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Best Practice & Research Clinical Gastroenterology 25 (2011) 519–534

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Best Practice & Research ClinicalGastroenterology

7

Curcumin: The potential for efficacy in gastrointestinaldiseases

Glen R.B. Irving, MB, ChB, BMedSci, MRCS, Clinical Research Fellow *,Ankur Karmokar, MSc, David P. Berry, MB, ChB, MD, FRCS, ConsultantHepatopancreatobiliary Surgeon, Karen Brown, B Pharm, MRPharmS,PhD, Reader, William P. Steward, MB, ChB, PhD, FRCP (Gla, Lon), FRCP(Canada), Head of DepartmentUniversity of Leicester, Department of Cancer Studies, Room 503, Robert Kilpatrick Clinical Sciences Building, Leicester RoyalInfirmary, Leicester LE2 7LX, UK

Keywords:CurcuminPharmacologyColorectal cancerInflammatory bowel diseaseAdenomaPolyps

* Corresponding author. Tel.: þ44 0116 2231852E-mail addresses: [email protected] (G.R.B. Irvin

[email protected] (K. Brown), [email protected] (W.P. Ste

1521-6918/$ – see front matter � 2011 Elsevier Ltdoi:10.1016/j.bpg.2011.09.005

Curcumin is a naturally occurring phytochemical and an extract ofTurmeric. Extensive in vitro and in vivo data have paved the way forcurcumin to become the subject of clinical trials. Curcuminmodulates key signalling pathways important in cellular processes.Numerous mechanisms of action have been elucidated. Thepotential for clinical efficacy is apparent from benign and malig-nant disease models. Curcumin has potent anti-inflammatory andanti-neoplastic properties used alone and in combination withstandard therapies. Early-phase trials have ascertained pharma-cological properties and consistently demonstrate it to be safe andwell tolerated. However, bioavailability is limited and efficaciousdoses have not yet been determined. Evidence of efficacy has beenderived from animal models or small clinical trials. There is onlyfinite data supporting the use of curcumin in phase III trials withspecific diseases (e.g. ulcerative colitis). However, for the vastmajority of conditions additional early-phase studies are requiredto justify larger trials determining efficacy.

� 2011 Elsevier Ltd. All rights reserved.

; fax: þ44 0116 2231855.g), [email protected] (A. Karmokar), [email protected] (D.P. Berry),ward).

d. All rights reserved.

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G.R.B. Irving et al. / Best Practice & Research Clinical Gastroenterology 25 (2011) 519–534520

Introduction

The history of curcumin as a medicinal agent

Turmeric is a rhizomatous plant (Curcuma longa) and a member of the Ginger family consisting ofapproximately 3% curcumin [1]. Asian communities consume w1.5 g turmeric daily per person.Turmeric use in the field of medicine was described in Asia thousands of years ago [2]. Evidencesuggests curcumin has the potential to prevent or treat various pathophysiological processes, includingcardiovascular disease, carcinogenesis, wound healing and inflammation. Asian populations experi-ence approximately half the incidence of inflammatory bowel diseases [3] and an eighth of the inci-dence of bowel cancer than that of Western populations [4] (30.8 vs. 3.9 cases of colorectal cancer per100,000 in the UK and India respectively). Diet is likely to be a major contributory factor.

The physical and molecular properties of curcumin

Curcumin exists as a bright yellow powder that provides the pigmentation to turmeric, and is usedin the dye industry. It carries food additive number E100. The extracted powder will typically containw75% curcumin in addition to derivatives of the parent compound in the form of other curcuminoids;w16% demethoxycurcumin (DMC), w8% bisdemethoxycurcumin (bDMC) and a small amount ofcyclocurcumin [5,6]. BDMC and DMC possess similar molecular and biological properties. It is proposedthat, within natural pathways (Fig.1), bDMC converts to DMCwhich then converts to curcumin [7]. Thepowder is exported for encapsulation and subsequent distributionwithinworld nutraceutical markets.Capsules are readily obtainable as a health food supplement.

Fig. 1. Proposed molecular pathway for the conversion of bDMC to DMC and finally to curcumin and the co-existence of keto andenol isomers of curcumin.

G.R.B. Irving et al. / Best Practice & Research Clinical Gastroenterology 25 (2011) 519–534 521

Curcumin (or diferuloylmethane) is a poly-phenolic molecule existing as a keto-enol tautomer, withthe enol isomer probably the more stable in both solid state and solution (Fig. 1) [8]. The molecule islipophilic consisting of two aromatic rings connected by two unsaturated carbonyl groups andtherefore has poor water solubility. The molecule is stabilised by hydrogen-bonding associated withthe central OH group. This may be one of the important functional sites responsible for the array ofmolecular biological activities [9]. Curcumin is photosensitive and precautions should be taken to avoidexposure and subsequent degradation.

Biochemical properties with clinical application

Much of the interest to medical research lies within the ability of curcumin to counteract thegeneration and subsequent effects of reactive oxygen species and nitrogen free-radicals, typicallymanifesting from damaged cells. Curcuminoids can avidly donate hydrogen ions and undergo nucle-ophilic addition. They possess several moieties with the potential to undergo biochemical modification[9] and impart the important reduction–oxidation, anti-oxidant and proton donating properties thatcan combat cell damage. The mechanisms which enable curcumin to scavenge and trap radicals(highlighted in Fig. 1) are numerous and complex [10]. One of the key attributes of curcuminoids likelyto evoke this benefit is the chain-breaking anti-oxidant activity from hydrogen atoms, most probablydonated from the phenol (OH) groups [11].

Curcumin is unstable under alkaline conditions and degrades in less than 30 min [12]. Under acidicconditions, the rate of decomposition is significantly reduced with less than 20% of total curcumindegraded in 1 h [13]. This may explain why curcumin seems to be stable within the gastrointestinaltract where the pH range is 1–6.

Mechanisms of action against inflammatory and neoplastic conditions

Many pathways are dysregulated in cancer. Curcumin may be able to modulate multiple cellularpathways involved in carcinogenesis and thus behave as a multi-targeted drug. This is of particularinterest in the management of neoplastic conditions. By not relying on a single target pathway, it mayhave activity across a wider population of tumour genotypes. Therapies may be rendered useless if thetargeted pathway is mutated or absent – for example, monoclonal antibodies targeting EGFR incolorectal cancers which have a KRAS mutation. The ability to exploit multiple pathways broadenstherapeutic options and can reduce the development of resistance induced when signalling occursthrough alternative pathways. A significant amount of the anti-carcinogenic mechanistic data isderived from in vitro and in vivo studies of colorectal adenocarcinoma. Curcumin appears to interactwith all of the key pathways associated with the adenoma–adenocarcinoma sequence including APC,TP53, KRAS and c-Myc. There is in vivo evidence that curcumin can prevent disease propagationby modulating cellular mechanisms involved in proliferation, angiogenesis and metastasis [14]. Figs. 2and 3 summarise the anti-inflammatory and anti-carcinogenic actions of curcumin.

Inhibition of pro-inflammatory pathways by curcuminInflammatory pathways are integral to most disease processes. Curcumin can impose desirable

effects upon multiple targets within the inflammatory cascade and its related signalling pathways(Fig. 2).

Curcumin inactivates NF-kB [15] an important transcription factor regulating cellular activity,particularly with respect to stress and injury, and is therefore critical to inflammation and immuneresponse. NF-kB activation appears to be crucial in the relationship between inflammation and thedevelopment of cancer as shown by amousemodel of colitis-induced cancer [16], inwhich the deletionof IkB from epithelial cells resulted in increased apoptosis and a reduction in tumour incidencealthough, in this study, neither inflammation nor tumour size seemed to be affected. In vitro studiesshow the inactivation of NF-kB by curcumin probably occurs by a number of mechanisms including theattenuation of IkB with the inhibition of TNF-dependent IkBa phosphorylation and degradation [17].Curcumin also inhibits IkB kinase, either directly or by inhibition of TNF [17]. Inactivation of NF-kB inturn leads to reduced expression of cyclo-oxygenase-2 (COX-2) and down-regulation of cytokines

Fig. 2. The multi-targeted effects of curcumin on inflammatory mediators.

Fig. 3. The effects of curcumin on the cellular mediators of carcinogenesis.



including tumour necrosis factor (TNF) and interleukins (IL) and a reduction in chemokines. Further-more, NF-kB is fundamental to cell growth, differentiation and proliferation and is a key player incarcinogenesis. An in vivomodel of colon cancer suggests curcumin modulates the NF-kB pathway andreduces metastatic potential [18].

Curcumin significantly reduces COX-2 expression through mechanisms additional to down-regulation of NF-kB. COX-2 expression induced by tissue-plasminogen activators and lipopolysac-charides can be blocked with curcumin [19,20]. It is likely that it directly modulates the metabolismof arachidonic acid, thus augmenting the anti-inflammatory action [21]. Elevated ESR and CRP levelsin patients with active inflammatory diseases are improved by oral curcumin [22–26]. Tumournecrosis factor (TNF-a) and nitric oxide (NO) production is inhibited by curcumin in vivo, conse-quently reducing tissue damage [27]. The promising outcomes from animal models of inflammatorybowel disease (IBD) treated with curcumin have so far been supported by early clinical trial data[26,28–30].

Immuno-modulatory effects of curcuminCurcumin modulates the response and growth of immune cells. Suppression of NK-kB and reduc-

tion of IL-2 inhibits T-lymphocyte proliferation. Paradoxically, curcumin may invoke a stimulatoryresponse at higher concentrations. It appears to increase both T and B-cell proliferation in the mouseintestine following dietary administration [31]. Curcumin also appears to increase production of IgG byT-lymphocytes and induces apoptosis in abnormal B-cells, again not only by inhibiting NF-kB but alsowith down-regulation of Bcl-XL and c-Myc, and over-expression of p53 [32]. Curcumin regulates theactivity of macrophages and natural killer cells [33]. This may be related to down-regulation of NO andthe cytokine response. It enhances the phagocytosis bymacrophages and reduces the ability to producereactive oxygen species [34].

Curcumin can inhibit and arrest the cell cycleThe loss of cell cycle control can lead to the bypassing of DNA-damage checkpoints and replication

of damaged cells with malignant potential. Curcumin promotes inhibition or arrest at all stages of thecell cycle. This is in part due to a curcumin-induced increase in p53 and p21 expression, however,curcumin can also inhibit G1/S mitotic arrest independently from p53 and p21 activity [35]. Curcumin-induced down-regulation of cyclin D [18] prevents cells progressing from the G1 to the S phase, thusfavouring apoptosis. In addition, it blocks the effect of cyclin-dependent kinases (CDK), in particularCDK4 and CDK6, the activation of which are required for cell cycle turnover. This may also be achievedby a curcumin-induced decrease in telomerase activity and by the inhibition of growth factor receptors(GFR). In colorectal cancer cell lines, curcumin causes G2/M arrest [35,36], inhibition of G1/S phase anddelay in mitotic exit [37]. In these cell lines, the IC50 of curcumin is typically 10–15 mmol [38,39] and athigher concentrations growth inhibition can reach 95% [36,39].

Curcumin is pro-apoptoticApoptosis is ultimately achieved either by caspase induction or p53 signalling. Several cell line

models, including colorectal cancer, demonstrate that curcumin promotes apoptosis via both theseroutes. Curcumin inhibits colorectal cancer cell growth by w20% in vitro at concentrations as low as5 mmol [40] and is a potent stimulator of caspase-3-induced apoptosis in hepatic cancer cell lines [41].It also increases the activation of caspase-7 [35,42] and caspase-8 and induces cytochrome-C release[43]. Curcumin increases p53 expression, p53-driven apoptosis and subsequent p21 expression inresponse to DNA damage [37,40]. In cell lines absent in p53, curcumin still enhances apoptosis viaalternative pathways (e.g. death receptor dependent) utilising caspase and NF-kB signalling [15,43].Breast cancer cells treated with curcumin have been observed to undergo apoptosis accompanied byan increase in p53, p53 DNA binding activity and subsequent rise in Bax expression [44]. C-Jun N-terminal kinases (JNK) and MAPK/p38 lie upstream from p53 in the apoptotic pathway. Curcumin mayincrease MAPK/p38 activation thus promoting apoptosis [45] though this has been disputed followingother studies [46]. This may be explained by a dose effect or differences between cancer cell lines.Curcumin also blocks the action or expression of the anti-apoptotic protein Bcl-2 in a number of celllines [47].


Curcumin prevents angiogenesis, proliferation and metastasisCurcumin has direct anti-angiogenic activity in vitro and in vivo [48] by inhibiting growth factors,

growth factor receptors or by modification of inflammatory mediators associated with neo-vascularisation. Curcumin suppresses TNF-induced NF-kB-dependent gene products (COX-2, cyclin-D, c-myc) involved in colorectal cancer cell proliferation [17]. By blocking NF-kB, other importantproteins involved in proliferation, adhesion and metastasis are inhibited, including matrix metallo-proteinase 9 (MMP9), vascular endothelial growth factor (VEGF) and intra-cellular adhesion mole-cule 1 (ICAM-1). Other molecules involved in intra-cellular adhesion are also affected by curcumin viacaspase-3-mediated degradation of b-catenin, E-cadherin and APC (also linked to apoptosis) [35].

By interfering with NF-kB activation curcumin may increase tumour response to some anti-cancerdrugs [49,50] as several chemotherapy agents target or interact with this pathway (e.g. paclitaxel, doxo-rubicin, oxaliplatin). NF-kB over-expression is common in pancreatic cancer and is associated with drug-resistance. Several in vivomodels show curcumin can inhibit angiogenesis and metastatic potential [48].

Stem cell theory and targeted therapyThe Cancer Stem Cell hypothesis states that the ability to initiate carcinogenesis is confined to

a subpopulation of highly tumourigenic cells. This subpopulation of tumour initiating cells (TIC) ischaracterised by stem cell-like phenotypes which include self-renewal and differentiation. The TICpopulation displays a more significant degree of innate or acquired chemo-resistance than is seen innon-TICs. TICs have been implicated in drug-resistance of colon and other cancers [51]. Multiple drug-resistant characteristics of TICs have been suggested to account for breast cancer resistance to cisplatinand paclitaxel in vitro and in vivo [52,53] and to pancreatic cancer resistance to gemcitabine [54]. TICscould provide a target to cancer therapy, resulting in greater efficacy compared to standard treatments.Recent studies have focussed on naturally occurring compounds, which may enhance the treatment ofcancers by targeting TICs.

Curcumin inhibits several important signalling pathways associated with cancer stem cell biology[55] including Notch, hedgehog and Wnt [56,57]. At 5 mM, curcumin decreases the TIC population by50% and inhibits Wnt signalling in primary breast tissues [58]. In vitro experiments suggest that cur-cumin targets Wnt signalling through its inhibitory effects on b-catenin, cyclin D1 and slug in breastcancer cells [59]. Interestingly, curcumin is effective in targeting FOLFOX-surviving HCT-116 or HT-29colon cancer TICs [60]. Further clarification of this effect is required particularly with primary cancercells to elucidate the underlying mechanisms. In vivo models of efficacy must also be established toassess candidate agents for targeting TICs.

Clinical trials

Approximately 40 clinical trials involving curcumin have been published, designed predominantlywith pharmacological and toxicological outcomes. Studies have not been adequately powered to reportclinical efficacy but crucial preliminary data has been obtained justifying further investigations. Thefindings of trials pertinent to gastrointestinal diseases are summarised in Table 1. Curcumin is thesubject of 62 trials that have been registered with http://clinicaltrials.gov/, with an additional 3 trialsregistered with http://controlled-trials.com/ (ISRCTN register). Trials investigating the specificgastrointestinal diseases discussed here are summarised in Table 2.

Pharmacokinetics and metabolism of curcumin

Absorption and systemic bioavailability. Clinical and in vivo studies report a limited systemic bioavail-ability of curcuminoids, with most of an oral dose excreted in faeces [61,62] and intravenous andintraperitoneal doses excreted in bile [63,64]. Curcumin is poorly absorbed but easily detectable in thegastrointestinal tract [62,65,66]. Traces of parent compound have been found in rat liver and kidney[61,64] confirming that uptake does occur in organs distal to the intestine albeit at low concentrations.In humans, plasma levels of curcumin reach a peak (27 nM) around 1–2 h [67] after oral administrationfurther confirming low bioavailability. It may be that exposure to low nanomolar concentrations issufficient, and perhaps only briefly, to exert a therapeutic effect. Despite the low bioavailability

http://clinicaltrials.gov/

http://controlled-trials.com/

Table 1Summary data from 15 selected published clinical trials where curcumin has been administered to patients with gastrointestinaldiseases.

Trial design, study groupand numbers takingcurcumin

Curcumin regimen Pharmacological observations Adverse event data and observationsrelating to efficacy or putativemechanisms of biological effect

Phase I [1]N¼ 15Colorectal cancer

Up to 4g ODcurcuma extractFour months

No curcumin or metabolitesfound in blood or urinebut in faeces.

5/15 radiologically stable diseasewith between two and four monthsof treatment.440 mg caused maximal (59%)Yglutathione S-transferase (GST)activity.


450 mg–3.6 g/dayFour months

Low systemic bioavailability.3.6 g generates detectableparent compound andconjugates in plasmaand urine.

Well tolerated at all dose levels.No dose-limiting toxicity observed.2 gastrointestinal adverse eventsprobably related to curcumin.Diarrhoea grades 1 and 2: 1 patientconsuming 0.45 g curcumin dailyand 1 patient consuming 3.6 gcurcumin daily one month and fourmonths into treatment, respectively.3.6 g inhibits PGE2 in leucocytes.M1G (DNA adduct) and GST notaffected. Recommends 3.6 g daily dose.


450 mg–3.6 g/dayone week

Trace in serum at highest dose.No parent compound in liver.Curcuminoids in liver onlyat 3.6 g. None found in urine.No change in DNA adducts.

[M1G levels post-treatment possiblyattributed to surgery.

Phase IIa [75]N¼ 40Colorectal cancerscreening

2 or 4 g OD30 days

25/41 participants (61%) had grade1 and 2 toxicity, primarilygastrointestinal.No drug discontinuation.2 g/day: 13 grade 1 and 2 toxicity,no grade 3 toxicity.4 g/day: 12 grade 1 and 2 toxicity,1 had grade 3 toxicity (atypical chestpain unrelated to curcumin).Liver function tests not affected.Yaberrant crypt foci number at 4 g,PGE2 concentrations did not changesignificantly.Curcumin did not reduce 5-HETEconcentrations (leukotriene synthesis).

Phase I [92]N¼ 63, with controls

Colorectal cancer

360 mg TDS10–30 days

No toxicities reported.[Weight in patients taking curcumin.[p53, [BAX, YBCl-2.

Phase I*N¼ 26Colorectal cancerand screening

2.35 g ODTwo weeks

Urine and plasma troughsafter 12 h.Mucosal tissue levels0–18 mg/g with higher levelsin the right colon. Persistenttopical presence.

20 events in 9 patients: 3 severeadverse events relating to surgeryunlikely due curcumin.2 withdrawals: One febrile illness andone due to abdominal pains, havinghad previous similar episodes.All other events grade 1 or 2; 5 wereprobably/possibly related tocurcumin. 3 grade 1 diarrhoea,2 nausea, 3 bloating, flatulence anddyspepsia. No effect on biochemistryor haematology profiles.*Unpublished data Irving et al,University of Leicester.

(continued on next page)


Table 1 (continued )

Trial design, study groupand numbers takingcurcumin

Curcumin regimen Pharmacological observations Adverse event data and observationsrelating to efficacy or putativemechanisms of biological effect


450 mg–3.6 g ODOne week

Negligible curcumindistribution outside thegut; 12.5 nmol/g in normalmucosa, 7.7 nmol/g inmalignant tissue.

No toxicities reported.Dose up to 3.6 g safe and issuggested minimum requiredfor efficacy.COX-2 not reduced in CRC tumourand not present in normal tissue.Decreases M1G.

Phase I [26]N¼ 5Crohn’s disease

360 mg QDSTwo months

Well tolerated.No toxicities reported.Reduced symptoms. Reducedinflammatory markers.

Phase II [29]N¼ 43 vs.

control armsUlcerative colitis

1 g BDþmesalazineSix months

Safe medication for maintainingremission in patients withquiescent UC.Improved clinical activity andendoscopic score indexes.

Phase I [85]N¼ 5FAP

480 mg TDSþQuercetin No laboratory adverse events.No appreciable toxicity.Potential to decrease polyp sizeand number.

Phase I [77]N¼ 25Pre-malignancies

0.5–12 g/dayThree months

Not found in urine.Plasma peak 1–2 h.Plasma peaks;4 g curcumin/0.51 mmol,6 g/6.33 mmol,8 g/1.77 mmol.

Tolerated up to 8 g when quantitybecame too bulky. No toxicityup to this dose for three months.No SUSARs reported. Evidenceof histological improvementin 7 patients.

Phase I [25]N¼ 10 vs. placeboTropical pancreatitis

500 mg ODþ 5mgpiperineSix weeks

No change in pain.Yinflammation (ESR)[glutathione synthesis.

Phase II [70]N¼ 25Pancreatic cancer

8 g/dayEight weeks thenuntil progression

Peak plasma curcumin41 ng/ml. Plasma peaks ofcurcumin released fromconjugate forms rangedfrom 0 to 125 ng/ml at 2 h.No cumulative effectnoticed at Four weeks.

Feasibility and tolerabilitydemonstrated. No treatment-relatedtoxic effects.Possible efficacy despite lowbioavailability.


4 g BDþ gemcitabineFour weeks

Feasible combination, Safe,possible efficacy.8 g is a large dose to administer andcan cause abdominal pains. Dosereduction to 4 g favourable.5 patients discontinued 2–14 daysdue to intractable abdominal fullnessor pain, dose of curcumin reducedto 4 g/day due to abdominalcomplaints in 2 other patients.


8 g/dayþ gemcitabine Plasma curcuminmeasuredin 5 patients was29–412 ng/ml.

Grades 3–4 haematological events:neutropaenia (38%). Grades 3–4 non-haematological events: fatigue (10%)drowsiness (n¼ 1), anorexia (n¼ 1),gastrointestinal obstruction (n¼ 1),and oedema (n¼ 1) attributed tochemotherapy or disease progression.4 patients with grade 1 diarrhoea.No withdrawals due to curcumin.Disease stable in 5 patients.


Table 2Details of 18 selected trials currently registered with http://clinicaltrials.gov/ specifically investigating curcumin and gastroin-testinal diseases. Details were obtained from the website on 25/8/2011. Where incomplete within the on-line informationassociated with some studies, the trial phase and dose schedule have been interpreted by the author from details therein.BD¼ twice daily.

ID, design, country Title of study Disease Oral dose Stage of study

NCT01294072 Study Investigating the Ability of PlantExosomes to Deliver Curcumin toNormal and Colon Cancer Tissue

Healthy andcolon cancer

3.6 g/day forone week

RecruitingPhase IUSANCT00973869 Curcumin in Preventing Colorectal Cancer

in Patients Undergoing ColorectalEndoscopy or Colorectal Surgery

Colon cancer 2.35 g/day fortwo weeks

RecruitmentcompletedPhase I

UKNCT01333917 Curcumin Biomarkers Screening colon

cancer4 g/day, 30 days Inviting

Phase IUSANCT00295035 Phase III Trial of Gemcitabine, Curcumin

and Celebrex in Patients With MetastaticColon Cancer

Colon cancer – UnknownPhase IIIIsraelNCT00027495 Curcumin for the Prevention of Colon

CancerColon cancer 2–4 g/day,

30 daysCompleted

Phase IUSA [75]NCT00745134 Curcumin With Pre-operative Capecitabine

and Radiation Therapy Followed bySurgery for Rectal Cancer

Rectal cancer 4 g BD Active, notrecruitingPhase II

USANCT00927485 Use of Curcumin for Treatment of Intestinal

Adenomas in Familial AdenomatousPolyposis (FAP)

FAP 1 g/day, one year RecruitingPhase IIUSANCT00641147 Curcumin for Treatment of Intestinal

Adenomas in Familial AdenomatousPolyposis (FAP)

FAP 1.5 g BD, one year RecruitingPhase IIUSANCT00248053 Use of Curcumin in the Lower

Gastrointestinal Tract in FamilialAdenomatous Polyposis Patients

FAP Terminatedearly, efficacywith quercetin

Phase IIUSA [85]NCT00118989 Curcumin for the Chemoprevention

of Colorectal CancerAdenoma 4 g/day, four

monthsOn-going, notrecruitingPhase II

USANCT00889161 Curcumin in paediatric inflammatory

bowel disease (IBD)IBD Up to 2 g BD

nine weeksCompleted

Phase IUSANCT01320436 CurcuminþAminosalicylic Acid (5ASA)

vs. 5ASA Alone in the Treatment ofMild to Moderate Ulcerative Colitis

IBD 2.5 g BD RecruitingPhase IIIsraelNCT00793130 The Efficacy and Tolerability of Coltect

as Add-on in Patients With ActiveUlcerative Colitis

IBD 1 g BD, twomonths

UnknownPhase I/IIIsraelNCT00486460 Phase III Trial of Gemcitabine, Curcumin

and Celebrex in Patients With Advanceor Inoperable Pancreatic Cancer

Pancreaticcancer

– UnknownPhase IIIIsraelNCT00094445 Trial of Curcumin in Advanced

Pancreatic CancerPancreaticcancer

8 g/day, eightweeks

On-going,not recruitingPhase II

USANCT00192842 Gemcitabine With Curcumin for

Pancreatic CancerPancreaticCancer

4 g BD CompletedPhase IIIsrael [79]NCT00779493 Curcumin (Turmeric) in the Treatment of

Irritable Bowel Syndrome: ARandomised-Controlled Trial (CuTIBS)

IBS 1.8 g RecruitingPhase IVUSANCT01167673 The Effect of Coltect (Selenium, Curcumin

and Green Tea) on Irritable BowelSyndrome

IBS 500 mg/day RecruitingPhase IIIsrael


http://clinicaltrials.gov/


reported from animal and human studies, early evidence of both local and systemic efficacy is apparentfrom the reduced tumour burden that has been observed in mouse models of familial adenomatouspolyposis (FAP) [68,69] and colorectal liver metastases [18] and some efficacy is suggested froma clinical trial of curcumin in patients with pancreatic cancer [70]. Hence, in the face of very low levelsof detectable curcumin at the target site, biological activity may occur.

Curcumin concentrations within the gastrointestinal tract and entero-hepatic circulation. Administrationof a high dose (1.2 g/kg) of curcumin to rats resulted in colonic mucosal levels of 1.8 mmol/g [66] thougha dose of this magnitude is not practical for humans. Oral curcumin has been successfully given ata dose of 3.6 g daily to patients undergoing operations for colorectal cancer [65,71] withmucosal levelsreaching w10 nmol/g [65]. The mean concentrations of curcumin in normal and malignant colorectaltissue of patients who had ingested this dose were 12.7 and 7.7 nmol/g tissue, respectively. Detectablelevels still persist topically on the mucosa several days after ingestion. This could be important becauseany therapeutic advantages conferred to mucosa are probably brought about by both topical andsystemic activity. The activity of topical curcumin has been explored [72] and is the subject of clinicaltrials.

Approximately a third of faecal curcumin is excreted without being systemically metabolised[61,63,66,73]. Curcumin is reduced and conjugated within the gastrointestinal tract and liver, resultingin very low amounts of the parent compound detected in the hepatic system [74]. Curcumin metab-olites have been found in intestinal tissue taken from very small endoscopic biopsy samples frompatients receiving 2 or 4 g daily [75].

Curcumin has been detected in portal venous blood of both rats and humans at very lowconcentrations soon after oral loading [64,71], further confirming poor absorption across the gut. Ata curcumin dose of 3.6 g daily, metabolites have been detected at nanomolar concentrations in thehuman liver [64] although at this dose no parent compound was demonstrated in the bile or liver[71]. Parenteral dosing in mice leads to 50% of the curcumin being excreted in bile. Furthermorecurcumin undergoes metabolic transformation during absorption across the intestine, followingwhich it may enter the entero-hepatic circulation [76]. Therefore, curcumin metabolites and toa lesser extent curcumin are excreted in bile. The presence of parent compound and metabolites inthe liver, biliary and portal systems means that it has potential to reach organs distant from thebowel. It is still unknown how much curcumin would be necessary to exert a pharmacologicaleffect.

Detection of systemic curcumin. Curcumin detection in plasma is variable due to poor bioavailability anda short plasma half-life. Initial studies using murine models consistently report low serum concen-trations with the majority of the compounds being undetectable after 1 h following enteric (up to 2 g/kg) and parenteric (up to 40 mg/kg) administration [63,67]. These data are mirrored by clinical trialswhere up to 12 g per day of oral curcumin has been given to patients and peak plasma levels occur 1–2 h following loading with trough levels at approximately 12 h [77]. Only trace levels of curcumin arefound in serum following oral doses less than 2 g per day. Following 4 g and 8 g of daily curcumin,serum levels of 0.51 mmol and 1.77 mmol have been reported [77] and similar values are achieved with3.6 g per day [65].

Urinary excretion of curcumin. Curcumin is poorly excreted in urine [62,66]. Murine models reportnegligible amounts are found in the urine even following intravenous doses of 1 g/kg [62,64]. Inhumans receiving oral curcumin for four months, at doses greater than 3.6 g daily it becomes possibleto detect curcuminoids in urine [73]. Human renal excretion remains poor even with increasing doses[71]. It is unlikely that curcumin metabolism either effects or is affected by renal function. Adverseevents due to curcumin relating to renal function have not been reported in any trial and there is someevidence that curcumin may even improve function in renal disease [78].

ToxicityToxicity or changes in body weight have not been seen in pre-clinical studies of long-term curcumin

use [49,63]. Little demonstrable toxicity is observed at in vivo doses of up to 5 g/kg [62]. No significant


toxicities have been reported from almost 40 clinical trials involving over 800 participants. The adverseevent data from studies involving gastrointestinal are included in Table 1.

Patients have tolerated up to 8 g oral curcumin daily for three months [77] and escalation beyondthis, although safely achievable, was limited by the volume of capsules necessary to deliver the dose.Side-effects are dose-related and typically gastrointestinal in origin, including loose stools, bloating,reflux and discomfort. Dose reduction usually leads to improvement. Trials consistently report cur-cumin has no effect on biochemical and haematological parameters during administration. There havebeen anecdotal reports of transient rises in liver enzymes although causality is unclear.

Dosing for pharmacological effectThe relative instability, rapid metabolism and short plasma half-life present difficulties when

establishing an appropriate dose for pharmacological effect. Determining a dose that is both toleratedand efficacious is challenging.

Several trials have used oral regimens of approximately 4 g daily curcumin however in vivo reportsimply a daily dose of 1.6 g in humans may be enough to exert a biological effect in the lumen, achievinga colonic mucosal concentration of 0.1 mmol/g [69]. Pre-clinical data is difficult to extrapolate intoa human dosing regimen. Other clinical studies have required 8 g orally [77] to achieve serum levelssuggested by in vivo studies to be necessary for efficacy. However, an increase in dosemay not equate toa proportional increase in systemic absorption [61]. Detection of curcuminoids in hepatic tissue hasbeen demonstrated in small amounts following 3.6 g per day for one week although not with lowerdoses [71]. Trace levels are detected in human serum at doses of 2 g. Based on that which is necessaryto furnish detectable levels of curcumin in serum, portal blood or hepatic tissue, it is possible thata dose in the region of 2–4 g is theminimum required to have pharmacological effect in organs distal tothe gut [71]. Patient-reported outcomes suggest doses much in excess of this may lead to reducedcompliance. In our experience, larger capsule size and number may reduce compliance, particularly inelderly populations. Compliance is excellent at doses in the region of 2–4 g per day [65,71,73] (andIrving et al unpublished data).

Importantly, adverse events may also increase beyond 4 g per day [77,79] although tolerance to 8 gfor three months [77], 4 g for four months [71,73,80] and 5 g for five months [81] has been demon-strated. Ingestion of curcumin in one single daily dose would achieve the highest possible peak plasmalevels but were a topical effect found to be of greatest benefit against luminal disease, then doses maybe equally effective if taken in a divided or less than daily regimen.

The potential for efficacyCurcumin has been shown to modulate pathways involved in gallstone formation, hepatitis and

pancreatitis, however, at present it is in the areas of luminal bowel disease and cancer where researchis most advanced.

Pre-malignant bowel conditions and inflammatory bowel disease. Curcumin inhibits cellular processesresponsible for Barrett’s metaplasia differentiating to oesophageal adenocarcinoma in vitro [82],mainly through NF-kB. Patients with pre-malignant conditions, including gastric metaplasia receivedup to 8 g daily oral curcumin for three months [77], following which histological improvement wasobserved in a third of cases, however 2 patients developed malignancy.

Animal models and early-phase trials with familial adenomatous polyposis (FAP) show greatpromise for curcumin as a chemopreventive agent [68,83,84] particularly in at-risk groups of patients(e.g. Apc mutants). In an Apc (min/þ) mouse model of FAP, curcumin reduced polyp formation [68]. Inhumans, it reduces polyp number and size when used alone and in combinationwith quercetin [85]. Inthis study of 5 patients awaiting colectomy for FAP, following wsix months treatment with curcumintaken in combination with another chemopreventive agent, quercetin, polyps were significantly(p< 0.05) reduced in number (60%) and size (51%). Larger studies are therefore required to furtherinvestigate these early reports of efficacy.

More recently, 39 patients undergoing colonoscopy for the screening of bowel neoplasia havesuccessfully consumed either 2 or 4 g of oral curcumin daily for one month [75]. The low plasmacurcuminoid concentrations were in keeping with previous reports confirming poor bioavailability,


however, rectal mucosal levels persisted to a mean of 8.2 mg/g of tissue. There was a significantreduction (40%) in aberrant crypt foci found in mucosal biopsies of patients taking 4 g per day thusproviding evidence of biological effect. In this study, curcumin did not seem to affect levels ofprostaglandin E2 (PGE2), which has also been a finding from a chemoprevention trial investigatingcelecoxib and FAP [86] where polyp regression was observed. If efficacious, curcumin could conferan advantage over non-steroidal anti-inflammatory drugs, such as aspirin and celecoxib, in thechemopreventive setting because of the reduced risk of gastrointestinal bleeding, nephro-toxicityor cardiac events. Trials investigating the role of curcumin in polyp prevention are under way(Table 2).

Animal models of colitis show a reduction in pro-inflammatory biomarkers, modulation ofinflammatory cells and inhibition of neoplastic change [30,87–89]. Curcumin is potentially safemedication for maintaining remission in patients with quiescent ulcerative colitis. Two early-phasetrials [26,29] have shown it to be well tolerated by patients with colitis and can lead to reducedsymptoms and inflammatory markers (Table 1).

Colorectal cancer. Copious in vitro and pre-clinical data support the use of curcumin in trials involvingthe spectrum of bowel neoplasia. Colon cancer is a common cancer in the UK, where surveillance andscreening are becoming well established. Much of the clinical data relating to curcumin has beenaccrued from this patient population but there have been no trials reporting efficacy.

Pre-clinical data suggests that curcumin enhances activity when used in combinationwith standardchemotherapy agents against cancer cells that would otherwise be chemo-resistant [40,90]. Itaugments the efficacy of oxaliplatin against chemo-resistant xenograft tumours [90]. This is importantbecause half of all colorectal cancers possess innate chemo-resistance, and all cancers inevitablyacquire resistance. A safe compound with the ability to improve the efficacy of chemotherapy isattractive. Curcumin in combinationwith chemotherapymay overcome or postpone chemo-resistance,or permit a dose reduction without loss of efficacy and even ameliorate dose-related side-effects.Evidence suggests curcumin could be of benefit to cancer patients due to additional non-cytotoxicactions. It attenuates pain in a mouse model of neuropathy [91] and appears to promote weight gainin humans receiving chemotherapy [92]. Trials using combination regimens have been conducted withpancreatic and breast cancers, but the addition of curcumin to colon cancer chemotherapy is at presentconfined to anecdote [81].

Pancreatic cancer. Curcumin has been administered alone [70] and in combination with gemcitabine[79,93] to patients with advanced pancreatic cancer. These studies have demonstrated long-termtolerance of curcumin by patients with advanced malignancy whilst they receive potentially toxicchemotherapy.

Unanswered questions: clinical targets, clinical efficacy

Currently, there are insufficient data to optimally design large phase III curcumin trials of efficacyinvolving gastrointestinal disease. Pharmacological and toxicity data have been established to a largeextent. It seems unlikely that curcuminwill be used as monotherapy to treat the established disease. Ifcurcumin is to have applications as a medicinal product, currently it appears to be of greatest benefit asa co-therapeutic agent. In the context of UK clinical trials with gastrointestinal cancer, curcumin islikely to be of optimal use in combinationwith existing chemotherapy regimens. Additional safety datais necessary when assessing curcumin as part of multi-drug regimens, which may only be achievedwith supporting in vivo data and accepted dose-escalation trial methods.

Improving efficacy by improving bioavailabilityCurcumin bioavailability can be increased in vivo ten-fold with the use of nanoparticles [94].

Alternative methods of delivery such as formulation on phospholipid complexes or liposome encap-sulation [95] could also assist in delivering efficacious tissue concentrations. In humans, the addition ofPiperine, an extract of pepper and an inhibitor of glucuronidation, may increase bioavailability 20-fold[67], whilst curcumin-phosphatidylcholine phytosome complexes (e.g. Meriva�) have even greater


bioavailability [96]. Structural analogues have also been developed with potentially improvedbioavailability while potentially maintaining the active moiety. At present the use of these products isconfined to pre-clinical and early clinical trials.

Conflict of interests

None.

Practice points

� Curcumin modulates pathways critical to inflammation and carcinogenesis.� Curcumin may have efficacy against a wide range of conditions in particular colorectalneoplasia.

� Pharmacodynamic, pharmacokinetic and safety profiles are well established supportingtolerance to doses up to 8 g daily although beyond this compliance and adverse events maybe affected.

� Doses required for efficacy are not yet established.� Bioavailability is poor and should be taken into account when planning sample scheduleswithin clinical trial protocols

Research agenda

� Novel pre-clinical models are being designed to ascertain the best strategies for medicinal usesuch as combination therapies, tumour initiating cells and drug-resistance.

� Additional pre-clinical and clinical data are required to determine likely efficacious doses andclinical endpoints prior to embarking on larger phase II/III trials.

� Potential for efficacy and options for dose reduction may be improved by a range of formu-lation techniques and modes of delivery with enhanced bioavailability

Acknowledgements

Mr Glen Irving is funded by the Royal of College Surgeons, England/Newman Research Fellowshipsupported by the Rosetrees trust.

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