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Curcumin Therapy in Inflammatory Bowel Disease: A Pilot Study

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Curcumin, a natural compound used as a food additive, has been shown to have anti-inflammatory and antioxidant properties in cell culture and animal studies. A pure curcumin preparation was administered in an open label study to five patients with ulcerative proctitis and five with Crohn's disease. All proctitis patients improved, with reductions in concomitant medications in four, and four of five Crohn's disease patients had lowered CDAI scores and sedimentation rates. This encouraging pilot study suggests the need for double-blind placebo-controlled follow-up studies.
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Digestive Diseases and Sciences, Vol. 50, No. 11 (November 2005), pp. 2191–2193 (
C
2005)
DOI: 10.1007/s10620-005-3032-8
Curcumin Therapy in Inflammatory Bowel
Disease: A Pilot Study
PETER R. HOLT, MD,* SEYMOUR KATZ, MD, and ROBERT KIRSHOFF
Curcumin, a natural compound used as a food additive, has been shown to have anti-inflammatory
and antioxidant properties in cell culture and animal studies. A pure curcumin preparation was
administered in an open label study to five patients with ulcerative proctitis and five with Crohn’s
disease. All proctitis patients improved, with reductions in concomitant medications in four, and four
of five Crohn’s disease patients had lowered CDAI scores and sedimentation rates. This encouraging
pilot study suggests the need for double-blind placebo-controlled follow-up studies.
KEY WORDS: curcumin; ulcerative proctitis; Crohn’s disease; inflammatory bowel disease.
Curcumin is a natural compound found in the plant Cur-
cuma longa which is used as a food additive known as
turmeric. The major pigment in turmeric is curcumin
(chemical name diferuloymethane), which possesses both
anti-inflammatory (1, 2) and antioxidant properties (3, 4)
Topical application of curcumin inhibits carcinogen-
induced DMA adduct formation and the development of
skin tumors. Curcumin also strongly inhibits proliferation
of HT-29 and HCT-15 human colon cancer cell lines (5).
Dietary administration of curcumin suppresses the devel-
opment of chemically induced cancers. These properties
have led to studies of the chemopreventive effects of cur-
cumin which also showed that the agent reduces colonic
inflammatory responses (6). The background for such anti-
inflammatory activity rests in in vitro and animal model
studies. We report here our experience with curcumin ther-
apy in 10 patients with inflammatory bowel disease.
MATERIALS AND METHODS
Five consecutive patients with ulcerative proctitis or proc-
tosigmoiditis who agreed to participate in this study were en-
tered (Table 1). There were three women and two men, aged 28
Manuscript received March 21, 2004; accepted August 10, 2004.
From *St. Luke’s Roosevelt Hospital Center, Columbia University
and Strang Cancer Center Research Laboratory, New York, New York,
and Long Island Clinical Research Associates, Great Neck, New York,
USA.
Address for reprint requests: Peter R. Holt, MD,15 West 81 Street,
New York, New York 10024, USA; pholt@chpnet.org.
to 54 years, who had complained of proctitis symptoms for 1 to
32 years. All had been previously treated with 5-aminosalicyclic
acid (5ASA) compounds by mouth and/or rectum, three had re-
ceived corticosteroid therapy at some time, and one subject was
taking prednisone, 10 mg per day, at study entry.
They were treated with 550 mg of curcumin (DFM 100; 99.5%
pure
1
) twice daily for 1 month and then 550 mg three times daily
for another month. All had blood taken for hematologic and bio-
chemical analysis and for indexes of inflammation (sedimenta-
tion rate and C-reactive protein [CRP]) and had sigmoidoscopies
and biopsies both at baseline and 2 months later when the study
ended.
Symptoms were assessed by a standard questionnaire at the
start and conclusion of the study and by a daily symptom dairy.
The endoscopic evaluation was not blinded since the investigator
wasaware of the timing of the procedure, however, the biopsies
were obtained and evaluated for the degree of inflammation with-
out knowledge of their timing.
Five subjects, three men and two women, with an established
diagnosis of Crohn’s disease were entered in this pilot study to
determine whether the addition of curcumin to existing treat-
ments for Crohn’s disease would result in a reduction of in-
flammation with the ability to reduce other concomitant anti-
inflammatory agents (Table 1). The subjects were treated with
curcumin, 360 mg (1 capsule) three times daily for 1 month
and then 360 mg (4 capsules) four times daily for the remaining
2 months. Crohn’s Disease Activity Index (CDAI), CRP, ery-
throcyte sedimentation rate (ESR), complete blood counts, and
liver and renal function studies were obtained in all patients. All
patients signed a consent form and IRB permission was obtained
for this study.
1
Kindly provided by R. Kane Products, Pennsauken, New Jersey.
Digestive Diseases and Sciences, Vol. 50, No. 11 (November 2005)
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0163-2116/05/1100-2191/0
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2005 Springer Science+Business Media, Inc.
HOLT ET AL.
T
ABLE 1. DATA ON ULCERATIVE PROCTOSIGMOIDITIS AND CROHNS DISEASE PATIENTS
Length of disease Medications at
Patient No. Age/sex Extent of disease history (yr) study entry
A. Ulcerative proctosigmoiditis
1. RK 52/F Proctitis 32 5ASA suppositories
Sulfasalazine, 2g 1d
2. EJ 30/F Proctitis 01 5ASA enemas and
suppositories
3. PM 28/M Proctitis 05 5ASA enemas
4. JM 29/M Proctitis 07 Sulfasalazine, 2g 1d
5ASA suppositories
5. RP 54/F Proctosigmoiditis 06 Prednisone, 10 mg
5ASA and enemas
Azathiopine, 100 mg
B. Crohn’s disease
1. JD 43/M lleocolitis 22 Colestid, 3/day
6MP, 75 mg
2. RK 47/M Crohn’s colitis 26 6MP, 75 mg
3. BE 65/F lleocolitis 11 6MP, 75 mg
4. JR 50/M lleojejunal colitis 23 Flagyl, 500 mg
Budesonide, 9 mg
5. JWP 33/F Ileitis 22 None
Note. 5ASA, 5-aminosalicylic acid; 6MP, 6-methylprednisone.
RESULTS
Overall, all five subjects with proctitis improved by the
end of the study as judged by a global score (P < 0.02;
Table 2). The major changes found were in the number and
quality of stools. Two subjects eliminated their prestudy
5ASA medications, two subjects reduced their medica-
tions (including termination of the prednisone therapy in
one subject), and one continued taking 5ASA supposito-
ries. In these patients with limited ulcerative colitis, sero-
logic indexes of inflammation, sedimentation rate, and
CRP returned to within normal limits at the conclusion
of the study.
The CDAI scores for all completed subjects fell, with
a mean reduction of 55 points; sedimentation rate fell
as well, with a mean reduction of 10 mm/hr (Table 3).
CRP was reduced by a mean of 0.1 mg/dl. There were no
changes in indexes of liver or renal function. Visits oc-
TABLE 2. EFFECTS OF CURCUMIN ADMINISTRATION IN ULCERATIVE PROCTITIS PATIENTS
General No. of Stool Stool Abdominal Rectal pain Global
Subject No. well-being stools quality blood pain urgency Medication Endoscopy score
1. Before 1 2–3 2 1 0 1 Eliminated 3 11
After 0 1 0 1 0 0 2 4
2. Before 1 4+ 13 02Unchanged 2 13
After 0 2–3 1 3 0 2 2 11
3. Before 0 2–3 1 0 0 0 Eliminated 0 4
After 0 1 0 0 0 0 0 1
4. Before 1 4+ 23 11Reduced++ 315
After 1 2–3 0 3 0 0 1 8
5. Before 4+ 1–2 1 0 1 Reduced 1 9
After 1–2 1–2 1 0 1 1 7
Note. Numbers represent semiquantitative scores ranging from 1 to 3. The higher the score, the worse the status.
curred every month, at which the four completed subjects
reported improvement in clinical symptoms as follows:
more formed stools, less frequent bowel movements, and
less abdominal pain and cramping. One subject reported
decreased muscle soreness, commonly felt after his exer-
cise routine. Of the five subjects, four successfully com-
pleted and one discontinued due to lack of treatment effect,
with a slight worsening of fistula output.
DISCUSSION
Curcumin has a profound immunosuppressive effect via
inhibition of IL-2 synthesis as well as IL-2 and mitogen
activation of human leukocytes. This immunosuppressive
effect may be mediated by NFκB inhibition (7).
Further support is offered by data indicating that cur-
cumin effectively inhibited tumor necrosis factor α and
2192 Digestive Diseases and Sciences, Vol. 50, No. 11 (November 2005)
CURCUMIN THERAPY IN INFLAMMATORY BOWEL DISEASE
T
ABLE 3. EFFECTS OF CURCUMIN ADMINISTRATION IN CROHNS
DISEASE PATIENTS
CDAI Sedimentation rate
Subject No. Index Change % change Rate Change % change
1. Before 225 23
After 196 29 12.9 19 4 17.4
2. Before 253 11
After 155 98 38.7 6 5 45.5
3. Before 250 24
After 239 11 44 7 17 70.8
4. Before 302 42
After 220 82 27.2 28 14 33.3
Note.CDAI, Crohn’s Disease Activity Index. Data for the four subjects
who completed the study.
phorbol ester-induced binding of NFκ B transcription
factors to sites located on the GSTP1-1 (glutathione
S-transferase P1-1) gene promoter. These results indi-
cate that curcumin could thereby induce apoptosis by its
ability to inhibit GSTP1-1 expression at the transcription
level (8).
In animal colitis models, curcumin has been shown to
attenuate or prevent DNB or trinitrobenzene sulfonic acid-
induced colitis in mice by suppressing CD4(+)T-cell in-
filtration and NHκ B activation as well as reducing p38
MAPX activity (9, 10). Based on these reports we have
shown that curcumin appears to have reduced the inflam-
matory response in four of five ulcerative colitis patients
and four of five Crohn’s disease patients.
Conclusion
The results of this pilot study indicate that further stud-
ies are warranted. A larger scale, double-blind, placebo-
controlled trial is indicated.
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Background: T cell mediated acute rejection of transplanted organ continues to be a significant problem in solid organ transplantation. We had shown that curcumin is a potent inhibitor of Cyclosporin A resistant T cell CD28 co-stimulation pathway. Here we report the inhibitory effects of curcumin on mitogen stimulated lymphocyte proliferation, IL-2 synthesis/ signaling and on NFκB (component of IL2 promoter gene) activation . Methods: Human lymphocytes were isolated from fresh human spleen (SP-L). Mitogens [final concentrations of 2 μg/ml of concanavalin A (Con A), 5 μg/ml of phytohemagglutinin (PHA) and 20 ng/ml of phorbol-12-myristate 13-acetate (PMA)] were added to the designated wells in 96 well plate with 0.2 million SP and cultured for 48 h and then assayed for IL-2 synthesis by ELISA and 3H-thymidine uptake. In another parallel experiment we added IL-2 (0.5 nM) to stimulate the cells to bypass curcumin’s inhibition of IL-2 synthesis as the sole reason for inhibition of proliferation. Electrophorectic magnetic shift assay (EMSA) was performed in PMA (20 ng/ml,1 h) stimulated cells with or without curcumin to assay NFκB activation. Results: Curcumin at 2.5 μg/ml inhibited Con A, PHA and PMA stimulated SP-L proliferation at 77%, 23% and 48% respectively over controls and curcumin at 5 μg/ml completely (nearly 100%) inhibited the mitogen stimulated proliferation. Curcumin inhibited IL-2 synthesis in Con A, PHA and PMA stimulated SP-L in a concentration dependent manner with an ED50 (concentration required for 50% inhibition) measured at 3.5 μg/ml. Exogenous IL-2 stimulated SP-L proliferation was also inhibited by curcumin in a concentration dependent manner with an ED50 of 2 μg/ml. EMSA assay indicated that PMA at 20 ng/ml stimulated NFκB activation 253% over control which was inhibited by 24%, 38% and 73% respectively with curcumin at final concentrations of 2.5, 5 and 10 μg/ml respectively. Conclusion: Curcumin has profound immunosuppressive effects mediated via inhibition of IL-2 synthesis, mitogen and IL-2 induced activation of human lymphocytes. This effect may be mediated via NFκB inhibition.
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The data reviewed indicate that extracts of Curcuma longa exhibit anti-inflammatory activity after parenteral application in standard animal models used for testing anti-inflammatory activity. It turned out that curcumin and the volatile oil are at least in part responsible for this action. It appears that when given orally, curcumin is far less active than after i.p. administration. This may be due to poor absorption, as discussed. Data on histamine-induced ulcers are controversial, and studies on the secretory activity (HCl, pepsinogen) are still lacking. In vitro, curcumin exhibited antispasmodic activity. Since there was a protective effect of extracts of Curcuma longa on the liver and a stimulation of bile secretion in animals, Curcuma longa has been advocated for use in liver disorders. Evidence for an effect on liver disease in humans is not yet available. From the facts that after oral application only traces of curcumin were found in the blood and that, on the other hand, most of the curcumin is excreted via the faeces it may be concluded that curcumin is absorbed poorly by the gastrointestinal tract and/or underlies pre-systemic transformation. Systemic effects therefore seem to be questionable after oral application except that they occur at very low concentrations of curcumin. This does not exclude a local action in the gastrointestinal tract.
A new model for evaluating nonsteroidal anti-inflammatory drugs (NSAIDs) is described. In this model of postoperative inflammation, the anti-inflammatory activity of curcumin (diferuloyl methane) was investigated in comparison with phenylbutazone and placebo. Phenylbutazone and curcumin produced a better anti-inflammatory response than placebo.
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Antioxidative components in the methanol extract of the rhizome of Curcuma longa L. were investigated by using our evaluation method based on the air oxidation of linoleic acid. Curcuminoids such as curcumin, 4-hydroxycinnamoyl (feruloyl) methane and bis (4-hydroxycinnamoyl) methane were found to be active components. Curcumin was the most active component and its 50% inhibitory concentrations for the air oxidation of linoleic acid were 1.83×10-2% (thiobarbituric acid value) and 1.15×10-2% (peroxide value). These values of curcumin are superior to those of dl-α-tocopherol.
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Curcumin, the active ingredient of the rhizome of the plant turmeric (Curcuma longa Linn), a commonly used spice, prevents cancer in animal tumor models. Its mechanism of action is unknown; curcumin may act by inhibiting arachidonic acid metabolism. To explore the mechanism of curcumin's chemopreventive effect, we studied its role in proliferation and apoptosis in the HT-29 and HCT-15 human colon cancer cell lines. Curcumin dose-dependently reduced the proliferation rate of both cell lines, causing a 96% decrease by 48 hours. No apoptosis was detected. The antiproliferative effect was preceded by accumulation of the cells in the G2/M phase of cell cycle. The effect of curcumin was similar in both cell lines, which, however, differ in their ability to produce prostaglandins. We conclude that curcumin inhibits colon cancer cell proliferation in vitro mainly by accumulating cells in the G2/M phase and that this effect is independent of its ability to inhibit prostaglandin synthesis. The role of curcumin's antiproliferative effect in human colon cancer remains to be established.
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A wide variety of phenolic substances derived from spice possess potent antimutagenic and anticarcinogenic activities. Examples are curcumin, a yellow colouring agent, contained in turmeric (Curcuma longa L., Zingiberaceae), [6]-gingerol, a pungent ingredient present in ginger (Zingiber officinale Roscoe, Zingiberaceae) and capsaicin, a principal pungent principle of hot chili pepper (Capsicum annuum L, Solanaceae). The chemopreventive effects exerted by these phytochemicals are often associated with their antioxidative and anti-inflammatory activities. Cyclo-oxygenase-2 (COX-2) has been recognized as a molecular target of many chemopreventive as well as anti-inflammatory agents. Recent studies have shown that COX-2 is regulated by the eukaryotic transcription factor NF-kappaB. This short review summarizes the molecular mechanisms underlying chemopreventive effects of the aforementioned spice ingredients in terms of their effects on intracellular signaling cascades, particularly those involving NF-kappaB and mitogen-activated protein kinases.
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Expression of glutathione S-transferase P1-1 (GSTP1-1) is correlated to carcinogenesis and resistance of cancer cells against chemotherapeutic agents. Curcumin, a natural compound extracted from Curcuma longa, has shown strong antioxidant and anticancer properties and also the ability to regulate a wide variety of genes that require activating protein 1 and nuclear factor kappaB (NF-kappaB) activation. In the present study, we examined the inhibitory effect of curcumin on the expression of GSTP1-1 mRNA as well as protein, and we correlated this inhibition with the apoptotic effect of curcumin on K562 leukemia cells. Curcumin efficiently inhibited the tumour necrosis factor alpha- and phorbol ester-induced binding of AP-1 and NF-kappaB transcription factors to sites located on the GSTP1-1 gene promoter. TNFalpha-induced GSTP1-1 promoter activity was also inhibited by curcumin as shown by reporter gene assay. In parallel, curcumin induced pro-caspases 8 and 9 as well as poly ADP ribose polymerase cleavage and thus leading to apoptosis in K562 cells. Our results overall add a novel role for curcumin as this chemoprotective compound could contribute to induce apoptosis by its ability to inhibit the GSTP1-1 expression at the level of transcription.
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T cell mediated acute rejection of transplanted organ continues to be a noticeable problem in solid organ transplantation. We showed that Curcumin is a potent inhibitor of Cyclosporin A resistant T cell CD28 co-stimulation pathway. Here we report the inhibitory effects of Curcumin on mitogen-stimulated lymphocyte proliferation, IL-2 synthesis/signaling, and NFkappaB (transcription factor of IL-2 promoter) activation. Human lymphocytes were isolated from fresh human spleen (SP-L). Mitogens [final concentrations of 2 microg/ml concanavalin A (Con A), 5 microg/ml phytohemagglutinin (PHA), and 20 ng/ml of phorbol-12-myristate-13-acetate (PMA)] were added to the designated wells in a 96-well plate with 0.2 million SP-L and cultured for 48 h and then assayed for IL-2 synthesis by ELISA and 3H-thymidine uptake. In another parallel experiment we added IL-2 (0.5 nM) to stimulate the cells to check if Curcumin's inhibition of IL-2 synthesis is the sole reason for inhibition of cell proliferation. Electrophoretic mobility shift assay (EMSA) was performed in PMA (20 ng/ml, 1 h) stimulated cells with or without Curcumin to assay NFkappaB activation. Curcumin at 2.5 microg/ml inhibited Con A, PHA, and PMA stimulated SP-L proliferation at 77, 23, and 48%, respectively, over controls and Curcumin at 5 microg/ml completely (nearly 100%) inhibited the mitogen stimulated proliferation. Curcumin inhibited IL-2 synthesis in Con A, PHA, and PMA stimulated SP-L in a concentration-dependent manner with an ED50 (concentration required for 50% inhibition) measured at 3.5 microg/ml. Exogenous IL-2 stimulated SP-L proliferation was also inhibited by Curcumin in a concentration-dependent manner with an ED50 of 2 microg/ml. EMSA assay indicated that PMA at 20 ng/ml stimulated NFkappaB activation 253% over control, which was inhibited by 24, 38, and 73%, respectively, with Curcumin at final concentrations of 2.5, 5, and 10 microg/ml, respectively. Curcumin has profound immunosuppressive effects mediated via inhibition of IL-2 synthesis, mitogen, and IL-2 induced activation of human lymphocytes. This effect may be mediated via NFkappaB inhibition.