anti-inflammatory properties of curcumin, a major ...turmeric (the common name for curcuma longa) i...

Alternative Medicine Review Volume 14, Number 2 2009

Anti-inflammatory Properties ofCurcumin, a Major Constituentof Curcuma longa: A Review of

Preclinical and Clinical Research

Julie S* Jurenka, MT(ASCP)

Abstract

Curcuma ¡onga (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.

('MemMe(i/?ev2009;14(2):141-153)

IntroductionTurmeric (the common name for Curcuma

longa) is an Indian spice derived from the rhizomes ofthe plant and has a long history of use in Ayurvedicmedicine as a treatment for inflammatory conditions. C.longa is a perennial member of the Zingiberaceae familyand is cultivated in India and other parts of SoutheastAsia.' The primary active constituent of turmeric andthe one responsible for its vibrant yellow color is cur-cumin, first identified in 1910 by Lampe and Milobed-zka." While curcumin has been attributed numerouspharmacological activities, including antioxidant^ andantimicrobial properties,' this article focuses on one ofthe best-explored actions, the anti-inflammatory eflFectsof curcumin. Curcumin's effect on cancer (from an anti-inflammatory perspective) is also discussed; however, anexhaustive review of its many anticancer mechanisms isoutside the scope of this article. Based on early researchconducted with cell cultures and animal models, pilotand clinical trials indicate curcumin may have potentialas a therapeutic agent in diseases such as inflammatorybowel disease, pancreatitis, arthritis, and chronic ante-rior uveitis, as well as certain types of cancer. Numerousclinical trials are currently in progress that, over the nextfew years, will provide an even deeper understanding ofthe therapeutic potential of curcumin.

Julie Jurenka, MT (ASCP) - Associate Editor. Alternative Medicine Review;technical assistant. Ttiorne Researcti. Inc. - the manufacturer ot MerivaCurcumin PhytosomeCorrespondence address: Thorne Research, Inc, PO Box 25. Dover, ID 83825Email: ] [email protected]

41


Active ConstituentsTurmeric is comprised of a group of three cur-

cuminoids: curcumin (diferuloylmethane), demethoxy-curcumin, and bisdemethoxycurcumin (Figure 1), aswell as volatile oils (tumerone, atlantone, and zingib-erone), sugars, proteins, and resins. The curcutiiinoidcomplex is also known as Indian saffron."' Curcumin isa lipophilic polyphenol that is nearly insoluble in water*"but is quite stable in the acidic pH of the stomach/

Absorption of CurcuminAnimal studies have shown curcumin is rapidly

metabolized, conjugated in the liver, and excreted in thefeces, therefore having hmited systemic bioavailability.A 40 mg/kg intravenous dose of curcumin given to ratsresulted in complete plasma clearance at one hout post-dose. An oral dose of 500 mg/kg given to rats resultedin a peak plasma concentration of only 1.8 ng/mL, withthe major metabolites identified being curcumin sulfateand curcumin glucuronide.*

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 withvarious precancerous lesions demonstrated oral dosesof 4, 6, and 8 g curcumin daily for three months yieldedserum curcumin concentrations of only 0.51 ± 0.11,0.63 ± 0.06, and 1.77 ± 1.87 fiM, respectively, indicat-ing curcumin is poorly absorbed and may have limitedsystemic bioavailability. Serum levels peaked betweenone and two hours post-dose and declined rapidly. Thisstudy did not identify curcumin metabolites and urinaryexcretion of curcumin was undetectable.'^

Another phase I trial, involving 15patients with advanced colorectal cancer, used cur-cumin at doses between 0.45 and 3.6 g daily for fourmonths. In three of six patients given the 3.6 g dose,mean plasma curcumin measured after one hour on day1 was 11.1 ± 0.6 nmol/L. IKis measurement remainedrelatively consistent at all time points measured duringthe first month of curcumin therapy. Curcumin was notdetected in the plasma of patients taking lower doses.Glucuronide and sulfate metabolites of curcumin weredetected in plasma of all six patients in the high-dosegroup at ail measurement points in the study.'" Cur-cumin levels repotted in this study are approximately

Figure 1. Structures of Curcumin(Diferuioylmethane), Demethoxycurcumin, andBisdemetnoxycurcumin

1/45 of the levels reported by Cheng et al, who useda similar dose of curcumin (4 g).^ The reason for thediscrepancy is unclear.

While systemic distribution of curcumin tendsto 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 pharmacologicallyefficacious levels of curcumin (12.7 ± 5.7 nmol/g) inboth malignant colorectal tissue and normal colorectaltissue (7.7 ± 1.8 nmol/g), perhaps accounting for theanti-inflammatory benefits of curcumin observed indiseases of the gastrointestinal tract."

Although research on curcumin pharmacoki-netics in healthy subjects is limited, one study using highdoses (10 and 12 g in a single oral dose) in 12 healthysubjects measured serum curcumin as well as its sulfateand glucuronide metabolites at various time points upto 72 hours post-dose. As in previous studies, curcuminwas rapidly cleared (only one subject had detectablefree curcumin in the serum) and subsequently conju-gated in the gastrointestinal tract and liver. Area under

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Figure 2. Absorption of Curcumin Phytosome (Meriva) Compared to Non-complexCurcumin in Humans

450mg MERIVA vs 4g curcumin45.

= ' 4 0 ,

00 1

00^.r-450mg MERIVA

• 4.0g non-complexed curcumin

6 8 10 12 14 16 18

Time after supplementation [hours]

20 22 24

the curve (AUC) for curcumin conjugates was surpris-ingly higher (35.33 ± 3.78 pg/mL) for the 10-g dosethan for the 12-g dose (26.57 ± 2.97 (ig/mL), perhapsindicating saturation of the transport mechanism inthe gut for free curcumin. Maximum serum concentra-tion (C ) for the 10-g dose was 2.30 ± 0.26 |ag/mLcompared to 1.73 ± 0.19 jxg/mL for the 12-g dose.'^

Because of curcumin's rapid plasma clearanceand conjugation, its therapeutic usefulness has heensomewhat limited, leading researchers to investigate thehenefits of complexing curcumin with other substancesto increase systemic bioavaility. One substance that hasbeen studied is the alkaloid piperine, a constituent fromblack pepper and long pepper [Piper nigrum and Piperlongum, respectively). In humans 20 mg piperine givenconcomitantly with 2 g curcumin increased serum cur-cumin bioavailability 20-fold, which was attributed topiperine's inhibition of hepatic glucuronidation and in-testinal metabolism.^'

Another method currently being investigatedis complexing curcumin with a phospholipid, knownas a phytosome. The phosphatidylcholine-curcumíncomplex (Meriva"^) is more readily incorporated intolipophilic cell membranes, making it significantly

more bioavailable than unbound curcumin. In rats,peak plasma concentration and AUC were five timeshigher for Meriva than for unbound curcumin.''' Onesmall unpublished, single-dose trial demonstrated 450mg of Meriva (phosphatidylcholine complexed with90 mg curcumin) was absorbed as efficiently as 4 gunbound Curcuma longa (95% curcumin), reflecting anapproximate 45- to 50-fold increase in bioavailability fotMeriva complex (Figure 2).'^

Anti-inflammatory MechanismsResearch 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 theactivity of cyclooxygenase-2 (COX-2), lipoxygenase,and inducible nitric oxide synthase (iNOS) en:2ymes;inhibits the production of the inflammatory cytokinestumor necrosis factor-alpha (TNF-a) , interleukin(IL) -1 , -2, -6, -8, and -12, monocyte chemoattractantprotein (MCP), and migration inhibitoryprotein; and down-regulates mi togen-activated andJanus ^

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COX-2 and iNOS inhibition are likely accom-plished via curcumin's suppression of nuclear factor-kappa B ( N F - K B ) activation."' N F - K B , a ubiquitouseukaryotic transcription factor, is involved in regulationof inflammation, cellular proliferation, transformation,and tumorigenesis. Curcumin is thought to suppressN F - K B activation and proinflammatory gene expres-sion by blocking phosphorylation ot inhibitory factorI-kappa B kinase ( IKB). Suppression of NF-ICB activa-tion subsequently down-regulates COX-2 and iNOSexpression, inhibiting the inflammatory process andtumorigenesis.'^''' In an animal model of inflammation,curcumin also inhibited arachidonic acid metabolismand inflammation in mouse skin epidermis via down-regulation of the cyclooxygenase and lipoxygenasepathways.-^"

Curcumin's inhibition of inflammatorycytokines is achieved through a number of mechanisms.In vitro studies indicate curcumin regulates activa-tion of certain transcription factors such as activatingprotein-1 (AP-1) and N F - K B in stimulated monocytesand alveolar macrophages, thereby blocking expres-sion of cytokine gene expression. Down-regulation ofintercellular signaling proteins, such as protein kinaseC, may be another way in which curcumin inhibitscytokine production.

Curcumin's Anti-inflammatoryProperties and Carcinogenesis

It is well understood that proinflammatorystates are linked to tumor promotion."'" Consequently,phytochemicals like curcumin that exert a strong anti-inflammatory effect are anticipated to have some degreeof chemopreventive activity. Preclinical cancer researchusing curcumin has shown it inhibits carcinogenesis in anumber of cancer types, including colorectal, pancreatic,gastric, prostate, hepatic, breast, and oral cancers, andleukemia, and at various stages of carcinogenesis.*' Anti-inflammatory mechanisms implicated in the anticarci-nogenic potential of curcumin include: (1) inhibitionof N F - K B and COX-2 {increased levels of COX-2 areassociated with many cancer types);" '̂"'̂ (2) inhibitionof arachidonic acid metabolism via lipoxygenase andscavenging of free radicals generated in this pathway;^"(3) decreased expression of inflammatory cytokines IL-lß , IL-6, and TNF-a , resulting in growth inhibition of

cancer cell lines;^^ and (4) down-regulation of enzymes,such as protein kinase C, that mediate inflammationand tumor-cell prohferation.^''

Animal Research on Curcumin andInflammationInflammation and Edema

Several animal studies have investigated theanti-inflammatory effects of curcumin. Early work bySrimal et al demonstrated curcumins anti-inflamma-tory action in a mouse and rat model of carrageenan-induced paw edema. In mice, curcumin inhibited edemaat doses between 50-200 mg/kg. A 50-percent reduc-tion in edema was achieved with a dose of 48 mg/kgbody weight, with curcumin nearly as effective as cor-tisone and phenylbutazone at similar doses. In rats, alower dose oí 20-80 mg/kg decreased paw edema andinflammation. Curcumin also inhibited formaldehyde-induced arthritis in rats at a dose of 40 mg/kg, had alower ulcerogenic index (0.60) than phenylbutazone(1.70) (an anti-inflammatory drug often used to treatarthritis and gout), and demonstrated no acute toxicityat doses up to 2 g/kg body weight.^^

Ulcerative ColitisCurcumin 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 sulphonicacid resulted in a significant amelioration of diarrhea,improved colonie architecture, and significantly reducedneutrophil infiltration and lipid peroxidation in colonietissue. Reduced levels of nitric oxide and O, radicalsand suppressed N F - K B activation in colonie mucosa,all indicators of reduced inflammation and symptomimprovement, were also reported."''

Rheumatoid ArthritisIn an animal model of streptococcal cell

wall-induced rheumatoid arthritis, a turmeric extractdevoid of essential oils was given to Wistar femalerats. Intraperitoneal injection of an extract containing4 mg total curcuminoids/kg/day for four days prior toarthritis induction significantly inhibited joint inflam-mation in both the acute (75%) and chronic (68%)phases. To test efficacy of an oral preparation, a 30-fold

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Alternative Medicine Volume 14, Number 2 2009

higher dose (to allow for possible low gastrointestinalabsorption) of the curcuminoid preparation, given torats four days prior to arthritis induction, significantlyreduced joint inflammation by 48 percent on the thirdday of administration."^'

PancreatitisIn two rat models of experimentally-induced

pancreatitis, curcumin decreased inflammation bymarkedly decreasing activation of N F - K B and AP-1 aswell as inhibiting mRNA induction of IL-6, TNF-a, andiNOS in the pancreas. In both cerulein- and ethanol-in-duced pancreatitis, curcumins inhibitory effect on inflam-matory mediators resulted in improvement in disease se-verity as measured by histology, serum amylase, pancreatictrypsin, and neutrophil infiltration.^"

CancerNumerous animal studies have explored cur-

cumins anti-inflammatory mechanisms and their influ-ence on carcinogenesis; however, discussion of thesestudies 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-inflammatorymechanisms.

Clinical Trials Exploring Curcumin's Anti-inflammatory Beneñts

Curcumins potent and-inflammatory propertieshave lead to active research on its use for a variety of inflam-matory conditions, including postoperative inflammation,arthritis, uveltis, inflammatory pseudotumors, dyspepsia,irritable bowel syndrome, inflammatory bowel disease,pancreatitis, and Helicohacter pylori infection. Most studiesare promising and further exploration of curcumin's thera-peutic value for inflammatory conditions is warranted.

Post-surgerySatoskar ec al examined the effects of curcumin

compared to phenylbutazone or placebo for spermaticcord 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), or100 mg phenylbutazone (Group C) three times daily tor six

days postoperatively. Parameters measured were spermaticcord edema, spermatic cord tenderness, operative site pain,and operative site tenderness (0: absent, 1: mud, 2: mod-erate, 3: severe) and reflected by intensity score (TIS) of0-12. TIS on day 6 decreased in Group A (curcumin) by84.2 percent, by 61.8 percent in Group B (placebo), and by86 percent in Group C (phenylbutazone). Although TISscores for cutcumin and phenylbutazone were similar onday 6, curcumin proved to be superior by reducing all tourparameters of inflammation. Phenylbutazone did not re-duce tenderness at the operative site.""

Rheumatoid ArthritisIn 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 beneflt, dosages, study size, and details were notavailable in English full

OsteoarthritisA crossover RCT examined the effect of tur-

meric extract (50 mg/capsule) in combination with zinccomplex (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 atwo-week washout period, switched to the oppositetreatment for another three months. Assessment everytwo weeks during the suidy demonstrated significantimprovements in pain severity (p<0.001) and disabilityscores (p<0.05), but no statistically significant changesin other parameters. Curcumin's role in this improve-ment cannot be confirmed due to the other botanicalsand zinc in the treatment compound.''^

Ocular ConditionsAnterior uveitis is a condition characterized by

inflammation of the uveal tract of the eye (including theiris) and if untreated can result in blurred vision andpermanent damage. Although the exact cause of ante-rior uveitis is not certain, it has been known to occur

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Alternative Medicine Reviev̂ í Volume 14, Number 2 2009

Table 1. Animal Studies Investigating the Anti-inflammatoty Effects of Curcuminin Cancer Models^* 'f«

Author

Chan et al 1998^^

Rao eíal l999^°

Rao et al 1995^^

Perkins et al 2002^^

Kwonetal2009^^

Dujic et al 2009^^

Garget al 2008-"'

Kawamori et al 1999""

Huang et al 1998^^

Tomita et al 2006"''

Animal Model

Murine (liver) iNOS production

Rat colonie aberrant crypt foci1Rat colon cancer

Murine familial adenomatouspolyposisRat colonie aberrant crypt foci

Rat colonie apoptosis

Murine xenograft tumor

Murine liver, lung tumor initiation

Rat colonie apoptosis

Murine lymphomas/leukemias

Murine breasfcènëëi'with lung metastasis

Murine T-eell leukemia

Route of CurcuminAdministration

Oral by gavage. Intravenous

Oral (diet),Subeutaneous

Oral (diet)

Oral (diet), Intraperitoneal

Oral (diet)

Oral

Intraperitoneal

Oral (diet)

Oral

Oral (diet)

Oral (diet)

Oral (gavage)

Dose

0.5 mL of lOpM solution0.5 pg/g body weight

50-2,000 ppm15 mg/kg body weight

2,000 ppm

0,1-, 0.2-, 0.5-% diet100 mg/kg body weight

0.6-% diet

0.6-% diet

200 pL of 0.2-1.0 Mg/mL-curcumin suspension

0.01-or 0.0-% diet

0.2-or 0.6-% diet

2-% diet ^ ^ .

2-% diet

300 mg/kg body weight

with trauma to the eye, other eye diseases, tuberculosis,rheumatoid arthritis, measles, or mumps. Treatment isusually aimed at decreasing inflammation."'''

In a clinical trial involving 32 patients (ages19-70} with anterior uveitis, 375 mg curcumin wasadministered alone or with antitubercular therapy (tothose patients demonstrating a positive PPD skin pricktest) three times daily for 12 weeks. Of those in thecurcumin-only group (n=18), 100 percent reportedmarked improvement after two weeks of therapy.

compared to 86 percent in the curcumin/antituberculartherapy group (n=14). Improvements were observed invisual acuity and aqueous flare and were accompaniedby a decrease in keratic precipitates.'^

Curcumin has been used for idiopathic orbitalinflammatory pseudotumors (IOIP). Orbital pseudo-tumors include ocular lesions that are non-neoplastic innature for which there is no clearly defined cause. Thecondition is an immunological inflammatory condi-tion characterized by a hard mass in the orbit, inflam-mation of the conjunctiva, and decreased visual acuity.

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tideAlternative Medicine Revievi/ Volume 14, Number 2 2009

Conventional treatment consisting of corticosteroids isoften ineffective.'*^ In a small study of eight patients withIOIP, 375 mg curcumin three times daily was given for6-22 months, until complete regression of symptomol-ogy was achieved. Patients were followed for two yearsand 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 ocularmovement.*'̂

Gastrointestinal ConditionsCurcumin's anti-inflammatory properties and

therapeutic benefit have been demonstrated for a vari-ety of gastrointestinal conditions, including dyspepsia,Hclicohactcr pylori infection, peptic ulcer, irritable bowelsyndrome, Crohn's disease, and ulcerative colitis.

Dyspepsia and Gastric UlcerIn a phase II clinical trial involving 45 sub-

jects (24 males, 21 females, ages 16-60 years), 25 withendoscopically diagnosed peptic ulcers were given 600mg curcumin five times daily 30-60 minutes beforemeals, at 4:00 pm, and at bedtime for 12 weeks. Ulcerswere absent in 12 patients (48%) after four weeks, in18 patients after eight weeks, and in 19 patients (76%)after 12 weeks. The remaining 20 patients, also givencurcumin, had no detectable ulcérations at the start ofthe study, but were symptomatic - erosions, gastritis,and dyspepsia. Within 1-2 weeks abdominal pain andother symptoms had decreased significantly.^^

Irritable Bowel SyndromeIn patients with irritable bowel syndrome

(IBS) the most common symptoms are abdominal pain,bloating, altered bowel habits, and increased stool fre-quency.'*'' It is thought that low-grade inflammation ofthe intestinal mucosa is responsible for some sympto-mology.^" In an eight-week pilot study of IBS patients,either 72 mg or 144 mg of a standardized turmericextract was administered to a group of 102 or 105 sub-jects, respectively. Aher four weeks, those in the 72-mggroup experienced a 53-percent reduction in IBS preva-lence, while the 144-mg group experienced a 60-percentdecrease. In posr-study analysis, abdominal pain anddiscomfort scores were reduced by 22 percent in the 72-mg group and 25 percent in the 144-mg group.^^

Inflammatory Bowel DiseaseCrohn's disease (CD) and ulcerative colitis

(UC) are the two primary forms of inflammatory boweldisease (IBD). The primary difference between the twois nature and location of inflammatory changes in thegastrointestinal tract. CD can affect any part of the gas-trointestinal tract and affects the entire bowel wall. Incontrast, UC is restricted to the colon and the rectumand disease is confined to the intestinal epithelium.Although very different in scope, both diseases maypresent with abdominal pain, vomiting, diarrhea, bloodystools, weight loss, and secondary sequelae such asarthritis, pyoderma gangrenosum, and primary scleros-ing cholangitis.''^

Holt et al conducted a pilot study to examinethe effect of curcumin therapy in 10 patients with IBD(five with CD and five with UC, ages 28-54) who hadpreviously received standard UC or CD therapy. Fivepatients with proctitis (UC of the rectal area) received550 mg curcumin twice daily for one month and thenwere given the same dose three times daily for an ad-ditional month. Hematological and biochemical bloodanalysis, erythrocyte sedimentation rate (ESR), C-reac-tive protein (CRP) (the latter two inflammatory indica-tors), sigmoidoscopy, and biopsy were all performed atbaseline and at the study end. Symptoms were assessedby questionnaire and daily symptom diary. The otherfive patients, with Crohn's disease, received 360 mg threetimes daily for one month and then four times daily for asecond month. Crohn's Disease Activity Index (CDAI),CRP, ESR, hematological blood analysis, and kidneyfunction was assessed in all patients at baseline and endof study. In the proctitis group all five patients improvedby 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 sérologie indices of inflammation after twomonths. In the CD group, CDAI scores decreased byan average of 55 points, and CRP and ESR decreasedin four of five patients.'^

Another clinical trial was conducted to assessthe efficacy of curcumin as a maintenance therapy in 82patients with quiescent UC. Subjects were randomizedto receive 1 g curcumin twice daily plus sulfasalazineor mesalamine (n=;43), or placebo plus sulfasalazineor mesalamine (n=39) for six months. Subjects wereassessed at baseline, every two months for six months.

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and again at the end of a six-month follow-up periodvia the Clinical Activity Index (CAI) and EndoscopieIndex (El). Only two of 43 patients (4.7%) receivingcurcumin plus sulfasalazine/mesalamine experienced arelapse during the six-month study, compared to eightof 39 subjects (20.5%) in the placebo plus sulfasalasine/mesalamine group. Subjects in the curcumin groupalso demonstrated significant improvement in CAI(p=:0.038) and El scores (p=0.001), indicating a de-crease in UC-associated morbidity. Interestingly, at theend of the six-month foUow-up period, during whichall patients took only sulfasalazine or mesalamine, eightadditional patients from the curcumin group relapsed(total of 23.3%) compared to six additional patients inthe placebo group (total of 35.9%). The authors con-cluded that curcumin plus standard therapy was moreeffective in maintaining remission than placebo plusstandard UC treatment.''''

PancreatitisClinical research on curcumin's therapeutic

benefit for pancreatitis is limited and has primarily fo-cused on its antioxidant properties. However, researchindicates the inflammatory response plays a criticalrole in development of pancreatitis and subsequent tis-sue damage.-̂ **" For tbis reason, it seems likely an anti-inflammatory agent like curcumin, effective against avariety of inflammatory molecular targets and shown todecrease inflammatory markers in an animal model ofpancreatitis,^"^ might prove to be effective in humans.

One pilot study examined the effect of cur-cumin for tropical pancreatitis in 15 patients. Subjectsreceived 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 erythrocytemalonylaldehyde (MDA; an indicator of lipid peroxida-tion) and glutathione (GSH) were assessed at baselineand after six weeks. In the curcumin group there wasa significant reduction in MDA levels (from 14.80 ±1.19 to 6.02 + 0.95). There was no significant change ineither GSH or pain value scores between the curcu-min and placebo groups. Further research is needed todetermine the role of lipid peroxidation in pain andother symptomology associated with pancreatitis.^^

Renal Grafi RejectionAn RCT investigated the effect of a com-

bination of 480 mg curcumin and 20 mg quercetin(per capsule) on delayed grafi: rejection (DGR) in 43kidney transplant patients. Subjects were randomizedto low-dose (one capsule), high-dose (two capsules), orplacebo (one capsule twice daily) groups for one monthpost-surgery. Of 39 participants who completed thestudy, two of 14 in the control group experienced DGRcompared to zero in either treatment group. Early fijnc-tion (significantly decreased serum creatinine 48 hourspost-transplant) was achieved in 43 percent ot subjectsin the control group, 71 percent of tbose in the low-dose treatment group, and 93 percent in the high-dosegroup. Since the amount of quercetin in the compoundwas minimal, the majority of benefit is thought to bedue to curcumin's anti-inflammatory and antioxidantactivity.^'

Likely mechanisms for improved early func-tion of transplanted kidneys include induction of thehemeoxygenase enzyme, inhibition of NF-tcB and pro-inflammatory cytokines, and scavenging of fi-ee radicalsassociated with tissue damage."

In addition to the research presented here,there are a number of ongoing chnical trials explor-ing the effects of curcumin in various inflammatoryconditions (Table 2).

Cancer Chemoprevention and Treatmentwith Curcumin

The impact of curcumins anti-inflammatoryeffects 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 andpromotion, curcumin modulates transcription factorscontrolling phase I and II detoxification of carcino-gens;"" down-regulates proin flam ma tory cytokines, freeradical-activated transcription factors, and arachidonicacid metabolism via cyclooxygenase and lipoxygenasepathways; and scavenges tree radicals.̂ '̂ ''' In the promo-tion and progression stages of carcinogenesis curcumindecreases frequency and size of tumors and inducesapoptosis via suppression of N F - K B and AP-1 in sev-eral cancer types 2O,Î7

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Table 2* Ongoing Clinical Trialf

Clinic TrialIdentifier

NCT00752154

Na00792818

NCT00793130

NCT00779493

NCT00528151

NCT00595582

Condition

Rheumatoid arthritis

Knee osteoarthritis

Uicerative colitis

Irritable bowelsyndrome

Leber's hereditaryoptical neuropathy

Mild cognitiveimpairment

Exploring Curcumins Benefits in Inflammatory Conditions^**

Trial Site

University of Califomia,Los Angeles

Mahidol University,National ResearchCouncil of Thailand

Tel-Aviv SouraskyMedical Center

Kaiser Permanente

Mahidol University

Louisiana StateUniversity

Intervention

Curcumin, 4-12 g daily

Curcuma longa extracts,Ibuprofen

Coltect-{curcumin1 g daily, green tea,selenium)

Curcumin, 900 mgtwice daily


Curcumin + Bioperine,5.4 g daily

Trial Phase

Pilot Study

Phase III

Unknown

Phase IV

Phase III

Unknown

CompletionDate

September 2009

November 2009

November 2009

November 2009

Unknown

January 2009

Clinical trials published in peer-reviewed lit-erature utilizing curcumin for chemoprevention or as acancer therapy are somewhat limited. A phase I clinicaltrial investigated the use of curcutnin as a chemopreven-tive agent in 25 patients with various types of high-riskor pre-maUgnant lesions. After an initial dose of 500 mgcurcumin daily, the dose was increased to as much as8 g daily for three months. Histological improvementof precancerous lesions was observed in one of fourpatients with cervical intraepithelial neoplasm (signifi-cant decreases in hyperkeratosis, parakeratosis), one ofsix 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/'

Three other clinical trials have investigated theuse of curcumin therapy in patients with establishedcolorectal cancer. Sharma et al conducted two sepa-rate clinical trials exploring curcumins effect on ma-lignancies and tumor marker levels.'"''^ In one trial, 15patients with advanced colorectal cancer were givena low'dose (440-2,200 mg daily) Curcuma extract

(equivalent ro 36-180 mg curcumin) for up to fourmonths. In one patient, measurement of serum tumormarker levels revealed a decrease of carcinoembryonicantigen levels from 310 ± 15 |ig/L to 175 ± 9 p.g/Lafter two months of treatment with 440 mg Curcumaextract. Stable disease via CT scan was observed in fiveof 15 patients — one taking 440 mg extract, one taking880 mg, and one taking 1,760 mg for three months, andin one taking 880 mg and one taking 1,320 mg for four

In the second trial, researchers used a higherpotency curcuminoid preparation, each capsule con-taining 450 mg curcumin, 40 mg demethoxycurcumin,and 10 mg bisdemethoxycurcumin. Fifteen patientswith 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 andvarious points throughout the trial. In six patients giv-en the 3,600-mg dose, mean prostaglandin E^ (PGE,)levels measured after 29 days of treatment decreased by46 percent compared to baseline.'" PGE is an end prod-uct of cyclooxygenase that has been shown to stimulategrowth of human colorectal cancer cells.̂ ^ In addition,

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Table 3. Clinical Trials Investigating the Use of Curcumin in Cancer^

Clinical Trial

Identifier

NCT00365209

NCTOOl18989

NCT00641147

NCT00745134

NCT00486460

NCT00094445

NCTOOl13841

NCT00689195

NCT00475683

Condit ion

Colon cancer prevention

Colon cancer prevention

Familial adenomatouspolyposis

Rectal cancer

Pancreatic cancer

Pancreatic cancer

Multiple myeloma

Osteosarcoma

Oral mucositis - childrenon chemotherapy

Site

Chao Family ComprehensiveCancer Center

University of Pennsylvania

Johns Hopkins University

MD Anderson Cancer Center

Tel-Aviv Sourasky MedicalPontofLei 1 Ici



Tata Memorial Hospital

Hadassah MedicalOrganization

Intervention

Curcumin

Curcuminoidcomplex, 4 g daily


Curcumin, 4 g daiiy,Capecitabine

Gemcitabine,Curcumin, Celebrex(doses unknown)

Curcumin, 8 g daily

Curcumin +Bioperine, 2 gtwice daily

Curcumin andAshwagandha(doses unknown)

Curcumin liquid

extract, 10-30 drops3 times daily

Trial Phase

Phase II

Phase II

Phase II

Phase 11

Phase III

Phase 11

Pilot Study

Phase 1 and II

Phase III

Completion

Date

Unknown

June 2009

March 2013

July 2010

Unknown

December 2009

December 2008

May 2012

December 2009

two patients (one taking 900 mg, the other taking 1,800mg} demonstrated stähle disease (determined via CTscan or MRI) after two months. The patient taking thehigher dose remained stable for four months hut with-drew due to diarrhea thought to be treatment related.'"

Another clinical trial investigated curcumin'seffects in patients with colorectal cancer at doses of450, 1,800, or 3,600 mg daily for seven days." Theaim of this study was to determine if these doses re-sulted in pharmacologically active levels of curcumin incolorectal tissue or had any effect on tissue levels of theoxidative DNA adduct pyrimido(l,2-a)purÍn-10(3H)-one (M|G) (a mutagenic byproduct of lipid peroxida-tion) or COX-2 - markers of DNA damage and in-Bammation. Tlie highest dose (3,600 mg) resulted in asigniftcant decrease in M^G adducts from 4.8 ± 2.9 to2.0 ±1.8 per 107 nucleotides. No curcumin dose had aneffect on tissue levels of COX-2 protein.

In another clinical trial, curcumin stabilizeddisease progression in patients with advanced pan-creatic cancer. Twenty-one patients received 8 g cur-cumin daily until disease progression. Serum cytokinelevels as well as N F - K B and COX-2 levels in peripheralblood mononuclear cells were monitored. One patientachieved disease stabilization for 18 months. Interest-ingly, a second patient experienced significant increasesin serum cytokine levels (4- to 35-foId) accompanied bya brief, but marked tumor regression (73%). Down-reg-ulation of NF-ICB and COX-2 were also observed.*^

Currently there are nine ongoing clinical trialsinvestigating the benefits of curcumin as a therapy forvarious cancers. Of these, three are preventive trials onsubjects with adenomatous polyps at risk for colorectalcancer. The remaining seven trials are investigating theeffects of curcumin (both alone and witb conventional

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medications) in patients with established cancer of vati-ous types. Table 3 lists ongoing clinical trials investigat-ing the anticancer potential of curcumin. It is hoped thecompletion of these trials over the next few years willprovide a better understanding of curcumin's efficacyfor chemoprevention and treatment of active cancer.

Cautionary InformationIn 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 thatin select settings have demonstrated potentially adverseeffects. In vitro, in the presence of copper and cyto-chrome p450 isoenzymes, curcumin induced DNAfragmentation and base damage.^' In a rat model of livercancer curcumin did not prevenr spontaneous hepatictumor formation and in fact, shortened life span from88.7 to 78.1 weeks (p=0.002).^^

There is also some evidence that curcumininhibits 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.̂ ^ Curcumin might also interfere withthe absorption and efficacy of the chemotherapy drugirinotecan, which is used to treat colon cancer.̂ ^

On the other hand, curcumin may enhancethe effects of some chemotherapy drugs. In a mousexenograft model of human breast cancer, curcumin inconjunction 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 studyappeared to be via curcumin's inhibition of NF-KB.'*^

ConclusionCurcumin's diverse array of molecular targets

affords it great potential as a therapeutic agent for avariety 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. The primary obstacleto 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 andbetter absorbed. Results from completed clinical trialsare encouraging and trials currently being conducted forboth inflammatory conditions and cancer should clarifycurcumin's value as a therapeutic agent and confirmsome of the mechanisms responsible for its efficacy.

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anti-inflammatory properties of curcumin, a major ...turmeric (the common name for curcuma longa) i...

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