IJC
International Journal of Cancer
The dark side of curcumin
Estefanı́a Burgos-Morón1, José Manuel Calderón-Montaño1, Javier Salvador2, Antonio Robles3 and Miguel López-Lázaro1
1
Department of Pharmacology, Faculty of Pharmacy, University of Seville, Spain
2
Oncology Unit, Hospital Universitario de Valme, Seville, Spain
3
Department of Pathology, Hospital Universitario de Valme, Seville, Spain
Dear Editor,
Curcumin is a yellow–orange pigment obtained from the
plant Curcuma longa. The powdered rhizome of this plant,
called turmeric, is a common ingredient in curry powders
and has a long history of use in traditional Asian medicine
for a wide variety of disorders. In the last decade a large
number of reports have been published on the beneficial
effects of curcumin, and it has repeatedly been claimed that
this natural product is efficient and safe for the prevention
and treatment of several diseases including cancer.1–3 It is
not surprising, therefore, that curcumin is currently sold as a
dietary supplement and that numerous clinical trials are
ongoing or recruiting participants to evaluate curcumin activ-
ity. But there is accumulating evidence that curcumin may
not be so effective and safe. Because such evidence is not
generally acknowledged, the purpose of this letter is to briefly
review the negative properties of curcumin so that they can
be balanced against its beneficial effects.
Most of the evidence that supports the therapeutic poten-
tial of curcumin is mainly based on in vitro studies in which
curcumin was tested at concentrations in the micromolar
range. Several reports have demonstrated, however, that the
plasma concentrations of curcumin in people taking relatively
high oral doses of this compound are very low, typically in
the nanomolar range (reviewed in Ref. 4). For instance, a
recent study examined the pharmacokinetics of a curcumin
preparation in 12 healthy human volunteers 0.25–72 hr after
an oral dose of 10 or 12 g. Using a high-performance liquid
chromatography assay with a limit of detection of 50 ng
mL
1, only 1 subject had detectable free curcumin at any of
the time points assayed.5 The fact that curcumin also under-
goes extensive metabolism in intestine and liver6,7 means that
high concentrations of curcumin cannot be achieved and
maintained in plasma and tissues after oral ingestion. This is
a major obstacle for the clinical development of this agent
and suggests that the therapeutic potential of oral curcumin
is limited. The low clinical efficiency of curcumin in the
treatment of several chronic diseases such as Alzheimer’s dis-
ease and cardiovascular diseases has been discussed recently.8
As far as cancer is concerned, in vitro studies have dem-
onstrated that cancer cells do not die unless they are exposed
to curcumin concentrations of 5–50 lM for several
hours.4,9,10 Because of its poor bioavailability, these concen-
trations are not achieved outside the gastrointestinal tract
when curcumin is taken orally. Because of its extensive me-
tabolism in intestine and liver, these concentrations cannot
Int. J. Cancer: 126, 1771–1775 (2010) V
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be maintained for several hours in the gastrointestinal tract.
This suggests that the chemotherapeutic potential of oral cur-
cumin is limited even for the treatment of cancers of the
gastrointestinal tract. Accordingly, when 15 patients with
advanced colorectal cancer were treated with curcumin at
daily doses of 3.6 g for up to 4 months, no partial responses
to treatment or decreases in tumor markers were observed.11
A search of the website www.clinicaltrials.gov in July 2009
showed 34 clinical trials using curcumin in a wide variety of
diseases, particularly in cancer. In some of these trials,
patients with several types of cancer are receiving or will
receive curcumin through the oral route. For instance, in an
ongoing Phase II clinical trial (NCT00094445), participants
with pancreatic cancer are receiving 8 g of curcumin by
mouth every day for several 8-week-periods. As discussed
before, the plasma concentrations of curcumin in people tak-
ing relatively high oral doses of curcumin are very low, typi-
cally in the nanomolar range. This means that the oral
administration of curcumin does not lead to cytotoxic con-
centrations outside the gastrointestinal tract. If one assumes
that tumor cell death is necessary to achieve an efficient ther-
apeutic response, one should not expect a very positive out-
come from this trial. A Phase II Trial is also recruiting par-
ticipants to test if a daily oral dose of 8 g of curcumin can
improve the efficacy of the standard chemotherapy gemcita-
bine in patients with locally advanced or metastatic adenocar-
cinoma of the pancreas (NCT00192842). The rationale for
this trial is based on in vitro and in vivo data that suggest
that noncytotoxic concentrations of curcumin may sensitize
cancer cells to the effects of anticancer drugs such as gemci-
tabine.4,12 Although a daily dose of 1 g kg
1 of curcumin
increased the antitumor effects of gemcitabine in an ortho-
topic model of pancreatic cancer,12 this dose of curcumin Letters to the Editor
(e.g. 70 g in a 70-kg person) is almost 10 times higher than
that used in the clinical trial testing the combination of cur-
cumin and gemcitabine (8 g). This makes the outcome of
this trial uncertain, as curcumin can either increase or reduce
the efficiency of chemotherapy depending on the concentra-
tion at which it is used.4,13
Several strategies have been proposed to overcome the low
oral bioavailability of curcumin.4,14–18 One of these strategies
has entered clinical trials and consists of using the black pep-
per alkaloid piperine (bioperine) to increase the bioavailabil-
ity of curcumin.14 This strategy, however, should be used
cautiously, as piperine is a potent inhibitor of drug
 1772
metabolism and may cause toxicity in people taking specific
drugs.8,19,20 In addition, it is important to note that any strategy
that increases the levels of curcumin in tissues will not only
increase the effectiveness of curcumin, but also its toxicity.
A relatively high number of reports suggests that curcu-
min may cause toxicity under specific conditions. In 1976
Goodpasture and Arrighi found that turmeric caused a dose-
and time-dependent induction of chromosome aberrations in
several mammalian cell lines; these alterations were observed
at concentrations of 10 lg mL
1.21 Accumulating data have
demonstrated since then that curcumin can induce DNA
damage and chromosomal alterations both in vitro and in
vivo at concentrations similar to those reported to exert bene-
ficial effect.22–30 For instance, curcumin concentrations of 2.5
and 5 lg mL
1 were shown to induce DNA damage to both
the mitochondrial and nuclear genomes in cells.28 These
reports raise concern about curcumin safety, as the induction
of DNA alterations is a common event in carcinogenesis.
In 1993 the National Toxicology Program (USA) published
an extensive report on the toxic and carcinogenic properties of
an organic extract of turmeric, called turmeric oleoresin.31
This extract is commonly added to food items and contains a
percentage of curcumin (79–85%) similar to that of commer-
cial grade curcumin. Rats and mice were fed diets containing
several concentrations of turmeric oleoresin for 3 months and
2 years, and the possible toxic and carcinogenic effects were
evaluated. In the 2-year feeding studies, turmeric oleoresin
ingestion was associated with increased incidences of ulcers,
hyperplasia, and inflammation of the forestomach, cecum and
colon in male rats and of the cecum in female rats. In female
mice, ingestion of diets containing turmeric oleoresin was
associated with an increased incidence of thyroid gland follicu-
lar cell hyperplasia. The report also concluded that there was
equivocal evidence of carcinogenic activity in female rats,
female mice, and male mice. These conclusions were based on
increased incidences of clitoral gland adenomas in female rats,
hepatocellular adenomas in female mice, and carcinomas of
the small intestine and hepatocellular adenomas in male mice.
The increased incidence of carcinomas of the small intestine
was observed in mice taking average daily doses of curcumin
of 0.2 mg kg
1 body weight.31 A recent report has also
shown that curcumin can promote lung cancer in mice.32
Letters to the Editor
These negative effects of curcumin may be mediated by
several possible mechanisms. Evidence suggests that reactive
oxygen species (ROS) such as superoxide anion and hydro-
gen peroxide may play an important role in carcinogene-
sis.33–36 This evidence is based on the facts that (i) ROS can
induce cell malignant transformation,37–40 (ii) cancer cells
commonly have increased levels of ROS,41–43 and (iii) the
malignant phenotype of cancer cells can be reversed by
reducing the cellular levels of ROS.40,44–48 Experimental stud-
ies have demonstrated that, although low concentrations of
curcumin induce antioxidant effects, higher concentrations of
this compound increase the cellular levels of ROS.4,9,23,28,49–53
The presence of 2 a,b-unsaturated ketones in the chemical
Letters to the Editor
structure of curcumin may also mediate some of its negative
properties. These chemical groups are known to react cova-
lently with exposed thiol groups of cysteine residues of pro-
teins through a reaction termed Michael addition. This reac-
tion may explain, for instance, why curcumin generates ROS
by irreversibly modifying the antioxidant enzyme thioredoxin
reductase,49 why curcumin induces topoisomerase II-medi-
ated DNA damage,10,54,55 and why curcumin inactivates the
tumor suppressor protein p53.56,57
Several other lines of evidence raise concern about curcu-
min safety. Curcumin was recently found to be an active iron
chelator in vivo and to induce a state of overt iron deficiency
anemia in mice fed with diets poor in iron.58 This suggests
that curcumin has the potential to affect systemic iron me-
tabolism, particularly in people with suboptimal iron sta-
tus.58,59 Curcumin has also been shown to inhibit the activity
of the drug-metabolizing enzymes cytochrome P450, glutathi-
one-S-transferase, and UDP-glucuronosyltransferase.8,60–62
The inhibition of these enzymes in people taking curcumin
may lead to an undesired increase in the plasma concentra-
tions of some drugs and cause toxicity.8
Although this letter is focused on the negative properties
of curcumin, it is important to note that there is evidence
suggesting that curcumin has beneficial properties and could
be developed into a drug for the prevention and treatment of
diseases such as cancer.1–4 There are indeed numerous
reports showing beneficial effects of curcumin in colon can-
cer, yet a potential role for curcumin in colon cancer has
been shown in few clinical studies only.63 In vivo data suggest
that curcumin may also exert beneficial effects in organs out-
side the gastrointestinal tract;4 however, since curcumin does
not reach these organs at high concentrations, it is not clear
at this point whether these beneficial effects are due to low
levels of curcumin, to metabolites of curcumin or to an
unknown indirect effect. To develop curcumin into a preven-
tive or therapeutic drug, it is important to consider the dose
levels which elicit desirable/undesirable effects. Based on
human studies, it is generally recognized that curcumin does
not cause significant short-term toxicity at doses up to 8 g
day
1; this dose of curcumin is considered suitable for trials
in which curcumin is administered for short periods of time.
This dose of curcumin is not completely harmless, however,
as human studies have shown that curcumin at doses ranging
from 0.9 to 3.6 g day
1 for 1–4 months originates some
adverse effects including nausea and diarrhea and causes an
increase in serum alkaline phosphatase and lactate dehydro-
genase.11 Curcumin could be used at doses higher than 8 g
day
1 in situations in which no effective therapies exist (e.g.
advanced pancreatic cancer), as toxicity is acceptable in these
situations. But no human studies have been conducted to
date to test the dose levels which cause long-term toxicity.
This information would be valuable in the design of chemo-
prevention trials, in which chemopreventive agents are
administered for long periods of time and toxicity is not
always acceptable. Epidemiological data suggest that the
Int. J. Cancer: 126, 1771–1775 (2010) V
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Letters to the Editor
lower incidence of gastrointestinal cancers in India may be
due to diets rich in curcumin, and it has been estimated that
the doses of curcumin in people consuming high amounts of
turmeric in their diet are 0.15 g day
1.63 In the absence of
long-term toxicity studies in humans, this dose may be consid-
ered suitable when curcumin is used for long periods of time.
This dose of curcumin is similar to that recommended by the
World Heath Organization,31 but 10 times lower than that
generally recommended by suppliers of curcumin supple-
ments. The lack of long-term toxicity studies in humans
should not only be considered by health professionals, but also
by people taking supplements of curcumin (with and without
piperine) that are readily available in the market.
It is unfortunate that curcumin is regarded in the scien-
tific literature as efficient and safe when its efficiency and
safety have not yet been proven. The fact that curcumin is a
common dietary constituent is not enough to prove its safety,
as other common dietary constituents have shown toxicity
when used as dietary supplements.64 The fact that no major
toxicity has been found in short-term studies in humans is not
a proof of curcumin safety either. For a drug to be safe, it
must also be devoid of long-term toxicity, and the most com-
plete long-term toxicity study conducted to date raises concern
about curcumin safety.31 In addition, the effectiveness of a
drug is usually established by randomized, placebo-controlled,
double-blind clinical trials, and no such trials have shown cur-
cumin to be effective so far.8 Finally, the fact that the number
of studies showing positive effects of curcumin is much higher
than that showing negative effects does not necessarily mean
that the benefit-risk ratio of curcumin is shifted towards the
benefit; it may just indicate that there are more researchers
evaluating the beneficial effects of curcumin than evaluating its
toxicity. It is the opinion of the authors that future research is
needed to establish the benefit-risk profile of curcumin. In the
meantime, we believe that it is important to acknowledge the
negative properties of curcumin so that the use of curcumin is
not based on unbalanced information.
Yours sincerely,
Estefanı́a Burgos-Morón
José Manuel Calderón-Montaño
Javier Salvador
Antonio Robles
Miguel López-Lázaro
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Key words: curcumin, toxicity, DNA damage, safety
DOI: 10.1002/ijc.24967
History: Received 31 Jul 2009; Accepted 1 Oct 2009; Online 14 Oct
2009
Correspondence to: Miguel López-Lázaro, Department of
Pharmacology, Faculty of Pharmacy. C/ Professor Garcia Gonzalez,
41012, Sevilla, Spain, Fax: þ345-954-23-37-65,
E-mail: mlopezlazaro@us.es
Letters to the Editor