 2).
Cancer Chemoprevention and Treatment
with Curcumin
e impact of curcumin’s anti-inflammatory
effects on carcinogenesis in humans remains to be de-
termined. However, animal research demonstrates in-
hibition at all three stages of carcinogenesis – initia-
tion, promotion, and progression. During initiation and
promotion, curcumin modulates transcription factors
controlling phase I and II detoxification of carcino-
gens;36 down-regulates proinflammatory cytokines, free
radical-activated transcription factors, and arachidonic
acid metabolism via cyclooxygenase and lipoxygenase
pathways; and scavenges free radicals.59-61 In the promo-
tion and progression stages of carcinogenesis curcumin
decreases frequency and size of tumors and induces
apoptosis via suppression of NF-κB and AP-1 in sev-
eral cancer types.20,37
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Alternative Medicine Review Volume 14, Number 2 2009
Review Article
Page 149
Clinical trials published in peer-reviewed lit-
erature utilizing curcumin for chemoprevention or as a
cancer therapy are somewhat limited. A phase I clinical
trial investigated the use of curcumin as a chemopreven-
tive agent in 25 patients with various types of high-risk
or pre-malignant lesions. After an initial dose of 500 mg
curcumin daily, the dose was increased to as much as
8 g daily for three months. Histological improvement
of precancerous lesions was observed in one of four
patients with cervical intraepithelial neoplasm (signifi-
cant decreases in hyperkeratosis, parakeratosis), one of
six patients with intestinal metaplasia of the stomach
(fewer goblet cells), one of two patients with recently re-
sected bladder cancer (decreased dysplasia and inflam-
mation), two of seven patients with oral leukoplakia,
and two of six patients with Bowen’s disease.9
ree other clinical trials have investigated the
use of curcumin therapy in patients with established
colorectal cancer. Sharma et al conducted two sepa-
rate clinical trials exploring curcumin’s effect on ma-
lignancies and tumor marker levels.10,62 In one trial, 15
patients with advanced colorectal cancer were given
a low-dose (440-2,200 mg daily) Curcuma extract
(equivalent to 36-180 mg curcumin) for up to four
months. In one patient, measurement of serum tumor
marker levels revealed a decrease of carcinoembryonic
antigen levels from 310 ± 15 μg/L to 175 ± 9 μg/L
after two months of treatment with 440 mg Curcuma
extract. Stable disease via CT scan was observed in five
of 15 patients – one taking 440 mg extract, one taking
880 mg, and one taking 1,760 mg for three months, and
in one taking 880 mg and one taking 1,320 mg for four
months.62
In the second trial, researchers used a higher
potency curcuminoid preparation, each capsule con-
taining 450 mg curcumin, 40 mg demethoxycurcumin,
and 10 mg bisdemethoxycurcumin. Fifteen patients
with advanced colorectal cancer were given curcumi-
noid doses of 450-3,600 mg daily for up to four months.
Blood and imaging tests were performed at baseline and
various points throughout the trial. In six patients giv-
en the 3,600-mg dose, mean prostaglandin E2 (PGE2)
levels measured after 29 days of treatment decreased by
46 percent compared to baseline.10 PGE2 is an end prod-
uct of cyclooxygenase that has been shown to stimulate
growth of human colorectal cancer cells.63 In addition,
Table 2. Ongoing Clinical Trials Exploring Curcumin’s Benefits in Inflammatory Conditions58
Clinic Trial
Identifier
Condition Trial Site Intervention Trial Phase Completion
Date
NCT00752154 Rheumatoid arthritis University of California,
Los Angeles
Curcumin, 4-12 g daily Pilot Study September 2009
NCT00792818 Knee osteoarthritis Mahidol University,
National Research
Council of Thailand
Curcuma longa
extracts,
Ibuprofen
Phase III November 2009
NCT00793130 Ulcerative colitis Tel-Aviv Sourasky
Medical Center
Coltect – (curcumin
1 g daily, green tea,
selenium)
Unknown November 2009
NCT00779493 Irritable bowel
syndrome
Kaiser Permanente Curcumin, 900 mg
twice daily
Phase IV November 2009
NCT00528151 Leber’s hereditary
optical neuropathy
Mahidol University Curcumin, 250 mg
twice daily
Phase III Unknown
NCT00595582 Mild cognitive
impairment
Louisiana State
University
Curcumin + Bioperine,
5.4 g daily
Unknown January 2009
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Alternative Medicine Review Volume 14, Number 2 2009
Curcumin
Page 150
two patients (one taking 900 mg, the other taking 1,800
mg) demonstrated stable disease (determined via CT
scan or MRI) after two months. e patient taking the
higher dose remained stable for four months but with-
drew due to diarrhea thought to be treatment related.10
Another clinical trial investigated curcumin’s
effects in patients with colorectal cancer at doses of
450, 1,800, or 3,600 mg daily for seven days.11 e
aim of this study was to determine if these doses re-
sulted in pharmacologically active levels of curcumin in
colorectal tissue or had any effect on tissue levels of the
oxidative DNA adduct pyrimido(1,2-a)purin-10(3H)-
one (M1G) (a mutagenic byproduct of lipid peroxida-
tion) or COX-2 – markers of DNA damage and in-
flammation. e highest dose (3,600 mg) resulted in a
significant decrease in M1G adducts from 4.8 ± 2.9 to
2.0 ±1.8 per 107 nucleotides. No curcumin dose had an
effect on tissue levels of COX-2 protein.
In another clinical trial, curcumin stabilized
disease progression in patients with advanced pan-
creatic cancer. Twenty-one patients received 8 g cur-
cumin daily until disease progression. Serum cytokine
levels as well as NF-κB and COX-2 levels in peripheral
blood mononuclear cells were monitored. One patient
achieved disease stabilization for 18 months. Interest-
ingly, a second patient experienced significant increases
in serum cytokine levels (4- to 35-fold) accompanied
by a brief, but marked tumor regression (73%). Down-
regulation of NF-κB and COX-2 were also observed.64
Currently there are nine ongoing clinical trials
investigating the benefits of curcumin as a therapy for
various cancers. Of these, three are preventive trials on
subjects with adenomatous polyps at risk for colorectal
cancer. e remaining seven trials are investigating the
effects of curcumin (both alone and with conventional
Table 3. Clinical Trials Investigating the Use of Curcumin in Cancer58
Clinical Trial
Identifier
Condition Site Intervention Trial Phase Completion
Date
NCT00365209 Colon cancer prevention Chao Family Comprehensive
Cancer Center Curcumin Phase II Unknown
NCT00118989 Colon cancer prevention University of Pennsylvania Curcuminoid
complex, 4 g daily Phase II June 2009
NCT00641147 Familial adenomatous
polyposis Johns Hopkins University Curcumin, 700 mg
twice daily Phase II March 2013
NCT00745134 Rectal cancer MD Anderson Cancer Center Curcumin, 4 g daily,
Capecitabine Phase II July 2010
NCT00486460 Pancreatic cancer Tel-Aviv Sourasky Medical
Center
Gemcitabine,
Curcumin, Celebrex
(doses unknown)
Phase III Unknown
NCT00094445 Pancreatic cancer MD Anderson Cancer Center Curcumin, 8 g daily Phase II December 2009
NCT00113841 Multiple myeloma MD Anderson Cancer Center
Curcumin +
Bioperine, 2 g
twice daily
Pilot Study December 2008
NCT00689195 Osteosarcoma Tata Memorial Hospital
Curcumin and
Ashwagandha
(doses unknown)
Phase I and II May 2012
NCT00475683 Oral mucositis – children
on chemotherapy
Hadassah Medical
Organization
Curcumin liquid
extract, 10-30 drops
3 times daily
Phase III December 2009
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Alternative Medicine Review Volume 14, Number 2 2009
Review Article
Page 151
medications) in patients with established cancer of vari-
ous types. Table 3 lists ongoing clinical trials investigat-
ing the anticancer potential of curcumin. It is hoped the
completion of these trials over the next few years will
provide a better understanding of curcumin’s efficacy
for chemoprevention and treatment of active cancer.
Cautionary Information
In every published clinical trial, curcumin ap-
pears to be extremely safe, even at doses up to 8 g daily.
Of less importance are in vitro and animal trials that
in select settings have demonstrated potentially adverse
effects. In vitro, in the presence of copper and cyto-
chrome p450 isoenzymes, curcumin induced DNA
fragmentation and base damage.65 In a rat model of liver
cancer curcumin did not prevent spontaneous hepatic
tumor formation and in fact, shortened life span from
88.7 to 78.1 weeks (p=0.002).66
ere is also some evidence that curcumin
inhibits the activity of certain chemotherapy drugs.
Research reveals curcumin decreased camptothecin-
induced death of cultured breast cancer cells and pre-
vented cyclophosphamide-induced breast tumor re-
gression in mice.67 Curcumin might also interfere with
the absorption and efficacy of the chemotherapy drug
irinotecan, which is used to treat colon cancer.68
On the other hand, curcumin may enhance
the effects of some chemotherapy drugs. In a mouse
xenograft model of human breast cancer, curcumin in
conjunction with paclitaxel (Taxol) significantly in-
hibited breast cancer metastasis to the lung to a great-
er degree than either curcumin or paclitaxel alone.
Prevention of breast cancer metastasis in this study
appeared to be via curcumin’s inhibition of NF-κB.39
Conclusion
Curcumin’s diverse array of molecular targets
affords it great potential as a therapeutic agent for a
variety of inflammatory conditions and cancer types.
Consequently, there is extensive interest in its thera-
peutic potential as evidenced by the number of ongo-
ing phase II and III clinical trials. e primary obstacle
to utilizing curcumin therapeutically has been its lim-
ited systemic bioavailability, but researchers are actively
investigating a number of different curcumin com-
pounds and analogs that may be more effective and
better absorbed. Results from completed clinical trials
are encouraging and trials currently being conducted for
both inflammatory conditions and cancer should clarify
curcumin’s value as a therapeutic agent and confirm
some of the mechanisms responsible for its efficacy.
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... Curcumin, a highly pleiotropic component, affects the inflammatory responses by downregulating the activities of lipoxygenase, cyclooxygenase-2, and inducible nitric oxide synthase enzymes (Jurenka, 2009). In addition,curcumin can interact with several molecular targets implicated in inflammation such that they are known to provide an inhibitory effect towards cytokines (Guil-Guerrero et al., 2017). ...
... From the findings of Shehzad et al. (2013), curcumin was also discovered to decrease many inflammatory cytokines such as tumor necrosis factor-alpha (TNF-a), interleukins (IL-1, -1b, -6, and -8), and cyclooxygenase-2. In addition, curcumin lowers the nuclear factor-kappa B (NF-κB) activation and decreases cell proliferation (Jurenka, 2009;Chandran, 2021). ...
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... Curcumin (CUR), as a natural substance derived from the plant Curcuma longa, with its unique features as an antioxidant, [1] antitumor, [2] and anti-inflammatory agent, [3] has been widely used in drug delivery systems and tissue engineering applications. [4] CUR can provide excellent free-radical scavenging activity, improving the neovascularization and increasing the migratory activity of various cells, including fibroblasts, dermal myofibroblasts, and macrophages onto the wound bed. ...
... The reason for which all of these parameters are used together is that each of these parameters shows accuracy/ inaccuracy of a given model in a different way. The mathematical expressions for each of the aforementioned parameters are provided in Equations (1)(2)(3)(4)(5). ...
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... Curcumin, derived from diferuloylmethane, is an important antioxidant which has been used as herbal therapy and as a dietary factor in many Eastern countries. Curcumin has also been shown to inhibit many proinflammatory cytokines and mediators such as IL-1, IL-8, and nitric oxide synthase [48]. Consequently, curcumin's beneficial effects on inflammatory disorders are due to the suppression of immune functions of T-cells, specially Th1, which plays a key role in the pathogenesis of chronic inflammatory disorders such as arthritis ( Figure 10) [14,15,18,49]. ...
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... Mainly, the effect of curcumin as anti-cancer (34)(35)(36), anti-oxidant (37)(38)(39), anti-inflammatory (40)(41)(42), antibacterial (43)(44)(45), etc., agent in the biomedical field has been extremely developed and established (46)(47)(48). Therefore, a large number of reviews have adopted this topic and elaborated. ...
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It is known that curcumin, a dietary pigment from the plant Curcuma longa, inhibits cell proliferation and induces apoptosis in different cell lines; however, the therapeutic benefit is hampered by very low absorption after transdermal or oral application. Recent studies from our laboratory have demonstrated that curcumin at low concentrations (0.2-1 microg/ml) offered the described effects only when applied with UVA or visible light. Nevertheless, the in vivo efficacy of this combination is lacking. In the present study, we used a xenograft tumor model with human epithelial carcinoma A431 cells to test the effect of curcumin and visible light on tumor growth. It was found that tumor growth was significantly inhibited in mice that were i.p. injected with curcumin and consecutively irradiated with visible light. Furthermore, immunohistochemistry showed a reduction of Ki 67 expression, indicating a decrease of cycling cells and induction of apoptotic bodies. The effect on apoptosis was further confirmed by Western blot analysis showing enhanced activation of caspases-9. Vice versa inhibition of extracellular regulated kinases (ERK) 1/2 and epidermal growth factor receptor (EGF-R) was observed which may aid inhibition of proliferation and induction of apoptosis. In summary, the present findings suggest a combination of curcumin and light as a new therapeutic concept to increase the efficacy of curcumin in the treatment of cancer.
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Eicosanoids have been implicated in colon carcinogenesis, but their role remains unclear. The levels of PGE2 are elevated in colon cancer tissues and in blood draining colon tumors. The effect of eicosanoids on the proliferation of colonic cells is unknown. We studied the effect of several prostaglandins (PGs) and leukotriene (LT)B4 on the proliferation rate of the human colon adenocarcinoma cell lines SW1116 and HT-29 and of 16,16-dimethyl PGE2 (dmPGE2) on the colon of BALB/c mine. PGs E2, F2α, I2, the methyl ester of, PGE2, dmPGE2, and LTB4 (10−10, 10−8, 10−6 M), administered for up to 72 h, stimulated cell proliferation in SW1116 cells and all t but PGF2α and PGI2 stimulated proliferation in HT-29 cells. The proliferative effect was time- and concentration-dependent. However, in SW1116 cells the response to PGs was ‘bell-shaped’, being maximal at 10−8 M, with the 10−10 and 10−6 M concentrations being less effective. In HT-29 cells, the addition of methyl groups to the PGE2 molecule increased the proliferative affect. None of these eicosanoids affected the distribution of these cells in the cell cycle or their rate of programmed cell death (apoptosis). dmPGE2 stimulated 3.6-fold the proliferation of colonocytes in normal BALB/c mice. This was determined by bivariate flow cytometric analysis of the expression of proliferating cell nuclear antigen (PCNA) in virtually pure populations of mouse colonocytes. dmPGE2 did not alter the cell cycle distribution of these cells. We conclude that several PGs as well as LTB4 stimulate the proliferation of human colon carcinoma cells in vitro, while dmPGE2 has a similar effect on mouse colonocytes in vivo. These findings raise the possibility that eicosanoids may contribute to colonic carcinogenesis by stimulating the proliferation rate of tumor cells in the colon.
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Curcumin, contained in the rhizome of the plant Curcuma longa Linn, is a naturally occurring phytochemical that has been used widely in India and Indonesia for the treatment of inflammation. The pleiotropic cytokine tumor necrosis factor-α (TNF) induces the production of interleukin-1 β (IL-1), and, together, they play significant roles in many acute and chronic inflammatory diseases. They have been implicated in the pathogenesis of intracellular parasitic infections, atherosclerosis, AIDS and autoimmune disorders. This report shows that, in vitro, curcumin, at 5 μM, inhibited lipopolysaccharide (LPS)-induced production of TNF and IL-1 by a human monocytic macrophage cell line, Mono Mac 6. In addition, it demonstrates that curcumin, at the corresponding concentration, inhibited LPS-induced activation of nuclear factor kappa B and reduced the biological activity of TNF in L929 fibroblast lytic assay.
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The degradation kinetics of curcumin under various pH conditions and the stability of curcumin in physiological matrices were investigated. When curcumin was incubated in 0.1 M phosphate buffer and serum-free medium, pH 7.2 at 37°C, about 90% decomposed within 30 min. A series of pH conditions ranging from 3 to 10 were tested and the result showed that decomposition was pH-dependent and occurred faster at neutral-basic conditions. It is more stable in cell culture medium containing 10% fetal calf serum and in human blood; less than 20% of curcumin decomposed within 1 h, and after incubation for 8 h, about 50% of curcumin is still remained. Trans-6-(4′-hydroxy-3′-methoxyphenyl)-2,4-dioxo-5-hexenal was predicted as major degradation product and vanillin, ferulic acid, feruloyl methane were identified as minor degradation products. The amount of vanillin increased with incubation time.