ArticlePDF AvailableLiterature Review

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

March 2009
Alternative Medicine Review: a Journal of Clinical Therapeutic 14(2):141-53

Source
PubMed

Authors:

Thorne Research

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.

. Ongoing Clinical Trials Exploring Curcumin's Benefits in Inflammatory Conditions 58

…

Absorption of Curcumin Phytosome (Meriva) Compared to Non-complex Curcumin in Humans

…

. Clinical Trials Investigating the Use of Curcumin in Cancer 58

…

Figures - uploaded by Julie Jurenka

Content may be subject to copyright.

Content uploaded by Julie Jurenka

Content may be subject to copyright.

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

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

OCH3

Curcumin

Demethoxycurcumin

Figure 1. Structures of Curcumin

(Diferuloylmethane), Demethoxycurcumin, and

Bisdemethoxycurcumin

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

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.

Curcumin’s 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

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.

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.

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

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

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,

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

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

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

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.

References

1. Ammon HP, Wahl MA. Pharmacology of Curcuma

longa. Planta Med 1991;57:1-7.

2. Lampe V, Milobedzka J. No title available. Ber Dtsch

Chem Ges 1913:46:2235.

3. Sharma OP. Antioxidant activity of curcumin

and related compounds. Biochem Pharmacol

1976;25:1811-1812.

4. Negi PS, Jayaprakasha GK, Jagan Mohan Rao L,

Sakariah KK. Antibacterial activity of turmeric oil: a

byproduct from curcumin manufacture. J Agric Food

Chem 1999;47:4297-4300.

5. National Toxicology Program. NTP toxicology

and carcinogenesis studies of turmeric oleoresin

(CAS No. 8024-37-1) (major component 79%-85%

curcurmin, CAS No. 458-37-7) in F344/N rats and

B6C3F1 mice (feed studies). Natl Toxicol Program

Tech Rep Ser 1993;427:1-275.

6. Aggarwal BB, Kumar A, Bharti AC. Anticancer

potential of curcumin: preclinical and clinical studies.

Anticancer Res 2003;23:363-398.

7. Wang YJ, Pan MH, Cheng AL, et al. Stability of

curcumin in buﬀer solutions and characterization

of its degradation products. J Pharm Biomed Anal

1997;15:1867-1876.

8. Ireson C, Orr S, Jones DJ, et al. Characterization of

metabolites of the chemopreventive agent curcumin

in human and rat hepatocytes and in the rat in vivo,

and evaluation of their ability to inhibit phorbol

ester-induced prostaglandin E2 production. Cancer

Res 2001;61:1058-1064.

9. Cheng AL, Hsu CH, Lin JK, et al. Phase I clinical

trial of curcumin, a chemopreventive agent, in

patients with high-risk or pre-malignant lesions.

Anticancer Res 2001;21:2895-2900.

10. Sharma RA, Euden SA, Platton SL, et al. Phase

I clinical trial of oral curcumin: biomarkers of

systemic activity and compliance. Clin Cancer Res

2004;10:6847-6854.

11. Garcea G, Berry DP, Jones DJ, et al. Consumption

of the putative chemopreventive agent curcumin

by cancer patients: assessment of curcumin levels

in the colorectum and their pharmacodynamic

consequences. Cancer Epidemiol Biomarkers Prev

2005:14:120-125.

Alternative Medicine Review Volume 14, Number 2 2009

Curcumin

Page 152

12. Vareed SK, Kakarala M, Ruﬃn MT, et al.

Pharmacokinetics of curcumin conjugate metabolites

in healthy human subjects. Cancer Epidemiol

Biomarkers Prev 2008;17:1411-1417.

13. Shoba G, Joy D, Joseph T, et al. Inﬂuence of piperine

on the pharmacokinetics of curcumin in animals and

human volunteers. Planta Med 1998;64:353-356.

14. Marczylo TH, Verschoyle RD, Cooke DN,

et al. Comparison of systemic availability of

curcumin with that of curcumin formulated with

phosphatidylcholine. Cancer Chemother Pharmacol

2007;60:171-177.

15. Personal communiction with Indena, Inc. March 13,

2009.

16. Goel A, Kunnumakkara AB, Aggarwal BB. Curcumin

as “curecumin”: from kitchen to clinic. Biochem

Pharmacol 2008;75:787-809.

17. Abe Y, Hashimoto S, Horie T. Curcumin

inhibition of inﬂammatory cytokine production by

human peripheral blood monocytes and alveolar

macrophages. Pharmacol Res 1999;39:41-47.

18. Surh YJ, Chun KS, Cha HH, et al. Molecular

mechanisms underlying chemopreventive activities of

anti-inﬂammatory phytochemicals: down-regulation

of COX-2 and iNOS through suppression of NF-

kappa B activation. Mutat Res 2001;480-481:243-

268.

19. Jobin C, Bradham CA, Russo MP, et al. Curcumin

blocks cytokine-mediated NF-kappa B activation

and proinﬂammatory gene expression by inhibiting

inhibitory factor I-kappa B kinase activity. J Immunol

1999;163:3474-3483.

20. Huang MT, Lysz T, Ferraro T, et al. Inhibitory

eﬀects of curcumin on in vitro lipoxygenase and

cyclooxygenase activities in mouse epidermis. Cancer

Res 1991;51:813-819.

21. Bennett A. e production of prostanoids in human

cancers, and their implications for tumor progression.

Prog Lipid Res 1986;25:539-542.

22. Qiao L, Kozoni V, Tsioulias GJ, et al. Selected

eicosanoids increase the proliferation rate of human

colon carcinoma cell lines and mouse colonocytes in

vivo. Biochim Biophys Acta 1995;1258:215-223.

23. Cho JW, Lee KS, Kim CW. Curcumin attenuates the

expression of IL-1beta, IL-6, and TNF-alpha as well

as cyclin E in TNF-alpha-treated HaCaT cells; NF-

kappaB and MAPKs as potential upstream targets.

Int J Mol Med 2007;19:469-474.

24. Liu JY, Lin SJ, Lin JK. Inhibitory eﬀects of

curcumin on protein kinase C activity induced by

12-O-tetradecanoyl-phorbol-13-acetate in NIH 3T3

cells. Carcinogenesis 1993;14:857-861.

25. Srimal RC, Dhawan BN. Pharmacology of

diferuloyl methane (curcumin), a non-steroidal anti-

inﬂammatory agent. J Pharm Pharmacol 1973;25:447-

452.

26. Ukil A, Maity S, Karmakar S, et al. Curcumin, the

major component of food ﬂavour turmeric, reduces

mucosal injury in trinitrobenzene sulphonic acid-

induced colitis. Br J Pharmacol 2003;139:209-218.

27. Funk JL, Oyarzo JN, Frye JB, et al. Turmeric extracts

containing curcuminoids prevent experimental

rheumatoid arthritis. J Nat Prod 2006;69:351-355.

28. Gukovsky I, Reyes CN, Vaquero EC, et al. Curcumin

ameliorates ethanol and nonethanol experimental

pancreatitis. Am J Physiol Gastrointest Liver Physiol

2003;284:G85-G95.

29. Chan MM, Huang HI, Fenton MR, Fong D. In vivo

inhibition of nitric oxide synthase gene expression by

curcumin, a cancer preventive natural product with

anti-inﬂammatory properties. Biochem Pharmacol

1998;55:1955-1962.

30. Rao CV, Kawamori T, Hamid R, Reddy BS.

Chemoprevention of colonic aberrant crypt foci by

an inducible nitric oxide synthase-selective inhibitor.

Carcinogenesis 1999;20:641-644.

31. Rao CV, Rivenson A, Simi B, Reddy BS.

Chemoprevention of colon carcinogenesis by dietary

curcumin, a naturally occurring plant phenolic

compound. Cancer Res 1995;55:259-266.

32. Perkins S, Verschoyle RD, Hill K, et al.

Chemopreventive eﬃcacy and pharmacokinetics of

curcumin in the min/+ mouse, a model of familial

adenomatous polyposis. Cancer Epidemiol Biomarkers

Prev 2002;11:535-540.

33. Shpitz B, Giladi N, Sagiv E, et al. Celecoxib and

curcumin additively inhibit the growth of colorectal

cancer in a rat model. Digestion 2006;74:140-144.

34. Kwon Y, Magnuson BA. Age-related diﬀerential

responses to curcumin-induced apoptosis during the

initiation of colon cancer in rats. Food Chem Toxicol

2009;47:377-385.

35. Dujic J, Kippenberger S, Ramirez-Bosca A, et al.

Curcumin in combination with visible light inhibits

tumor growth in a xenograft tumor model. Int J

Cancer 2009;124:1422-1428.

36. Garg R, Gupta S, Maru GB. Dietary curcumin

modulates transcriptional regulators of phase I and

phase II enzymes in benzo[a]pyrene-treated mice:

mechanism of its anti-initiating action. Carcinogenesis

2008;29:1022-1032.

37. Kawamori T, Lubet R, Steele VE, et al.

Chemopreventive eﬀect of curcumin, a naturally

occurring anti-inﬂammatory agent, during the

promotion/progression stages of colon cancer. Cancer

Res 1999;59:597-601.

38. Huang MT, Lou YR, Xie JG, et al. Eﬀect of dietary

curcumin and dibenzoylmethane on formation of

7,12-dimethylbenz[a]anthracene-induced mammary

tumors and lymphomas/leukemias in Sencar mice.

Carcinogenesis 1998;19:1697-1700.

39. Aggarwal BB, Shishodia S, Takada Y, et al. Curcumin

suppresses the paclitaxel-induced nuclear factor-

kappaB pathway in breast cancer cells and inhibits

lung metastasis of human breast cancer in nude mice.

Clin Cancer Res 2005;11:7490-7498.

Alternative Medicine Review Volume 14, Number 2 2009

Review Article

Page 153

40. Tomita M, Kawakami H, Uchihara J, et al. Curcumin

(diferuloylmethane) inhibits constitutive active NF-

kappaB, leading to suppression of cell growth of

human T-cell leukemia virus type I-infected T-cell

lines and primary adult T-cell leukemia cells. Int J

Cancer 2006;118;765-772.

41. Satoskar RR, Shah SJ, Shenoy SG. Evaluation

of anti-inﬂammatory property of curcumin

(diferuloyl methane) in patients with postoperative

inﬂammation. Int J Clin Pharmacol er Toxicol

1986;24:651-654.

42. Deodhar SD, Sethi R, Srimal RC. Preliminary study

on antirheumatic activity of curcumin (diferuloyl

methane). Indian J Med Res 1980;71:632-634.

43. Kulkarni RR, Patki PS, Jog VP, et al. Treatment of

osteoarthritis with a herbomineral formulation: a

double-blind, placebo controlled, cross-over study. J

Ethnopharmacol 1991;33:91-95.

44. Anterior uveitis. http://www.aoa.org/x4719.xml

[Accessed March 15, 2009]

45. Lal B, Kapoor AK, Asthana OP, et al. Eﬃcacy of

curcumin in the management of chronic anterior

uveitis. Phytother Res 1999;13:318-322.

46. Mombaerts I , Goldschmeding R, Schlingemann RO,

Koornneef L. What is orbital pseudotumour? Surv

Ophthalmol 1996;41:66-78.

47. Lal B, Kapoor AK, Agrawal PK, et al. Role of

curcumin in idiopathic inﬂammatory orbital

pseudotumours. Phytother Res 2000;14:443-447.

48. Prucksunand C, Indrasukhsri B, Leethochawalit M,

Hungspreugs K. Phase II clinical trial on eﬀect of the

long turmeric (Curcuma longa Linn) on healing of

peptic ulcer. Southeast Asian J Trop Med Public Health

2001;32:208-215.

49. Camilleri M. Dyspepsia, irritable bowel syndrome,

and constipation: review and what’s new. Rev

Gastroenterol Disord 2001;1:2-17.

50. Barbara G, De Giorgio R, Stanghellini V, et al. A role

for inﬂammation in irritable bowel syndrome? Gut

2002;51:i41-i44.

51. Bundy R, Walker AF, Middleton RW, Booth J.

Turmeric extract may improve irritable bowel

syndrome symptomology in otherwise healthy

adults: a pilot study. J Altern Complement Med

2004;10:1015-1018.

52. Inﬂammatory bowel disease. http://en.wikipedia.org/

wiki/Inﬂammatory_bowel_disease [Accessed March

14, 2009]

53. Holt PR, Katz S, Kirshoﬀ R. Curcumin therapy in

inﬂammatory bowel disease: a pilot study. Dig Dis Sci

2005;50:2191-2193.

54. Hanai H, Iida T, Takeuchi K, et al. Curcumin

maintenance therapy for ulcerative colitis:

randomized, multicenter, double-blind, placebo-

controlled trial. Clin Gastroenterol Hepatol

2006;4:1502-1506.

55. Vaquero E, Gukovsky I, Zaninovic V, et al.

Localized pancreatic NF- kappaB activation and

inﬂammatory response in taurocholate-induced

pancreatitis. Am J Physiol Gastronintest Liver Physiol

2001;280:G1197-G1208.

56. Durgaprasad S, Pai CG, Vasanthkumar, et al. A pilot

study of the antioxidant eﬀect of curcumin in tropical

pancreatitis. Indian J Med Res 2005;122;315-318.

57. Shoskes D, Lapierre C, Cruz-Corerra M, et al.

Beneﬁcial eﬀects of the bioﬂavonoids curcumin

and quercetin on early function in cadaveric renal

transplantation: a randomized placebo controlled

trial. Transplantation 2005;80;1556-1559.

58. Curcumin clinical trials. http://clinicaltrials.gov/ct2/

results?intr=%22Curcumin%22&pg=2 [Accessed

March 14, 2009]

59. Chan MM. Inhibition of tumor necrosis factor by

curcumin, a phytochemical. Biochem Pharmacol

1995;49:1551-1556.

60. Singh S, Aggarwal BB. Activation of transcription

factor NF- kappa B is suppressed by curcumin

(diferuloylmethane) [corrected]. J Biol Chem

1995;270:24995-25000.

61. Hong J, Bose M, Ju J, et al. Modulation of

arachidonic acid metabolism by curcumin and

related beta-diketone derivatives: eﬀects on

cytosolic phospholipase A(2), cyclooxygenases and

5-liposygenase. Carcinogenesis 2004;25:1671-1679.

62. Sharma RA, McLelland HR, Hill KA, et al.

Pharmacodynamic and pharmacokinetic study of oral

Curcuma extract in patients with colorectal cancer.

Clin Cancer Res 2001;7:1894-1900.

63. Shao J, Lee SB, Guo H, et al. Prostaglandin E2

stimulates the growth of colon cancer cells via

induction of amphiregulin. Cancer Res 2003;63:5218-

5223.

64. Dhillon N, Aggarwal BB, Newman RA, et al. Phase

II trial of curcumin in patients with advanced

pancreatic cancer. Clin Cancer Res 2008;14:4491-

4499.

65. Sakano K, Kawanishi S. Metal-mediated DNA

damage induced by curcumin in the presence of

human cytochrome p450 isozymes. Arch Biochem

Biophys 2002;405:223-230.

66. Frank N, Knauft J, Amelung F, et al. No prevention

of liver and kidney tumors in Long-Evans Cinnamon

rats by dietary curcumin, but inhibition at other sites

and of metastases. Mutat Res 2003;523-524:127-135.

67. Somasundaram S, Edmund NA, Moore DT, et al.

Dietary curcumin inhibits chemotherapy-induced

apoptosis in models of human breast cancer. Cancer

Res 2002;62:3868-3875.

68. Johnson JJ, Mukhtar H. Curcumin for

chemoprevention of colon cancer. Cancer Lett

2007;255:170-181.

Anti-Cryptosporidial Drug-Discovery Challenges and Existing Therapeutic Avenues: A “One-Health” Concern

Article

Full-text available

Jan 2024

Cryptosporidiosis is the leading cause of life-threatening diarrheal infection, especially in infants. Oocysts contaminate the environment, and also, being a zoonotic disease, cryptosporidiosis is a threat to One Health. Nitazoxanide is the only FDA-approved drug, effective only in immunocompetent adults, and is not safe for infants. The absence of mitochondria and apicoplast, the presence of an electron-dense band (ED band), hindrances in its genetic and phenotypic manipulations, and its unique position inside the host cell are some challenges to the anti-cryptosporidial drug-discovery process. However, many compounds, including herbal products, have shown efficacy against Cryptosporidium during in vitro and in vivo trials. Still, the “drug of choice” against this protozoan parasite, especially in immunocompromised individuals and infants, has not yet been explored. The One-Health approach addresses this issue, focusing on the intersection of animal, human, and environmental health. The objective of this review is to provide knowledge about novel anti-cryptosporidial drug targets, available treatment options with associated limitations, and possible future shifts toward natural products to treat cryptosporidiosis. The current review is organized to address the treatment and prevention of cryptosporidiosis. An anti-cryptosporidial drug that is effective in immunocompromised individuals and infants is a necessity of our time.

Therapeutic potential and underlying mechanisms of phytoconstituents: emphasizing on resveratol, curcumin, quercetin, berberine, and hesperidin in ulcerative colitis

Article

Full-text available

Jan 2025
N Schmied Arch Pharmacol

Ulcerative colitis is a long-term inflammatory colon illness that significantly affects patients quality of life. Traditional medicines and therapies often come with challenges such as side effects, instability, unpredictability, and high costs. This has captured interest in natural products that have huge health benefits. Various natural compounds, including resveratrol, curcumin, quercetin, berberine, and hesperidin demonstrate immunomodulatory and oxido-inflammatory properties inside the gut epithelium, showing potential in managing ulcerative colitis. These compounds attenuate inflammatory mediators, NF-κB, and TLR4 signaling leading to a reduction in the production of inflammation-related cytokines, including TNF-α and IL-6. They also augment the activity of internal defense compounds, including superoxide radical dismutase enzyme and heme oxygenase-1, thereby alleviating oxidative damage. In addition, natural compounds have a profound effect on the endogenous microbiota and thus, support mucosal healing and intercellular barrier integrity. Both experimental and clinical analyses provide evidence that these bioactive compounds may help reduce clinical manifestations, induce and sustain remission, and improve the well-being of individuals suffering from ulcerative colitis. This review seeks to discuss various aspects of natural compounds in the management of ulcerative colitis, including mechanisms, therapeutic prospects, and hurdles, and hence the basis for future research and practice. Graphical Abstract

Curcumin Reduces Depression in Obese Patients with Type 2 Diabetes: A Randomized Controlled Trial

Article

Full-text available

Jul 2024

Type 2 diabetes and depression co-occur in a bidirectional manner. Curcumin supplements exhibit antidepressant effects that may mitigate depression by modulating neurotransmitters and reducing inflammatory and oxidative stress pathways. This study aimed to evaluate the efficacy of curcumin in improving depression severity in obese type 2 diabetes patients. The study employed a randomized, double-blind, placebo-controlled trial design with 227 participants. The primary end-point was depression severity assessed using the Patient Health Questionnaire-9. Biomarkers were measured at baseline and at 3-, 6-, 9-, and 12-month intervals. The biomarkers assessed were serotonin levels, pro-inflammatory cytokines (interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha), antioxidant activities (total antioxidant status, glutathione peroxidase, and superoxide dismutase), and malondialdehyde. After 12 months, the curcumin group exhibited significantly improved depression severity (p = 0.000001). The curcumin group had higher levels of serotonin (p < 0.0001) but lower levels of interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha (p < 0.001 for all) than the placebo group. Total antioxidant status, glutathione peroxidase activity, and superoxide dismutase activity were elevated in the curcumin group, whereas malondialdehyde levels were greater in the placebo group (p < 0.001 for all). These findings suggest curcumin may have antidepressant effects on obese type 2 diabetes patients.

New Perspectives on the Therapeutic Potentials of Bioactive Compounds from Curcuma longa: Targeting COX-1 & 2, PDE-4B, and Antioxidant Enzymes to Counteract Oxidative Stress and Inflammation

Article

Full-text available

May 2024
NAT PROD COMMUN

Background Inflammations, oxidative stress, and pains underlie the pathogenesis of non-communicable diseases (NCDs) like respiratory disorders and cancer; however, they are scientifically treated with Curcuma longa. Therefore, the pharmacological screening (antioxidant, anti-inflammatory, and analgesic) of the plant's rhizome, isolation and characterization of its compounds, as well as their in silico profiling with cyclooxygenases, phosphodiesterase, superoxide dismutase, glutathione peroxidase, and catalase could yield lead compounds with better benefit-to-risk ratio against oxidative stress and inflammation. Methods The collection of the plant's rhizomes, extract preparation, anti-inflammatory, analgesic, and antioxidant studies, retrieval of target proteins, GC-MS, ADME, and docking analyses were done using standard protocols. Results Curcuma longa's percentage edema inhibition and analgesic potentials were better than aspirin in both acute and sub-acute inflammations as well as chemical and thermal-induced pains; moreover, its antioxidant activities were better than vitamin C. Moreover, twenty compounds with anti-inflammatory, analgesic, and antioxidant activities were unraveled from the GC-MS analysis. Ar-tumerone, curcumin, γ-sitosterol, α-tocopherol, isocurcumenol, adamantane, and curdione were the lead compounds based on their binding affinities (for PDE-4B, COX-1, COX-2, SOD, CAT, GPx), lower molecular weights, non-permeation of blood brain barrier, bioavailability profiles, non-inhibition of metabolizing enzymes, faster renal clearance, and non-violation of Lipinski's rules. Conclusion Adamantane, α-tocopherol, and γ-sitosterol reported for the first time in the plant's rhizome could mitigate oxidative stress and inflammation as mediators of apoptosis, cytotoxic impaired autophagy, DNA damages, and mitochondrial dysfunction that contributes to the progression of non-communicable diseases (NCDs).

Biological Activities of Deer Antler-Derived Peptides on Human Chondrocyte and Bone Metabolism

Article

Full-text available

Mar 2024

Orally administered “tortoiseshell and deer antler gelatin” is a common traditional medicine for patients with osteoporosis or osteoarthritis. From the pepsin-digested gelatin, we previously isolated and identified the osteoblast-stimulating pentapeptide, TSKYR. Its trypsin digestion products include the dipeptide YR, enhancing calcium ion uptake, and tripeptide TSK, resulting in remarkable 30- and 50-fold increases in mineralized nodule area and density in human osteoblast cells. These peptides were chemically synthesized in this study. The composition of deer antler preparations comprises not only proteins and peptides but also a significant quantity of metal ion salts. By analyzing osteoblast growth in the presence of peptide YR and various metal ions, we observed a synergistic effect of calcium and strontium on the effects of YR. Those peptides could also stimulate the growth of C2C12 skeletal muscle cells and human chondrocytes, increasing collagen and glycosaminoglycan content in a three-dimensional environment. The maintenance of bone homeostasis relies on a balance between osteoclasts and osteoblasts. Deer antler peptides were observed to inhibit osteoclast differentiation, as evidenced by ROS generation, tartrate-resistant acid phosphatase (TRACP) activity assays, and gene expression in RAW264.7 cells. In summary, our findings provide a deep understanding of the efficacy of this folk medicine.

Investigating the Superiority of Chitosan/ D-alpha-tocopheryl Polyethylene Glycol Succinate Binary Coated Bilosomes in Promoting the Cellular Uptake and Anti-SARS-CoV-2 Activity of Polyphenolic Herbal Drug Candidate

Article

Sep 2023

The evolution of a safe and effective therapeutic system to conquer SAR-CoV-2 infection deemed to be a crucial worldwide demand. Curcumin (CUR) is a phytomedicinal polyphenolic drug that exhibited a well-reported anti-SAR-CoV-2. However, the therapeutic activity of CUR is hindered by its poor intestinal permeability and diminished aqueous solubility. Therefore, this study strived to develop D-alpha-tocopheryl polyethylene glycol succinate (TPGS) bilosomes (TPGS-Bs) adopting 23 full factorial designs to improve solubility and intestinal permeability of CUR, hence boosting its anti-SARS-CoV-2 activity. Eight experimental runs were attained considering three independent variables: soybean phosphatidylcholine amount (mg) (SPC amount), bile salt amount (mg) (BS amount), and TPGS amount(mg). The optimum formula (F4) exhibited EE % (88.5 ± 2.4 %), PS (181.5 ± 21.6 nm), and ZP (-34.5 ± 3.7 mV) with desirability value = 0.739 was picked as an optimum formula. Furthermore, the optimum formula (F4) was extra coated with chitosan (CS) to improve permeability and anti-SAR-CoV-2 activity. Caco-2 cell uptake after 2 hr revealed the superiority of CS-F4 and F4 by 6 and 5 folds relative to CUR dispersion, respectively. Furthermore, CS-F4 exhibited a significantly higher anti-SARS-CoV-2 activity with IC50 (0.24µg/ml) by 8.3 times than F4 (1.99µg/ml). Besides, the mechanistic study demonstrated that the two formulae imparted antiviral activity by inhibiting the spike protein by virucidal potentialities. In addition, the conducted molecular docking and MD simulations towards the SARS-CoV-2 Mpro enzyme confirmed the interaction of CUR with key residues of the virus enzymes. Based on the preceded, CS-F4 could be assumed to be used to effectively eradicate SARS-CoV-2 infection.

Diarylidene‐N‐Methyl‐4‐Piperidones and Spirobibenzopyrans as Antioxidant and Anti‐Inflammatory Agents

Article

Aug 2023

Curcumin has anti‐oxidant properties resulting from its radical scavenging ability and inhibition of inflammation‐associated factors. However, its lack of solubility, instability, and poor bioavailability are impediments to its therapeutic use. As potential alternatives, we synthesized and performed chemical analysis of thirty diarylidene‐N‐methyl‐4‐piperidone (DANMP), diheteroarylidene‐N‐methyl‐4‐piperidone (DHANMP), and spirobibenzopyran (SBP) derivatives, one of which was also characterized by single crystal X‐ray diffraction. All compounds were evaluated for anti‐oxidant activity via 2,2‐Diphenyl‐1‐picrylhydrazyl (DPPH) radical scavenging assays and for drug‐like properties in silico. A subset of five compounds was investigated in terms of aqueous solubilities, which were significantly improved compared to that of curcumin. In vitro assessments of cellular and anti‐inflammatory effects were conducted via real time polymerase chain reaction (RT‐PCR) and Griess assays to evaluate the presence of inflammatory/activated (M1) markers and production of nitric oxide (NO) species, which are associated with inflammation. The five compounds reduced levels of markers and NO to extents similar to or better than curcumin in inflamed cells, and showed no adverse effects on cell viability. We show that these compounds possess anti‐inflammatory properties and may be used as curcumin‐substitutes with improved characteristics.

Curcumin and its derivatives as nutraceuticals: an update

Chapter

Jan 2023

Emerging therapeutic avenues against Cryptosporidium: A comprehensive review

Article

Aug 2024
VET PARASITOL

Cryptosporidium is among the top causes of life-threatening diarrheal infection in public health and livestock sectors. Despite its high prevalence and economic importance, currently, there is no vaccine. Control of this protozoan is difficult due to the excretion of many resistant oocysts in the feces of the infected host, which contaminate the environment. Paromomycin shows inconsistent results and isn’t considered a reliable therapy for cryptosporidiosis. Nitazoxanide (NTZ), the only FDA-approved drug against this parasite, is less productive in impoverished children and PLWHA (people living with HIV/AIDS). The absence of mitochondria and apicoplast, its unique location inside enterocytes separated by parasitophorous vacuole, and, most importantly, challenges in its genetic manipulations are some hurdles to the drug-discovery process. A library of compounds has been tested against Cryptosporidium during in vitro and in vivo trials. However, there has still not been sufficient success in finding the drug of choice against this parasite. Recent genome editing technologies based on CRISPR/Cas-9 have explored the functions of the vital genes by producing transgenic parasites that help to screen a collection of compounds to find target-specific drugs, provided the sufficient availability of in vitro culturing platforms, efficient transfection methods, and analytic techniques. The use of herbal remedies against Cryptosporidium is also an emerging area of interest with sufficient clinical success due to enhanced concern regarding anthelmintic resistance. Here, we highlighted present treatment options with their associated limitations, the use of genetic tools and natural products against it to find safe, effective, and inexpensive drugs to control the ever-increasing global burden of this disease.

Interaction Effect of Curcumin and Various Exercise Training Strategies on Adipokines and Adipocytokines in the Human Body: An Overview

Article

Full-text available

May 2024

Chemopreventive efficacy and pharmacokinetics of curcumin in the Min/+ mouse, a model of familial adenomatous polyposis

Article

Full-text available

Jun 2002

Curcumin, the major yellow pigment in turmeric, prevents the development of adenomas in the intestinal tract of the C57Bl/6J Min/ mouse, a model of human familial APC. To aid the rational development of curcumin as a colorectal cancer-preventive agent, we explored the link between its chemopreventive potency in the Min/ mouse and levels of drug and metabolites in target tissue and plasma. Mice received dietary curcumin for 15 weeks, after which adenomas were enumerated. Levels of curcumin and metabolites were determined by high-performance liquid chromatography in plasma, tissues, and feces of mice after either long-term ingestion of dietary curcumin or a single dose of [14C]curcumin (100 mg/kg) via the i.p. route. Whereas curcumin at 0.1% in the diet was without effect, at 0.2 and 0.5%, it reduced adenoma multiplicity by 39 and 40%, respectively, compared with untreated mice. Hematocrit values in untreated Min/ mice were drastically reduced compared with those in wild-type C57Bl/6J mice. Dietary curcumin partially restored the suppressed hematocrit. Traces of curcumin were detected in the plasma. Its concentration in the small intestinal mucosa, between 39 and 240 nmol/ g of tissue, reflects differences in dietary concentration. [14C]Curcumin disappeared rapidly from tissues and plasma within 2?8 h after dosing. Curcumin may be useful in the chemoprevention of human intestinal malignancies related to Apc mutations. The comparison of dose, resulting curcumin levels in the intestinal tract, and chemopreventive potency suggests tentatively that a daily dose of 1.6 g of curcumin is required for efficacy in humans. A clear advantage of curcumin over nonsteroidal anti-inflammatory drugs is its ability to decrease intestinal bleeding linked to adenoma maturation.

Activation of Transcription Factor NF- B Is Suppressed by Curcumin (Diferuloylmethane)

Article

Full-text available

Oct 1995

When activated, NF-κB, a ubiquitous transcription factor, binds DNA as a heterodimeric complex composed of members of the Rel/NF-κB family of polypeptides. Because of its intimate involvement in host defense against disease, this transcription factor is an important target for therapeutic intervention. In the present report we demonstrate that curcumin (diferuloylmethane), a known anti-inflammatory and anticarcinogenic agent, is a potent inhibitor of NF-κB activation. Treatment of human myeloid ML-1a cells with tumor necrosis factor (TNF) rapidly activated NF-κB, which consists of p50 and p65 subunits, and this activation was inhibited by curcumin. AP-1 binding factors were also found to be down-modulated by curcumin, whereas the Sp1 binding factor was unaffected. Besides TNF, curcumin also blocked phorbol ester- and hydrogen peroxide-mediated activation of NF-κB. The TNF-dependent phosphorylation and degradation of IκBα was not observed in curcumin-treated cells; the translocation of p65 subunit to the nucleus was inhibited at the same time. The mechanism of action of curcumin was found to be different from that of protein tyrosine phosphatase inhibitors. Our results indicate that curcumin inhibits NF-κB activation pathway at a step before IκBα phosphorylation but after the convergence of various stimuli.

Phase II Trial of Curcumin in Patients with Advanced Pancreatic Cancer

Article

Full-text available

Jul 2008

Pancreatic cancer is almost always lethal, and the only U.S. Food and Drug Administration-approved therapies for it, gemcitabine and erlotinib, produce objective responses in <10% of patients. We evaluated the clinical biological effects of curcumin (diferuloylmethane), a plant-derived dietary ingredient with potent nuclear factor-kappaB (NF-kappaB) and tumor inhibitory properties, against advanced pancreatic cancer. Patients received 8 g curcumin by mouth daily until disease progression, with restaging every 2 months. Serum cytokine levels for interleukin (IL)-6, IL-8, IL-10, and IL-1 receptor antagonists and peripheral blood mononuclear cell expression of NF-kappaB and cyclooxygenase-2 were monitored. Twenty-five patients were enrolled, with 21 evaluable for response. Circulating curcumin was detectable as drug in glucuronide and sulfate conjugate forms, albeit at low steady-state levels, suggesting poor oral bioavailability. Two patients showed clinical biological activity. One had ongoing stable disease for >18 months; interestingly, one additional patient had a brief, but marked, tumor regression (73%) accompanied by significant increases (4- to 35-fold) in serum cytokine levels (IL-6, IL-8, IL-10, and IL-1 receptor antagonists). No toxicities were observed. Curcumin down-regulated expression of NF-kappaB, cyclooxygenase-2, and phosphorylated signal transducer and activator of transcription 3 in peripheral blood mononuclear cells from patients (most of whom had baseline levels considerably higher than those found in healthy volunteers). Whereas there was considerable interpatient variation in plasma curcumin levels, drug levels peaked at 22 to 41 ng/mL and remained relatively constant over the first 4 weeks. Oral curcumin is well tolerated and, despite its limited absorption, has biological activity in some patients with pancreatic cancer.

ACTIVATION OF TRANSCRIPTION FACTOR NF-KAPPA-B IS SUPPRESSED BY CURCUMIN (DIFERULOYLMETHANE) (VOL 270, PG 24995, 1995)

Article

Dec 1995

Selected eicosanoids increase the proliferation rate of human colon carcinoma cells and mouse colonocytesin vivo

Article

Jan 1995
Biochim Biophys Acta

EICOSANOIDS INCREASE THE PROLIFERATION RATE IN HUMAN COLON-CARCINOMA CELL-LINES AND MOUSE COLON CELLS

Article

Apr 1995
GASTROENTEROLOGY

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 mice. PGs E2, F2 alpha, 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 but PGF2 alpha 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 effect. 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.

Curcumin in combination with visible light inhibits tumor growth in a xenograft tumor modelInt

Article

Mar 2009

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.

Qiao L, Kozoni V, Tsioulias GJ, Koutsos MI, Hanif R, Shiff SJ, Rigas BSelected eicosanoids increase the proliferation rate of human colon carcinoma cell lines and mouse colonocytes in vivo. Biochim Biophys Acta 1258: 215-223

Article

Oct 1995
Biochim Biophys Acta

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.

Inhibition of tumor necrosis factor by curcumin, a phytochemical

Article

Jun 1995
BIOCHEM PHARMACOL

Marion Man-Ying Chan

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.

Stability of curcumin in buffer solution and characterization of its degradation products

Article

Sep 1997
J PHARMACEUT BIOMED

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.

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

Abstract and Figures

Recommended publications

Anti-inflammatory Properties of Curcumin, a Major Constituent of Curcuma Longa: A Review of Preclini...

Turmeric ( Curcuma longa L.): A promising spice for phytochemical and pharmacological activities

A REVIEW ON PHARMACOLOGICAL POTENTIAL OF CURCUMA LONGA (TURMERIC)

Medicinal and pharmacological properties of Turmeric (Curcuma longa): A review