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

Contents lists available at SciVerse ScienceDirect

Best Practice & Research Clinical

Gastroenterology

Curcumin: The potential for efficacy in gastrointestinal

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

Keywords:
Curcumin is a naturally occurring phytochemical and an extract of
Curcumin Turmeric. Extensive in vitro and in vivo data have paved the way for
Pharmacology curcumin to become the subject of clinical trials. Curcumin
Colorectal cancer modulates key signalling pathways important in cellular processes.
Inflammatory bowel disease Numerous mechanisms of action have been elucidated. The
Adenoma potential for clinical efficacy is apparent from benign and malig-
Polyps nant disease models. Curcumin has potent anti-inflammatory and
anti-neoplastic properties used alone and in combination with
standard therapies. Early-phase trials have ascertained pharma-
cological properties and consistently demonstrate it to be safe and
well tolerated. However, bioavailability is limited and efficacious
doses have not yet been determined. Evidence of efficacy has been
derived from animal models or small clinical trials. There is only
finite data supporting the use of curcumin in phase III trials with
specific diseases (e.g. ulcerative colitis). However, for the vast
majority of conditions additional early-phase studies are required
to justify larger trials determining efficacy.
Ó 2011 Elsevier Ltd. All rights reserved.

* Corresponding author. Tel.: þ44 0116 2231852; fax: þ44 0116 2231855.
E-mail addresses: grbi1@le.ac.uk (G.R.B. Irving), ak241@le.ac.uk (A. Karmokar), david.berry@wales.nhs.uk (D.P. Berry),
kb20@le.ac.uk (K. Brown), wps1@le.ac.uk (W.P. Steward).

1521-6918/$ – see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bpg.2011.09.005
520 G.R.B. Irving et al. / Best Practice & Research Clinical Gastroenterology 25 (2011) 519–534

Introduction

The history of curcumin as a medicinal agent

Turmeric is a rhizomatous plant (Curcuma longa) and a member of the Ginger family consisting of
approximately 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]. Evidence
suggests curcumin has the potential to prevent or treat various pathophysiological processes, including
cardiovascular 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 per
100,000 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 used
in the dye industry. It carries food additive number E100. The extracted powder will typically contain
w75% 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 of
cyclocurcumin [5,6]. BDMC and DMC possess similar molecular and biological properties. It is proposed
that, within natural pathways (Fig. 1), bDMC converts to DMC which then converts to curcumin [7]. The
powder is exported for encapsulation and subsequent distribution within world 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 and
enol 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, with

the enol isomer probably the more stable in both solid state and solution (Fig. 1) [8]. The molecule is
lipophilic consisting of two aromatic rings connected by two unsaturated carbonyl groups and
therefore has poor water solubility. The molecule is stabilised by hydrogen-bonding associated with
the central OH group. This may be one of the important functional sites responsible for the array of
molecular biological activities [9]. Curcumin is photosensitive and precautions should be taken to avoid
exposure and subsequent degradation.

Biochemical properties with clinical application

Much of the interest to medical research lies within the ability of curcumin to counteract the
generation and subsequent effects of reactive oxygen species and nitrogen free-radicals, typically
manifesting 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 that
can 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 likely
to evoke this benefit is the chain-breaking anti-oxidant activity from hydrogen atoms, most probably
donated from the phenol (OH) groups [11].
Curcumin is unstable under alkaline conditions and degrades in less than 30 min [12]. Under acidic
conditions, the rate of decomposition is significantly reduced with less than 20% of total curcumin
degraded in 1 h [13]. This may explain why curcumin seems to be stable within the gastrointestinal
tract 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 cellular
pathways involved in carcinogenesis and thus behave as a multi-targeted drug. This is of particular
interest in the management of neoplastic conditions. By not relying on a single target pathway, it may
have activity across a wider population of tumour genotypes. Therapies may be rendered useless if the
targeted pathway is mutated or absent – for example, monoclonal antibodies targeting EGFR in
colorectal cancers which have a KRAS mutation. The ability to exploit multiple pathways broadens
therapeutic options and can reduce the development of resistance induced when signalling occurs
through alternative pathways. A significant amount of the anti-carcinogenic mechanistic data is
derived from in vitro and in vivo studies of colorectal adenocarcinoma. Curcumin appears to interact
with 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 propagation
by modulating cellular mechanisms involved in proliferation, angiogenesis and metastasis [14]. Figs. 2
and 3 summarise the anti-inflammatory and anti-carcinogenic actions of curcumin.

Inhibition of pro-inflammatory pathways by curcumin

Inflammatory 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 immune
response. NF-kB activation appears to be crucial in the relationship between inflammation and the
development of cancer as shown by a mouse model of colitis-induced cancer [16], in which the deletion
of IkB from epithelial cells resulted in increased apoptosis and a reduction in tumour incidence
although, in this study, neither inflammation nor tumour size seemed to be affected. In vitro studies
show the inactivation of NF-kB by curcumin probably occurs by a number of mechanisms including the
attenuation 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 in
turn leads to reduced expression of cyclo-oxygenase-2 (COX-2) and down-regulation of cytokines
522 G.R.B. Irving et al. / Best Practice & Research Clinical Gastroenterology 25 (2011) 519–534

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

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

 G.R.B. Irving et al. / Best Practice & Research Clinical Gastroenterology 25 (2011) 519–534 523

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 in
carcinogenesis. An in vivo model of colon cancer suggests curcumin modulates the NF-kB pathway and
reduces 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 metabolism
of arachidonic acid, thus augmenting the anti-inflammatory action [21]. Elevated ESR and CRP levels
in patients with active inflammatory diseases are improved by oral curcumin [22–26]. Tumour
necrosis 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 inflammatory
bowel disease (IBD) treated with curcumin have so far been supported by early clinical trial data
[26,28–30].

Immuno-modulatory effects of curcumin

Curcumin 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 stimulatory
response at higher concentrations. It appears to increase both T and B-cell proliferation in the mouse
intestine following dietary administration [31]. Curcumin also appears to increase production of IgG by
T-lymphocytes and induces apoptosis in abnormal B-cells, again not only by inhibiting NF-kB but also
with down-regulation of Bcl-XL and c-Myc, and over-expression of p53 [32]. Curcumin regulates the
activity of macrophages and natural killer cells [33]. This may be related to down-regulation of NO and
the cytokine response. It enhances the phagocytosis by macrophages and reduces the ability to produce
reactive oxygen species [34].

Curcumin can inhibit and arrest the cell cycle

The 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 the
cell 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, thus
favouring apoptosis. In addition, it blocks the effect of cyclin-dependent kinases (CDK), in particular
CDK4 and CDK6, the activation of which are required for cell cycle turnover. This may also be achieved
by 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 and
delay in mitotic exit [37]. In these cell lines, the IC50 of curcumin is typically 10–15 mmol [38,39] and at
higher concentrations growth inhibition can reach 95% [36,39].

Curcumin is pro-apoptotic
Apoptosis is ultimately achieved either by caspase induction or p53 signalling. Several cell line
models, including colorectal cancer, demonstrate that curcumin promotes apoptosis via both these
routes. Curcumin inhibits colorectal cancer cell growth by w20% in vitro at concentrations as low as
5 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 in
response to DNA damage [37,40]. In cell lines absent in p53, curcumin still enhances apoptosis via
alternative 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 by
an 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 may
increase MAPK/p38 activation thus promoting apoptosis [45] though this has been disputed following
other 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 cell
lines [47].
524 G.R.B. Irving et al. / Best Practice & Research Clinical Gastroenterology 25 (2011) 519–534

Curcumin prevents angiogenesis, proliferation and metastasis

Curcumin 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 important
proteins 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 via
caspase-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-cancer
drugs [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 vivo models show curcumin can inhibit angiogenesis and metastatic potential [48].

Stem cell theory and targeted therapy

The 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) is
characterised by stem cell-like phenotypes which include self-renewal and differentiation. The TIC
population displays a more significant degree of innate or acquired chemo-resistance than is seen in
non-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 cisplatin
and paclitaxel in vitro and in vivo [52,53] and to pancreatic cancer resistance to gemcitabine [54]. TICs
could 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 of
cancers 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 by
50% 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 breast
cancer cells [59]. Interestingly, curcumin is effective in targeting FOLFOX-surviving HCT-116 or HT-29
colon cancer TICs [60]. Further clarification of this effect is required particularly with primary cancer
cells to elucidate the underlying mechanisms. In vivo models of efficacy must also be established to
assess candidate agents for targeting TICs.

Clinical trials

Approximately 40 clinical trials involving curcumin have been published, designed predominantly
with pharmacological and toxicological outcomes. Studies have not been adequately powered to report
clinical efficacy but crucial preliminary data has been obtained justifying further investigations. The
findings of trials pertinent to gastrointestinal diseases are summarised in Table 1. Curcumin is the
subject of 62 trials that have been registered with http://clinicaltrials.gov/, with an additional 3 trials
registered with http://controlled-trials.com/ (ISRCTN register). Trials investigating the specific
gastrointestinal 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 and
intraperitoneal doses excreted in bile [63,64]. Curcumin is poorly absorbed but easily detectable in the
gastrointestinal 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 administration
further confirming low bioavailability. It may be that exposure to low nanomolar concentrations is
sufficient, and perhaps only briefly, to exert a therapeutic effect. Despite the low bioavailability
 G.R.B. Irving et al. / Best Practice & Research Clinical Gastroenterology 25 (2011) 519–534 525

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

Trial design, study group Curcumin regimen Pharmacological observations Adverse event data and observations
and numbers taking relating to efficacy or putative
curcumin mechanisms of biological effect
Phase I [1] Up to 4g OD No curcumin or metabolites 5/15 radiologically stable disease
N ¼ 15 curcuma extract found in blood or urine with between two and four months
Colorectal cancer Four months but in faeces. of treatment.
440 mg caused maximal (59%)
Yglutathione S-transferase (GST)
activity.

Phase I [73] 450 mg–3.6 g/day Low systemic bioavailability. Well tolerated at all dose levels.
N ¼ 15 Four months 3.6 g generates detectable No dose-limiting toxicity observed.
Colorectal cancer parent compound and 2 gastrointestinal adverse events
conjugates in plasma probably related to curcumin.
and urine. Diarrhoea grades 1 and 2: 1 patient
consuming 0.45 g curcumin daily
and 1 patient consuming 3.6 g
curcumin daily one month and four
months into treatment, respectively.
3.6 g inhibits PGE2 in leucocytes.
M1G (DNA adduct) and GST not
affected. Recommends 3.6 g daily dose.

Phase I [71] 450 mg–3.6 g/day Trace in serum at highest dose. [M1G levels post-treatment possibly
N ¼ 12 one week No parent compound in liver. attributed to surgery.
Colorectal cancer Curcuminoids in liver only
at 3.6 g. None found in urine.
No change in DNA adducts.

Phase IIa [75] 2 or 4 g OD 25/41 participants (61%) had grade

N ¼ 40 30 days 1 and 2 toxicity, primarily
Colorectal cancer gastrointestinal.
screening 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 chest
pain unrelated to curcumin).
Liver function tests not affected.
Yaberrant crypt foci number at 4 g,
PGE2 concentrations did not change
significantly.
Curcumin did not reduce 5-HETE
concentrations (leukotriene synthesis).

Phase I [92] 360 mg TDS No toxicities reported.

N ¼ 63, with controls 10–30 days [Weight in patients taking curcumin.
Colorectal cancer [p53, [BAX, YBCl-2.
Phase I* 2.35 g OD Urine and plasma troughs 20 events in 9 patients: 3 severe
N ¼ 26 Two weeks after 12 h. adverse events relating to surgery
Colorectal cancer Mucosal tissue levels unlikely due curcumin.
and screening 0–18 mg/g with higher levels 2 withdrawals: One febrile illness and
in the right colon. Persistent one due to abdominal pains, having
topical presence. had previous similar episodes.
All other events grade 1 or 2; 5 were
probably/possibly related to
curcumin. 3 grade 1 diarrhoea,
2 nausea, 3 bloating, flatulence and
dyspepsia. No effect on biochemistry
or haematology profiles.
*Unpublished data Irving et al,
University of Leicester.
(continued on next page)
526 G.R.B. Irving et al. / Best Practice & Research Clinical Gastroenterology 25 (2011) 519–534

Table 1 (continued )

Trial design, study group Curcumin regimen Pharmacological observations Adverse event data and observations
and numbers taking relating to efficacy or putative
curcumin mechanisms of biological effect
Phase I [65] 450 mg–3.6 g OD Negligible curcumin No toxicities reported.
N ¼ 12 One week distribution outside the Dose up to 3.6 g safe and is
Colorectal cancer gut; 12.5 nmol/g in normal suggested minimum required
mucosa, 7.7 nmol/g in for efficacy.
malignant tissue. COX-2 not reduced in CRC tumour
and not present in normal tissue.
Decreases M1G.

Phase I [26] 360 mg QDS Well tolerated.

N¼5 Two months No toxicities reported.
Crohn’s disease Reduced symptoms. Reduced
inflammatory markers.

Phase II [29] 1 g BD þ mesalazine Safe medication for maintaining

N ¼ 43 vs. Six months remission in patients with
control arms quiescent UC.
Ulcerative colitis Improved clinical activity and
endoscopic score indexes.

Phase I [85] 480 mg TDS þ Quercetin No laboratory adverse events.

N¼5 No appreciable toxicity.
FAP Potential to decrease polyp size
and number.

Phase I [77] 0.5–12 g/day Not found in urine. Tolerated up to 8 g when quantity
N ¼ 25 Three months Plasma peak 1–2 h. became too bulky. No toxicity
Pre-malignancies Plasma peaks; up to this dose for three months.
4 g curcumin/0.51 mmol, No SUSARs reported. Evidence
6 g/6.33 mmol, of histological improvement
8 g/1.77 mmol. in 7 patients.

Phase I [25] 500 mg OD þ 5mg No change in pain.

N ¼ 10 vs. placebo piperine Yinflammation (ESR)
Tropical pancreatitis Six weeks [glutathione synthesis.

Phase II [70] 8 g/day Peak plasma curcumin Feasibility and tolerability

N ¼ 25 Eight weeks then 41 ng/ml. Plasma peaks of
Pancreatic cancer until progression curcumin released from
conjugate forms ranged
from 0 to 125 ng/ml at 2 h.
No cumulative effect
noticed at Four weeks.
demonstrated. No treatment-related
toxic effects.
Possible efficacy despite low
bioavailability.

Phase II [79] 4 g BD þ gemcitabine Feasible combination, Safe,

N ¼ 17 Four weeks possible efficacy.
Pancreatic cancer 8 g is a large dose to administer and
can cause abdominal pains. Dose
reduction to 4 g favourable.
5 patients discontinued 2–14 days
due to intractable abdominal fullness
or pain, dose of curcumin reduced
to 4 g/day due to abdominal
complaints in 2 other patients.

Phase II [93] 8 g/day þ gemcitabine Plasma curcumin Grades 3–4 haematological events:
N ¼ 21 measured neutropaenia (38%). Grades 3–4 non-
Pancreatic cancer in 5 patients was haematological events: fatigue (10%)
29–412 ng/ml. drowsiness (n ¼ 1), anorexia (n ¼ 1),
gastrointestinal obstruction (n ¼ 1),
and oedema (n ¼ 1) attributed to
chemotherapy or disease progression.
4 patients with grade 1 diarrhoea.
No withdrawals due to curcumin.
Disease stable in 5 patients.
 G.R.B. Irving et al. / Best Practice & Research Clinical Gastroenterology 25 (2011) 519–534 527

Table 2
Details 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 information
associated with some studies, the trial phase and dose schedule have been interpreted by the author from details therein.
BD ¼ twice daily.

ID, design, country Title of study Disease Oral dose Stage of study
NCT01294072 Study Investigating the Ability of Plant Healthy and 3.6 g/day for Recruiting
Phase I Exosomes to Deliver Curcumin to colon cancer one week
USA Normal and Colon Cancer Tissue
NCT00973869 Curcumin in Preventing Colorectal Cancer Colon cancer 2.35 g/day for Recruitment
Phase I in Patients Undergoing Colorectal two weeks completed
UK Endoscopy or Colorectal Surgery
NCT01333917 Curcumin Biomarkers Screening colon 4 g/day, 30 days Inviting
Phase I cancer
USA
NCT00295035 Phase III Trial of Gemcitabine, Curcumin Colon cancer – Unknown
Phase III and Celebrex in Patients With Metastatic
Israel Colon Cancer
NCT00027495 Curcumin for the Prevention of Colon Colon cancer 2–4 g/day, Completed
Phase I Cancer 30 days
USA [75]
NCT00745134 Curcumin With Pre-operative Capecitabine Rectal cancer 4 g BD Active, not
Phase II and Radiation Therapy Followed by recruiting
USA Surgery for Rectal Cancer
NCT00927485 Use of Curcumin for Treatment of Intestinal FAP 1 g/day, one year Recruiting
Phase II Adenomas in Familial Adenomatous
USA Polyposis (FAP)
NCT00641147 Curcumin for Treatment of Intestinal FAP 1.5 g BD, one year Recruiting
Phase II Adenomas in Familial Adenomatous
USA Polyposis (FAP)
NCT00248053 Use of Curcumin in the Lower FAP Terminated
Phase II Gastrointestinal Tract in Familial early, efficacy
USA [85] Adenomatous Polyposis Patients with quercetin
NCT00118989 Curcumin for the Chemoprevention Adenoma 4 g/day, four On-going, not
Phase II of Colorectal Cancer months recruiting
USA
NCT00889161 Curcumin in paediatric inflammatory IBD Up to 2 g BD Completed
Phase I bowel disease (IBD) nine weeks
USA
NCT01320436 Curcumin þ Aminosalicylic Acid (5ASA) IBD 2.5 g BD Recruiting
Phase II vs. 5ASA Alone in the Treatment of
Israel Mild to Moderate Ulcerative Colitis
NCT00793130 The Efficacy and Tolerability of Coltect IBD 1 g BD, two Unknown
Phase I/II as Add-on in Patients With Active months
Israel Ulcerative Colitis
NCT00486460 Phase III Trial of Gemcitabine, Curcumin Pancreatic – Unknown
Phase III and Celebrex in Patients With Advance cancer
Israel or Inoperable Pancreatic Cancer
NCT00094445 Trial of Curcumin in Advanced Pancreatic 8 g/day, eight On-going,
Phase II Pancreatic Cancer cancer weeks not recruiting
USA
NCT00192842 Gemcitabine With Curcumin for Pancreatic 4 g BD Completed
Phase II Pancreatic Cancer Cancer
Israel [79]
NCT00779493 Curcumin (Turmeric) in the Treatment of IBS 1.8 g Recruiting
Phase IV Irritable Bowel Syndrome: A
USA Randomised-Controlled Trial (CuTIBS)
NCT01167673 The Effect of Coltect (Selenium, Curcumin IBS 500 mg/day Recruiting
Phase II and Green Tea) on Irritable Bowel
Israel Syndrome
528 G.R.B. Irving et al. / Best Practice & Research Clinical Gastroenterology 25 (2011) 519–534

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

Curcumin concentrations within the gastrointestinal tract and entero-hepatic circulation. Administration
of a high dose (1.2 g/kg) of curcumin to rats resulted in colonic mucosal levels of 1.8 mmol/g [66] though
a dose of this magnitude is not practical for humans. Oral curcumin has been successfully given at
a dose of 3.6 g daily to patients undergoing operations for colorectal cancer [65,71] with mucosal levels
reaching w10 nmol/g [65]. The mean concentrations of curcumin in normal and malignant colorectal
tissue of patients who had ingested this dose were 12.7 and 7.7 nmol/g tissue, respectively. Detectable
levels still persist topically on the mucosa several days after ingestion. This could be important because
any therapeutic advantages conferred to mucosa are probably brought about by both topical and
systemic activity. The activity of topical curcumin has been explored [72] and is the subject of clinical
trials.
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, resulting
in 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 from
patients receiving 2 or 4 g daily [75].
Curcumin has been detected in portal venous blood of both rats and humans at very low
concentrations soon after oral loading [64,71], further confirming poor absorption across the gut. At
a curcumin dose of 3.6 g daily, metabolites have been detected at nanomolar concentrations in the
human 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. Furthermore
curcumin undergoes metabolic transformation during absorption across the intestine, following
which it may enter the entero-hepatic circulation [76]. Therefore, curcumin metabolites and to
a lesser extent curcumin are excreted in bile. The presence of parent compound and metabolites in
the liver, biliary and portal systems means that it has potential to reach organs distant from the
bowel. It is still unknown how much curcumin would be necessary to exert a pharmacological
effect.

Detection of systemic curcumin. Curcumin detection in plasma is variable due to poor bioavailability and
a 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 trials
where 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 are
found 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 with
3.6 g per day [65].

Urinary excretion of curcumin. Curcumin is poorly excreted in urine [62,66]. Murine models report
negligible amounts are found in the urine even following intravenous doses of 1 g/kg [62,64]. In
humans receiving oral curcumin for four months, at doses greater than 3.6 g daily it becomes possible
to 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. Adverse
events due to curcumin relating to renal function have not been reported in any trial and there is some
evidence that curcumin may even improve function in renal disease [78].

Toxicity
Toxicity 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
 G.R.B. Irving et al. / Best Practice & Research Clinical Gastroenterology 25 (2011) 519–534 529

toxicities have been reported from almost 40 clinical trials involving over 800 participants. The adverse
event 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 beyond
this, 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 have
been anecdotal reports of transient rises in liver enzymes although causality is unclear.

Dosing for pharmacological effect

The 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 tolerated
and efficacious is challenging.
Several trials have used oral regimens of approximately 4 g daily curcumin however in vivo reports
imply a daily dose of 1.6 g in humans may be enough to exert a biological effect in the lumen, achieving
a colonic mucosal concentration of 0.1 mmol/g [69]. Pre-clinical data is difficult to extrapolate into
a human dosing regimen. Other clinical studies have required 8 g orally [77] to achieve serum levels
suggested by in vivo studies to be necessary for efficacy. However, an increase in dose may not equate to
a proportional increase in systemic absorption [61]. Detection of curcuminoids in hepatic tissue has
been demonstrated in small amounts following 3.6 g per day for one week although not with lower
doses [71]. Trace levels are detected in human serum at doses of 2 g. Based on that which is necessary
to furnish detectable levels of curcumin in serum, portal blood or hepatic tissue, it is possible that
a dose in the region of 2–4 g is the minimum required to have pharmacological effect in organs distal to
the gut [71]. Patient-reported outcomes suggest doses much in excess of this may lead to reduced
compliance. In our experience, larger capsule size and number may reduce compliance, particularly in
elderly populations. Compliance is excellent at doses in the region of 2–4 g per day [65,71,73] (and
Irving et al unpublished data).
Importantly, adverse events may also increase beyond 4 g per day [77,79] although tolerance to 8 g
for 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 plasma
levels but were a topical effect found to be of greatest benefit against luminal disease, then doses may
be equally effective if taken in a divided or less than daily regimen.

The potential for efficacy

Curcumin 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 research
is most advanced.

Pre-malignant bowel conditions and inflammatory bowel disease. Curcumin inhibits cellular processes
responsible for Barrett’s metaplasia differentiating to oesophageal adenocarcinoma in vitro [82],
mainly through NF-kB. Patients with pre-malignant conditions, including gastric metaplasia received
up to 8 g daily oral curcumin for three months [77], following which histological improvement was
observed in a third of cases, however 2 patients developed malignancy.
Animal models and early-phase trials with familial adenomatous polyposis (FAP) show great
promise 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]. In
humans, it reduces polyp number and size when used alone and in combination with quercetin [85]. In
this study of 5 patients awaiting colectomy for FAP, following wsix months treatment with curcumin
taken 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 further
investigate these early reports of efficacy.
More recently, 39 patients undergoing colonoscopy for the screening of bowel neoplasia have
successfully consumed either 2 or 4 g of oral curcumin daily for one month [75]. The low plasma
curcuminoid concentrations were in keeping with previous reports confirming poor bioavailability,
530 G.R.B. Irving et al. / Best Practice & Research Clinical Gastroenterology 25 (2011) 519–534

however, rectal mucosal levels persisted to a mean of 8.2 mg/g of tissue. There was a significant
reduction (40%) in aberrant crypt foci found in mucosal biopsies of patients taking 4 g per day thus
providing evidence of biological effect. In this study, curcumin did not seem to affect levels of
prostaglandin E2 (PGE2), which has also been a finding from a chemoprevention trial investigating
celecoxib and FAP [86] where polyp regression was observed. If efficacious, curcumin could confer
an advantage over non-steroidal anti-inflammatory drugs, such as aspirin and celecoxib, in the
chemopreventive setting because of the reduced risk of gastrointestinal bleeding, nephro-toxicity
or 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 of
inflammatory cells and inhibition of neoplastic change [30,87–89]. Curcumin is potentially safe
medication for maintaining remission in patients with quiescent ulcerative colitis. Two early-phase
trials [26,29] have shown it to be well tolerated by patients with colitis and can lead to reduced
symptoms and inflammatory markers (Table 1).

Colorectal cancer. Copious in vitro and pre-clinical data support the use of curcumin in trials involving
the spectrum of bowel neoplasia. Colon cancer is a common cancer in the UK, where surveillance and
screening are becoming well established. Much of the clinical data relating to curcumin has been
accrued from this patient population but there have been no trials reporting efficacy.
Pre-clinical data suggests that curcumin enhances activity when used in combination with standard
chemotherapy agents against cancer cells that would otherwise be chemo-resistant [40,90]. It
augments the efficacy of oxaliplatin against chemo-resistant xenograft tumours [90]. This is important
because half of all colorectal cancers possess innate chemo-resistance, and all cancers inevitably
acquire resistance. A safe compound with the ability to improve the efficacy of chemotherapy is
attractive. Curcumin in combination with chemotherapy may 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-cytotoxic
actions. It attenuates pain in a mouse model of neuropathy [91] and appears to promote weight gain
in humans receiving chemotherapy [92]. Trials using combination regimens have been conducted with
pancreatic and breast cancers, but the addition of curcumin to colon cancer chemotherapy is at present
confined 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-term
tolerance of curcumin by patients with advanced malignancy whilst they receive potentially toxic
chemotherapy.

Unanswered questions: clinical targets, clinical efficacy

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

Improving efficacy by improving bioavailability

Curcumin 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 of
Piperine, an extract of pepper and an inhibitor of glucuronidation, may increase bioavailability 20-fold
[67], whilst curcumin-phosphatidylcholine phytosome complexes (e.g. MerivaÔ) have even greater
 G.R.B. Irving et al. / Best Practice & Research Clinical Gastroenterology 25 (2011) 519–534 531

bioavailability [96]. Structural analogues have also been developed with potentially improved
bioavailability while potentially maintaining the active moiety. At present the use of these products is
confined 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 colorectal
neoplasia.
 Pharmacodynamic, pharmacokinetic and safety profiles are well established supporting
tolerance to doses up to 8 g daily although beyond this compliance and adverse events may
be affected.
 Doses required for efficacy are not yet established.
 Bioavailability is poor and should be taken into account when planning sample schedules
within clinical trial protocols

Research agenda

 Novel pre-clinical models are being designed to ascertain the best strategies for medicinal use
such as combination therapies, tumour initiating cells and drug-resistance.
 Additional pre-clinical and clinical data are required to determine likely efficacious doses and
clinical 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 Fellowship
supported by the Rosetrees trust.

References

[1] Sharma RA, McLelland HR, Hill KA, Ireson CR, Euden SA, Manson MM, et al. Pharmacodynamic and pharmacokinetic
study of oral Curcuma extract in patients with colorectal cancer. Clin Cancer Res 2001 Jul;7(7):1894–900.
[2] Aggarwal BB, Sundaram C, Malani N, Ichikawa H. Curcumin: the Indian solid gold. Adv Exp Med Biol 2007;595:1–75.
[3] Loftus Jr EV. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences.
Gastroenterology 2004 May;126(6):1504–17.
[4] World Health Organisation. Cancer incidence and mortality worldwide in 2008. Available from: http://globocan.iarc.fr/.
[5] Kiuchi F, Goto Y, Sugimoto N, Akao N, Kondo K, Tsuda Y. Nematocidal activity of turmeric: synergistic action of curcu-
minoids. Chem Pharm Bull (Tokyo) 1993 Sep;41(9):1640–3.
[6] Rahman I, Biswas SK, Kirkham PA. Regulation of inflammation and redox signaling by dietary polyphenols. Biochem
Pharmacol 2006 Nov 30;72(11):1439–52.
[7] Kita T, Imai S, Sawada H, Kumagai H, Seto H. The biosynthetic pathway of curcuminoid in turmeric (Curcuma longa) as
revealed by 13C-labeled precursors. Biosci Biotechnol Biochem 2008 Jul;72(7):1789–98.
[8] Balasubramanian K. Molecular orbital basis for yellow curry spice curcumin’s prevention of Alzheimer’s disease. J Agric
Food Chem 2006 May 17;54(10):3512–20.
532 G.R.B. Irving et al. / Best Practice & Research Clinical Gastroenterology 25 (2011) 519–534

[9] Priyadarsini KI, Maity DK, Naik GH, Kumar MS, Unnikrishnan MK, Satav JG, et al. Role of phenolic O–H and
methylene hydrogen on the free radical reactions and antioxidant activity of curcumin. Free Radic Biol Med 2003
Sep 1;35(5):475–84.
[10] Weber WM, Hunsaker LA, Abcouwer SF, Deck LM, Vander Jagt DL. Anti-oxidant activities of curcumin and related enones.
Bioorg Med Chem 2005 Jun 1;13(11):3811–20.
[11] Barclay LR, Vinqvist MR, Mukai K, Goto H, Hashimoto Y, Tokunaga A, et al. On the antioxidant mechanism of curcumin:
classical methods are needed to determine antioxidant mechanism and activity. Org Lett 2000 Sep 7;2(18):2841–3.
[12] Lin JK, Pan MH, Lin-Shiau SY. Recent studies on the biofunctions and biotransformations of curcumin. Biofactors 2000;
13(1–4):153–8.
[13] Wang YJ, Pan MH, Cheng AL, Lin LI, Ho YS, Hsieh CY, et al. Stability of curcumin in buffer solutions and characterization of
its degradation products. J Pharm Biomed Anal 1997 Aug;15(12):1867–76.
*[14] Li L, Braiteh FS, Kurzrock R. Liposome-encapsulated curcumin: in vitro and in vivo effects on proliferation, apoptosis,
signaling, and angiogenesis. Cancer 2005 Sep 15;104(6):1322–31.
*[15] Li L, Aggarwal BB, Shishodia S, Abbruzzese J, Kurzrock R. Nuclear factor-kappaB and IkappaB kinase are constitutively
active in human pancreatic cells, and their down-regulation by curcumin (diferuloylmethane) is associated with the
suppression of proliferation and the induction of apoptosis. Cancer 2004 Nov 15;101(10):2351–62.
[16] Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ, et al. IKKbeta links inflammation and tumorigenesis in a mouse
model of colitis-associated cancer. Cell 2004 Aug 6;118(3):285–96.
[17] Aggarwal S, Ichikawa H, Takada Y, Sandur SK, Shishodia S, Aggarwal BB. Curcumin (diferuloylmethane) down-regulates
expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IkappaBalpha
kinase and Akt activation. Mol Pharmacol 2006 Jan;69(1):195–206.
[18] Kunnumakkara AB, Diagaradjane P, Anand P, Kuzhuvelil HB, Deorukhkar A, Gelovani J, et al. Curcumin sensitizes human
colorectal cancer to capecitabine by modulation of cyclin D1, COX-2, MMP-9, VEGF and CXCR4 expression in an orthotopic
mouse model. Int J Cancer 2009 Nov 1;125(9):2187–97.
[19] Lee KW, Kim JH, Lee HJ, Surh YJ. Curcumin inhibits phorbol ester-induced up-regulation of cyclooxygenase-2 and matrix
metalloproteinase-9 by blocking ERK1/2 phosphorylation and NF-kappaB transcriptional activity in MCF10A human
breast epithelial cells. Antioxid Redox Signal 2005 Nov–Dec;7(11–12):1612–20.
[20] Plummer SM, Hill KA, Festing MF, Steward WP, Gescher AJ, Sharma RA. Clinical development of leukocyte cyclooxygenase
2 activity as a systemic biomarker for cancer chemopreventive agents. Cancer Epidemiol Biomarkers Prev 2001 Dec;
10(12):1295–9.
[21] Rao CV, Rivenson A, Simi B, Reddy BS. Chemoprevention of colon carcinogenesis by dietary curcumin, a naturally
occurring plant phenolic compound. Cancer Res 1995 Jan 15;55(2):259–66.
[22] Aggarwal BB. Prostate cancer and curcumin: add spice to your life. Cancer Biol Ther 2008 Sep;7(9):1436–40.
[23] Belcaro G, Cesarone MR, Dugall M, Pellegrini L, Ledda A, Grossi MG, et al. Efficacy and safety of MerivaÒ, a curcumin-
phosphatidylcholine complex, during extended administration in osteoarthritis patients. Altern Med Rev 2010 Dec;
15(4):337–44.
[24] Belcaro G, Cesarone MR, Dugall M, Pellegrini L, Ledda A, Grossi MG, et al. Product-evaluation registry of MerivaÒ,
a curcumin-phosphatidylcholine complex, for the complementary management of osteoarthritis. Panminerva Med 2010
Jun;52(2 Suppl. 1):55–62.
[25] Durgaprasad S, Pai CG, Vasanthkumar, Alvres JF, Namitha S. A pilot study of the antioxidant effect of curcumin in tropical
pancreatitis. Indian J Med Res 2005 Oct;122(4):315–8.
[26] Holt PR, Katz S, Kirshoff R. Curcumin therapy in inflammatory bowel disease: a pilot study. Dig Dis Sci 2005 Nov;50(11):
2191–3.
[27] Sharma S, Kulkarni SK, Agrewala JN, Chopra K. Curcumin attenuates thermal hyperalgesia in a diabetic mouse model of
neuropathic pain. Eur J Pharmacol 2006 May 1;536(3):256–61.
[28] Billerey-Larmonier C, Uno JK, Larmonier N, Midura AJ, Timmermann B, Ghishan FK, et al. Protective effects of dietary
curcumin in mouse model of chemically induced colitis are strain dependent. Inflamm Bowel Dis 2008 Jun;14(6):780–93.
*[29] Hanai H, Iida T, Takeuchi K, Watanabe F, Maruyama Y, Andoh A, et al. Curcumin maintenance therapy for ulcerative
colitis: randomized, multicenter, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol 2006 Dec;4(12):
1502–6.
[30] Larmonier CB, Midura-Kiela MT, Ramalingam R, Laubitz D, Janikashvili N, Larmonier N, et al. Modulation of neutrophil
motility by curcumin: implications for inflammatory bowel disease. Inflamm Bowel Dis 2011 Feb;17(2):503–15.
[31] Churchill M, Chadburn A, Bilinski RT, Bertagnolli MM. Inhibition of intestinal tumors by curcumin is associated with
changes in the intestinal immune cell profile. J Surg Res 2000 Apr;89(2):169–75.
[32] Han SS, Chung ST, Robertson DA, Ranjan D, Bondada S. Curcumin causes the growth arrest and apoptosis of B cell
lymphoma by downregulation of egr-1, c-myc, bcl-XL, NF-kappa B, and p53. Clin Immunol 1999 Nov;93(2):152–61.
[33] Bhaumik S, Jyothi MD, Khar A. Differential modulation of nitric oxide production by curcumin in host macrophages and
NK cells. FEBS Lett 2000 Oct 13;483(1):78–82.
[34] Joe B, Lokesh BR. Role of capsaicin, curcumin and dietary n-3 fatty acids in lowering the generation of reactive oxygen
species in rat peritoneal macrophages. Biochim Biophys Acta 1994 Nov 10;1224(2):255–63.
[35] Jaiswal AS, Marlow BP, Gupta N, Narayan S. Beta-catenin-mediated transactivation and cell-cell adhesion pathways are
important in curcumin (diferuylmethane)-induced growth arrest and apoptosis in colon cancer cells. Oncogene 2002 Dec
5;21(55):8414–27.
[36] Hanif R, Qiao L, Shiff SJ, Rigas B. Curcumin, a natural plant phenolic food additive, inhibits cell proliferation and induces
cell cycle changes in colon adenocarcinoma cell lines by a prostaglandin-independent pathway. J Lab Clin Med 1997 Dec;
130(6):576–84.
[37] Basile V, Ferrari E, Lazzari S, Belluti S, Pignedoli F, Imbriano C. Curcumin derivatives: molecular basis of their anti-cancer
activity. Biochem Pharmacol 2009 Nov 15;78(10):1305–15.
[38] Du B, Jiang L, Xia Q, Zhong L. Synergistic inhibitory effects of curcumin and 5-fluorouracil on the growth of the human
colon cancer cell line HT-29. Chemotherapy 2006;52(1):23–8.
 G.R.B. Irving et al. / Best Practice & Research Clinical Gastroenterology 25 (2011) 519–534 533

[39] Verma SP, Goldin BR, Lin PS. The inhibition of the estrogenic effects of pesticides and environmental chemicals by
curcumin and isoflavonoids. Environ Health Perspect 1998 Dec;106(12):807–12.
*[40] Howells LM, Mitra A, Manson MM. Comparison of oxaliplatin- and curcumin-mediated antiproliferative effects in
colorectal cell lines. Int J Cancer 2007 Jul 1;121(1):175–83.
[41] Notarbartolo M, Poma P, Perri D, Dusonchet L, Cervello M, D’Alessandro N. Antitumor effects of curcumin, alone or in
combination with cisplatin or doxorubicin, on human hepatic cancer cells. Analysis of their possible relationship to
changes in NF-kB activation levels and in IAP gene expression. Cancer Lett 2005 Jun 16;224(1):53–65.
[42] Milacic V, Banerjee S, Landis-Piwowar KR, Sarkar FH, Majumdar AP, Dou QP. Curcumin inhibits the proteasome activity in
human colon cancer cells in vitro and in vivo. Cancer Res 2008 Sep 15;68(18):7283–92.
[43] Anto RJ, Mukhopadhyay A, Denning K, Aggarwal BB. Curcumin (diferuloylmethane) induces apoptosis through activation
of caspase-8, BID cleavage and cytochrome c release: its suppression by ectopic expression of Bcl-2 and Bcl-xl. Carci-
nogenesis 2002 Jan;23(1):143–50.
[44] Choudhuri T, Pal S, Agwarwal ML, Das T, Sa G. Curcumin induces apoptosis in human breast cancer cells through p53-
dependent Bax induction. FEBS Lett 2002 Feb 13;512(1–3):334–40.
[45] Weir NM, Selvendiran K, Kutala VK, Tong L, Vishwanath S, Rajaram M, et al. Curcumin induces G2/M arrest and apoptosis in
cisplatin-resistant human ovarian cancer cells by modulating Akt and p38 MAPK. Cancer Biol Ther 2007 Feb;6(2):178–84.
[46] Squires MS, Hudson EA, Howells L, Sale S, Houghton CE, Jones JL, et al. Relevance of mitogen activated protein kinase
(MAPK) and phosphotidylinositol-3-kinase/protein kinase B (PI3K/PKB) pathways to induction of apoptosis by curcumin
in breast cells. Biochem Pharmacol 2003 Feb 1;65(3):361–76.
[47] Chiu TL, Su CC. Curcumin inhibits proliferation and migration by increasing the Bax to Bcl-2 ratio and decreasing NF-
kappaBp65 expression in breast cancer MDA-MB-231 cells. Int J Mol Med 2009 Apr;23(4):469–75.
[48] Arbiser JL, Klauber N, Rohan R, van Leeuwen R, Huang MT, Fisher C, et al. Curcumin is an in vivo inhibitor of angiogenesis.
Mol Med 1998 Jun;4(6):376–83.
[49] Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res 2003
Jan–Feb;23(1A):363–98.
[50] Aggarwal BB, Shishodia S, Takada Y, Banerjee S, Newman RA, Bueso-Ramos CE, et al. Curcumin suppresses the paclitaxel-
induced nuclear factor-kappaB pathway in breast cancer cells and inhibits lung metastasis of human breast cancer in
nude mice. Clin Cancer Res 2005 Oct 15;11(20):7490–8.
[51] Wang Z, Li Y, Ahmad A, Azmi AS, Kong D, Banerjee S, et al. Targeting miRNAs involved in cancer stem cell and EMT
regulation: an emerging concept in overcoming drug resistance. Drug Resist Updat 2010 Aug–Oct;13(4–5):109–18.
[52] Shafee N, Smith CR, Wei S, Kim Y, Mills GB, Hortobagyi GN, et al. Cancer stem cells contribute to cisplatin resistance in
Brca1/p53-mediated mouse mammary tumors. Cancer Res 2008 May 1;68(9):3243–50.
[53] Bidard FC, Tournigand C, Andre T, Mabro M, Figer A, Cervantes A, et al. Efficacy of FOLFIRI-3 (irinotecan D1, D3 combined
with LV5-FU) or other irinotecan-based regimens in oxaliplatin-pretreated metastatic colorectal cancer in the GERCOR
OPTIMOX1 study. Ann Oncol 2009 Jun;20(6):1042–7.
[54] Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, et al. Distinct populations of cancer stem cells determine
tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 2007 Sep 13;1(3):313–23.
[55] Sarkar FH, Li Y, Wang Z, Kong D. The role of nutraceuticals in the regulation of Wnt and Hedgehog signaling in cancer.
Cancer Metastasis Rev 2010 Sep;29(3):383–94.
[56] Ryu MJ, Cho M, Song JY, Yun YS, Choi IW, Kim DE, et al. Natural derivatives of curcumin attenuate the Wnt/beta-catenin
pathway through down-regulation of the transcriptional coactivator p300. Biochem Biophys Res Commun 2008 Dec 26;
377(4):1304–8.
[57] Wang Z, Desmoulin S, Banerjee S, Kong D, Li Y, Deraniyagala RL, et al. Synergistic effects of multiple natural products in
pancreatic cancer cells. Life Sci 2008 Aug 15;83(7–8):293–300.
[58] Kakarala M, Brenner DE, Korkaya H, Cheng C, Tazi K, Ginestier C et-al. Targeting breast stem cells with the cancer
preventive compounds curcumin and piperine. Breast Cancer Res Treat. Aug;122(3):777-785.
[59] Prasad CP, Rath G, Mathur S, Bhatnagar D, Ralhan R. Potent growth suppressive activity of curcumin in human breast
cancer cells: modulation of Wnt/beta-catenin signaling. Chem Biol Interact 2009 Oct 7;181(2):263–71.
[60] Yu Y, Kanwar SS, Patel BB, Nautiyal J, Sarkar FH, Majumdar AP. Elimination of colon cancer stem-like cells by the
combination of curcumin and FOLFOX. Transl Oncol 2009 Dec;2(4):321–8.
[61] Ravindranath V, Chandrasekhara N. Metabolism of curcumin – studies with [3H]curcumin. Toxicology 1981;22(4):337–44.
[62] Wahlstrom B, Blennow G. A study on the fate of curcumin in the rat. Acta Pharmacol Toxicol (Copenh) 1978 Aug;43(2):86–92.
[63] Holder GM, Plummer JL, Ryan AJ. The metabolism and excretion of curcumin (1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-
heptadiene-3,5-dione) in the rat. Xenobiotica 1978 Dec;8(12):761–8.
*[64] Ravindranath V, Chandrasekhara N. Absorption and tissue distribution of curcumin in rats. Toxicology 1980;16(3):259–65.
[65] Garcea G, Berry DP, Jones DJ, Singh R, Dennison AR, Farmer PB, et al. Consumption of the putative chemopreventive agent
curcumin by cancer patients: assessment of curcumin levels in the colorectum and their pharmacodynamic conse-
quences. Cancer Epidemiol Biomarkers Prev 2005 Jan;14(1):120–5.
[66] Sharma RA, Ireson CR, Verschoyle RD, Hill KA, Williams ML, Leuratti C, et al. Effects of dietary curcumin on glutathione S-
transferase and malondialdehyde-DNA adducts in rat liver and colon mucosa: relationship with drug levels. Clin Cancer
Res 2001 May;7(5):1452–8.
[67] Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS. Influence of piperine on the pharmacokinetics of curcumin
in animals and human volunteers. Planta Med 1998 May;64(4):353–6.
[68] Perkins S, Verschoyle RD, Hill K, Parveen I, Threadgill MD, Sharma RA, et al. Chemopreventive efficacy and pharmaco-
kinetics of curcumin in the min/þ mouse, a model of familial adenomatous polyposis. Cancer Epidemiol Biomarkers Prev
2002 Jun;11(6):535–40.
[69] Shpitz B, Giladi N, Sagiv E, Lev-Ari S, Liberman E, Kazanov D, et al. Celecoxib and curcumin additively inhibit the growth
of colorectal cancer in a rat model. Digestion 2006;74(3–4):140–4.
*[70] Dhillon N, Aggarwal BB, Newman RA, Wolff RA, Kunnumakkara AB, Abbruzzese JL, et al. Phase II trial of curcumin in
patients with advanced pancreatic cancer. Clin Cancer Res 2008 Jul 15;14(14):4491–9.
534 G.R.B. Irving et al. / Best Practice & Research Clinical Gastroenterology 25 (2011) 519–534

*[71] Garcea G, Jones DJ, Singh R, Dennison AR, Farmer PB, Sharma RA, et al. Detection of curcumin and its metabolites in
hepatic tissue and portal blood of patients following oral administration. Br J Cancer 2004 Mar 8;90(5):1011–5.
[72] LoTempio MM, Veena MS, Steele HL, Ramamurthy B, Ramalingam TS, Cohen AN, et al. Curcumin suppresses growth of
head and neck squamous cell carcinoma. Clin Cancer Res 2005 Oct 1;11(19 Pt 1):6994–7002.
[73] Sharma RA, Euden SA, Platton SL, Cooke DN, Shafayat A, Hewitt HR, et al. Phase I clinical trial of oral curcumin:
biomarkers of systemic activity and compliance. Clin Cancer Res 2004 Oct 15;10(20):6847–54.
*[74] Ireson CR, Jones DJ, Orr S, Coughtrie MW, Boocock DJ, Williams ML, et al. Metabolism of the cancer chemopreventive
agent curcumin in human and rat intestine. Cancer Epidemiol Biomarkers Prev 2002 Jan;11(1):105–11.
[75] Carroll RE, Benya RV, Turgeon DK, Vareed S, Neuman M, Rodriguez L, et al. Phase IIa clinical trial of curcumin for the
prevention of colorectal neoplasia. Cancer Prev Res (Phila) 2011 Mar;4(3):354–64.
[76] Ravindranath V, Chandrasekhara N. In vitro studies on the intestinal absorption of curcumin in rats. Toxicology 1981;
20(2–3):251–7.
[77] Cheng AL, Hsu CH, Lin JK, Hsu MM, Ho YF, Shen TS, et al. Phase I clinical trial of curcumin, a chemopreventive agent, in
patients with high-risk or pre-malignant lesions. Anticancer Res 2001 Jul–Aug;21(4B):2895–900.
[78] Shoskes D, Lapierre C, Cruz-Correa M, Muruve N, Rosario R, Fromkin B, et al. Beneficial effects of the bioflavonoids
curcumin and quercetin on early function in cadaveric renal transplantation: a randomized placebo controlled trial.
Transplantation 2005 Dec 15;80(11):1556–9.
*[79] Epelbaum R, Schaffer M, Vizel B, Badmaev V, Bar-Sela G. Curcumin and gemcitabine in patients with advanced pancreatic
cancer. Nutr Cancer 2010 Nov;62(8):1137–41.
[80] Sharma RA, Steward WP, Gescher AJ. Pharmacokinetics and pharmacodynamics of curcumin. Adv Exp Med Biol 2007;
595:453–70.
[81] Braumann C, Guenther N, Loeffler LM, Dubiel W. Liver metastases after colonic carcinoma – palliative chemotherapy plus
curcumin. Int J Colorectal Dis 2009 Jul;24(7):859–60.
[82] Hartojo W, Silvers AL, Thomas DG, Seder CW, Lin L, Rao H, et al. Curcumin promotes apoptosis, increases chemo-
sensitivity, and inhibits nuclear factor kappaB in esophageal adenocarcinoma. Transl Oncol 2010 Apr;3(2):99–108.
[83] Perkins S, Clarke AR, Steward W, Gescher A. Age-related difference in susceptibility of Apc(Min/þ) mice towards the
chemopreventive efficacy of dietary aspirin and curcumin. Br J Cancer 2003 May 6;88(9):1480–3.
[84] Tunstall RG, Sharma RA, Perkins S, Sale S, Singh R, Farmer PB, et al. Cyclooxygenase-2 expression and oxidative DNA
adducts in murine intestinal adenomas: modification by dietary curcumin and implications for clinical trials. Eur J Cancer
2006 Feb;42(3):415–21.
[85] Cruz-Correa M, Shoskes DA, Sanchez P, Zhao R, Hylind LM, Wexner SD, et al. Combination treatment with curcumin and
quercetin of adenomas in familial adenomatous polyposis. Clin Gastroenterol Hepatol 2006 Aug;4(8):1035–8.
[86] Sinicrope FA, Half E, Morris JS, Lynch PM, Morrow JD, Levin B, et al. Cell proliferation and apoptotic indices predict
adenoma regression in a placebo-controlled trial of celecoxib in familial adenomatous polyposis patients. Cancer Epi-
demiol Biomarkers Prev 2004 Jun;13(6):920–7.
[87] Larmonier CB, Uno JK, Lee KM, Karrasch T, Laubitz D, Thurston R, et al. Limited effects of dietary curcumin on Th-1 driven
colitis in IL-10 deficient mice suggest an IL-10-dependent mechanism of protection. Am J Physiol Gastrointest Liver
Physiol 2008 Nov;295(5):G1079–91.
[88] Salh B, Assi K, Templeman V, Parhar K, Owen D, Gomez-Munoz A, et al. Curcumin attenuates DNB-induced murine colitis.
Am J Physiol Gastrointest Liver Physiol 2003 Jul;285(1):G235–43.
[89] Villegas I, Sanchez-Fidalgo S, de la Lastra CA. Chemopreventive effect of dietary curcumin on inflammation-induced
colorectal carcinogenesis in mice. Mol Nutr Food Res 2011 Feb;55(2):259–67.
*[90] Howells LM, Sale S, Sriramareddy SN, Irving GR, Jones DJ, Ottley CJ, et al. Curcumin ameliorates oxaliplatin-induced
chemoresistance in HCT116 colorectal cancer cells in vitro and in vivo. Int J Cancer 2010;129(2):476–86.
[91] Khajavi M, Shiga K, Wiszniewski W, He F, Shaw CA, Yan J, et al. Oral curcumin mitigates the clinical and neuropathologic
phenotype of the Trembler-J mouse: a potential therapy for inherited neuropathy. Am J Hum Genet 2007 Sep;81(3):438–53.
[92] He ZY, Shi CB, Wen H, Li FL, Wang BL, Wang J. Upregulation of p53 expression in patients with colorectal cancer by
administration of curcumin. Cancer Invest 2011 Mar;29(3):208–13.
[93] Kanai M, Yoshimura K, Asada M, Imaizumi A, Suzuki C, Matsumoto S, et al. A phase I/II study of gemcitabine-based
chemotherapy plus curcumin for patients with gemcitabine-resistant pancreatic cancer. Cancer Chemother Pharmacol
2011;68(1):157–64.
[94] Shaikh J, Ankola DD, Beniwal V, Singh D, Kumar MN. Nanoparticle encapsulation improves oral bioavailability of cur-
cumin by at least 9-fold when compared to curcumin administered with piperine as absorption enhancer. Eur J Pharm Sci
2009 Jun 28;37(3–4):223–30.
[95] Marczylo TH, Verschoyle RD, Cooke DN, Morazzoni P, Steward WP, Gescher AJ. Comparison of systemic availability of
curcumin with that of curcumin formulated with phosphatidylcholine. Cancer Chemother Pharmacol 2007 Jul;60(2):
171–7.
[96] Cuomo J, Appendino G, Dern AS, Schneider E, McKinnon TP, Brown MJ, et al. Comparative absorption of a standardized
curcuminoid mixture and its lecithin formulation. J Nat Prod 2011 Apr 25;74(4):664–9.