CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2006;4:1035–1038

Combination Treatment With Curcumin and Quercetin of

Adenomas in Familial Adenomatous Polyposis
MARCIA CRUZ–CORREA,*,‡ DANIEL A. SHOSKES,§ PATRICIA SANCHEZ,* RHONGUA ZHAO,*
LINDA M. HYLIND,‡ STEVEN D. WEXNER,储 and FRANCIS M. GIARDIELLO‡,¶,#
Departments of *Medicine, §Kidney Transplant, and 储Surgery, Cleveland Clinic, Weston, Florida; ‡Department of Medicine, ¶Oncology Center,
and #Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland

Background & Aims: Familialadenomatous polyposis ies with sulindac4 and with celecoxib, a selective inhibitor
(FAP) is an autosomal-dominant disorder characterized by of cyclooxygenase 2.5 Although effective in adenoma regres-
the development of hundreds of colorectal adenomas and sion, cyclooxygenase 1 and 2 inhibitors possess side effects
eventual colorectal cancer. Regression of adenomas in this that limit the use of these drugs as true chemopreventive
syndrome occurs with the administration of nonsteroidal
agents.
anti-inflammatory drugs and cyclooxygenase-2 inhibitors,
but these compounds can have considerable side effects.
Curcumin is the major yellow pigment extracted from
We evaluated the efficacy of the combination of diet- turmeric, the powdered root of the herb Curcuma longa.
derived nonprescription supplements curcumin and quer- Curcumin long has been used as a spice in Asia and is
cetin to regress adenomas in patients with FAP. Methods: considered a safe food additive.6 In murine models, this
Five FAP patients with prior colectomy (4 with retained agent shows preventive activity in the initiation and pro-
rectum and 1 with an ileal anal pouch) received curcumin gression stages of colorectal carcinogenesis.6 Also, several
480 mg and quercetin 20 mg orally 3 times a day. The reports using this compound in patients with colorectal
number and size of polyps were assessed at baseline and cancer, and high risk for premalignant conditions, have
after therapy. The Wilcoxon signed-rank test was used to stimulated interest in curcumin as a chemopreventive
determine differences in the number and size of polyps.
agent.7,8 In patients with advanced colorectal malignancy
Treatment side effects and medication compliance also
were evaluated. Results: All 5 patients had a decreased
refractory to standard chemotherapy, 5 of 15 individuals
polyp number and size from baseline after a mean of 6 given daily oral curcumin had stable disease at 4 months of
months of treatment with curcumin and quercetin. The follow-up evaluation.8 Also, histologic improvement of pre-
mean percent decrease in the number and size of polyps cancerous lesions in patients taking this agent was noted in
from baseline was 60.4% (P < .05) and 50.9% (P < .05), 1 of 2 patients with resected bladder cancer, 2 of 7 with oral
respectively. Minimal adverse side effects and no labora- leukoplakia, 1 of 6 with gastric intestinal metaplasia, and 2
tory abnormalities were noted. Conclusions: The combina- of 6 with Bowen’s disease.
tion of curcumin and quercetin appears to reduce the Quercetin belongs to a group of plant-derived polyphe-
number and size of ileal and rectal adenomas in patients nolic substances known as flavonoids, recognized for their
with FAP without appreciable toxicity. Randomized con-
antioxidant properties. Rich sources of quercetin include
trolled trials are needed to validate these findings.
onions, red wine, green tea, and St. John’s wort. Quercetin
appears to inhibit cell growth of human colon cancer cell
amilial adenomatous polyposis (FAP) is an autosomal-
F dominant form of hereditary colorectal cancer caused by
germline mutation of the Adenomatous Polyposis Coli gene
lines9 and colorectal neoplasia development in murine mod-
els.10,11
Because cell culture and animal evidence of chemopre-
located on chromosome 5q21.1 FAP is characterized by the ventive activity exists against colorectal neoplasia for both
development of hundreds of colorectal adenomas in adoles- curcumin and quercetin, each with potentially different
cence.2 Nearly all affected individuals will develop colorec- mechanisms of action, these compounds were used together.
tal cancer by the 6th decade of life if prophylactic colectomy
Therefore, we evaluated the effectiveness and toxicity of the
is not performed.2
Regression of adenomatous polyps in FAP was first noted
in a case series by Waddell et al3 in 1983. These investi- Abbreviation used in this paper: FAP, familial adenomatous polyp-
gators described decrease in adenomas with sulindac, a osis
© 2006 by the American Gastroenterological Association Institute
nonsteroidal anti-inflammatory drug. Subsequently, this 1542-3565/06/$32.00
observation was confirmed by randomized controlled stud- doi:10.1016/j.cgh.2006.03.020
1036 CRUZ–CORREA ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 8

Table 1. Demographic Characteristics of Study Patients nitrogen, serum creatinine, serum electrolytes, and bilirubin were
Baseline measured at each visit. Adverse events were graded in accordance
Baseline size of with the Common Toxicity Criteria of the National Cancer In-
Surgical number of the largest stitute.12
Patient Age, y Sex, M/F status polyps polyp, mm
Statistical Analysis
1 49 F IAP (15) 4
2 21 M IRA 45 8 The outcome variables analyzed were the number and size
3 51 F IRA 11 4 of polyps at the end of treatment. In addition, the percentage
4 54 M IRA 5 4 change from baseline in the number and size of polyps was
5 22 M IRA 15 5
evaluated. Mean, standard deviation, median, and range were
NOTE. Parentheses indicate ileal polyps. reported where appropriate. Hypothesis testing was performed by
IAP, total proctocolectomy with ileoanal pouch; IRA, colectomy with Wilcoxon signed-rank test (pair analysis) using STATA 8.0 sta-
ileorectal anastomosis.
tistical software (STATA Corporation, College Station,TX).

Results
combination of curcumin and quercetin to regress intestinal
adenomas in 5 patients with FAP. Clinical Effect
Table 1 shows the demographic characteristics of
Methods the study patients. Four of the patients had colectomy with
Patients ileorectal anastomosis and retained rectum and 1 had proc-
tocolectomy with an ileoanal pouch. All patients had 5 or
Five white FAP patients with previous colectomy, 4 with
more polyps at baseline. Patients were treated for a mean of
ileorectal anastomosis and 1 with ileoanal pull through with ileal
anal pouch, were enrolled in the study. Patients were recruited
6 months of therapy (range, 3–9 mo). Patient 1 was found
from the Cleveland Clinic in Weston, Florida. Inclusion criteria to be noncompliant with scheduled treatment doses be-
were patients with FAP who had undergone colectomy with tween 3 and 6 months of therapy. After re-instruction of the
retained rectum or ileal pouch who had 5 or more adenomas. patient concerning the medication schedule, she was con-
Exclusion criteria included the use of nonsteroidal anti-inflam- tinued on therapy for an additional 3 months (months 6 –9).
matory drugs for more than 1 week over the prior 3 months. The Patient 5 was lost to follow-up evaluation after 3 months of
study was approved by the Cleveland Clinic Institutional Review treatment.
Board, and informed consent was obtained from the patients. Figure 1 shows the polyp number for the 5 patients over
Study Design the course of treatment with curcumin and quercetin. A
decrease in polyp number from baseline was noted in 4 of 5
Participants were examined by flexible sigmoidoscopy patients at 3 months and 4 of 4 patients at 6 months of
using an Olympus flexible sigmoidoscope (Olympus, Melville,
treatment. Of note, polyp number in patient 1 paralleled
NY) before administration (0 mo) and at 3-month intervals
medication compliance with resolution of polyps after 3
(range, 3–9 mo) after the initiation of treatment with curcumin
and quercetin. The number and size of polyps were evaluated at months, recrudescence of polyps between 3 and 6 months
each visit. Also, at each endoscopy examination, 2 polyps were (medication noncompliance), and regression again by 9
sampled for histology with care taken not to remove the polyps. months. Figure 2 shows representative endoscopic photo-
No effort was made to clear the rectum of polyps by polypectomy graphs of the retained rectum of patient 3 before and after
or excisional biopsy procedure. One observer (M.C.C.) performed treatment with curcumin and quercetin.
all assessments. The endoscopist counted the total number of The mean decrease in polyp number from baseline with
polyps in the entire circumference of the rectum from the ileo- treatment was 60.4% (P ⫽ .043) (Table 2). The mean
rectal anastomosis to the anal verge or in the ileoanal pouch. The decrease in polyp size from baseline with treatment was
diameter of the largest polyp was measured in millimeters, with 50.9% (P ⫽ .039).
a graduated scale passed through the sigmoidoscopy biopsy chan-
nel. Adverse Effects and Compliance
Each patient received curcumin 480 mg and quercetin 20 mg
Few adverse side effects were reported with combi-
orally 3 times a day using Oxy-Q tablets (Farr Laboratories, Santa
Clarita, CA). Also, patients were instructed not to take nonste-
nation treatment with curcumin and quercetin. One patient
roidal anti-inflammatory drugs during this trial. Patient compli- reported a grade 1 episode of nausea and sour taste that
ance with drug administration was assessed by tablet count and occurred for 1–2 hours after pill ingestion and abated after
monthly telephone contact. Safety was monitored by monthly 3 days without recurrence. One patient had a grade 1
telephone interviews and at follow-up visits. In addition, com- self-limited episode of loose stools for 5 days during the
plete blood count was obtained and levels of glucose, blood urea study period. Abnormalities in laboratory study results were
August 2006 CURCUMIN AND QUERCETIN TREATMENT IN FAP 1037

regress colorectal adenomas in FAP patients, including su-

lindac and cyclooxygenase-2 inhibitors, have defined toxic-
ities. During this trial of curcumin and quercetin, study
patients had virtually no adverse events and no perturba-
tions in laboratory values.
Findings of adenoma regression in FAP patients with
curcumin are consistent with the effect of this agent in
animal studies of colorectal carcinogenesis. In azoxymeth-
ane-induced murine models, curcumin inhibited the inci-
dence and multiplicity of colonic adenocarcinomas15 and
adenomas.17 Inhibition of colonic neoplasia was noted in
both the initiation and promotion/progression phase of
Figure 1. Polyp number after treatment with curcumin and quercetin.
colon carcinogenesis.18 Some similar studies have been pub-
‘
}, Patient 1; , patient 2; * ●
, patient 3; , patient 4; , patient 5.
lished with quercetin.10,11 Also, in the murine model of
FAP (Min mouse) curcumin significantly decreased tumor
not noted in any patient with curcumin and quercetin formation by 64%.19 Few clinical trials of curcumin or
treatment. The compliance with scheduled drug doses by quercetin exist. Sharma et al8 treated 15 patients with
pill count was 92% (excluding the 3- to 6-month period for advanced colorectal cancer refractory to standard chemo-
patient 1). therapy with curcumin for up to 4 months and reported
radiographically stable disease in 5 patients for 2– 4 months
Discussion of therapy.
In this study combination therapy with curcumin The putative anticancer mechanisms of curcumin in-
and quercetin appeared effective in reducing the number clude up-regulation of carcinogen-detoxifying enzymes
and size of adenomatous polyps in both the retained rectum such as glutathione S-transferases,20 antioxidation,21 and
and ileoanal pouch of patients with FAP with prior colec- suppression of the isoenzyme cyclooxygenase-2.22 In a
tomy. Evidence of ileal adenoma regression is of clinical phase I clinical trial, orally administered curcumin pro-
importance because recent reports highlight a risk for ade- duced a 57%– 62% decrease in inducible prostaglandin
noma and adenocarcinoma development in the ileal E2 levels as measured in blood leukocytes.23 Of interest,
pouch.13 Of note, patient 1 developed an increase in polyp an association between adenoma regression in FAP pa-
number between 3 and 6 months. Investigation revealed tients and prostaglandin levels has been noted in several
patient noncompliance with treatment dosing during this recent studies of colorectal mucosal prostanoids after
period. With re-establishment of compliance between 6 and sulindac treatment.24
9 months, the polyp number again decreased. Curcumin, a The potential anticarcinogenic mechanisms of quercetin
food spice, is used commonly in Asian meal preparation and are less well understood. Of interest, flavonoid compounds
is considered to have an absence of side effects.14,15 Also, are able to target the function of ras gene products.25
quercetin, a dietary-derived supplement, has a dearth of Quercetin specifically inhibits p21-Ras expression in hu-
reported adverse effects, although limited experience with man colon cancer cell lines and in primary colorectal can-
this agent exists.16 In contrast, agents previously shown to cers.26

Figure 2. Endoscopic photographs of the retained rectal segment of patient 3 before and during treatment with curcumin and quercetin. (A)
Before treatment, patient 3 had 11 adenomas averaging 4 mm in size. (B) At 3 months of treatment, the rectum was polyp free.
1038 CRUZ–CORREA ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 8

Table 2. Effect of Curcumin and Quercetin on Polyp Number and Polyp Size
Percent
Range of reduction from
Mean (SD) polyps baseline P valuea

Polyp number
Baseline 23.7 (18.6) 11–45
Treatment 7.2 (6.8) 2–19 60.4 .043
Polyp size (mm)
Baseline 5.3 (2.3) 4–8
Treatment 2.7 (.9) 2–4 50.9 .039
aP values determined by Wilcoxon signed-rank test.

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supported by animal studies and this human observational chemicals, curcumin and quercetin, upon azosymethane-induced
data. However, these findings need validation in a random- colon cancer and 7,12-dimethylbenz (a) anthracene-induced
ized, double-blind, placebo-controlled trial. mammary cancer in rats. Carcinogenesis 1996;17:1305–1311.
18. Kawamori T, Lubet R, Steele VE, et al. Chemopreventive effect of
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