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1062
Review
Curcumin and the cellular stress response in free
radical-related diseases
Vittorio Calabrese1, Timothy E. Bates2, Cesare Mancuso3, Carolin Cornelius1,
Bernardo Ventimiglia4, Maria Teresa Cambria1, Laura Di Renzo5, Antonino De Lorenzo5
and Albena T. Dinkova-Kostova6, 7
1Department of Chemistry, Clinical Biochemistry and Clinical Molecular Biology Chair, University of
Catania, Catania, Italy
2School of Biomedical Sciences, University of Nottingham, Nottingham, UK
3Institute of Pharmacology, Catholic University School of Medicine, Roma, Italy
4Department of Science of Senescence, Urology and Neuro-Urology, University of Catania, Italy
5Human Nutrition Unit, Department of Neuroscience, University of Rome Tor Vergata, Rome, Italy
6Division of Clinical Pharmacology, Departments of Medicine and Pharmacology and Molecular Sciences,
Johns Hopkins University School of Medicine, Baltimore, MD, USA
7Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
Free radicals play a main pathogenic role in several human diseases such as neurodegenerative disor-
ders, diabetes, and cancer. Although there has been progress in treatment of these diseases, the devel-
opment of important side effects may complicate the therapeutic course. Curcumin, a well known
spice commonly used in India to make foods colored and flavored, is also used in traditional medicine
to treat mild or moderate human diseases. In the recent years, a growing body of literature has unrav-
eled the antioxidant, anticarcinogenic, and antinfectious activity of curcumin based on the ability of
this compound to regulate a number of cellular signal transduction pathways. These promising data
obtained in vitro are now being translated to the clinic and more than ten clinical trials are currently
ongoing worldwide. This review outlines the biological activities of curcumin and discusses its poten-
tial use in the prevention and treatment of human diseases.
Keywords: Curcumin / Free radicals / Heat shock proteins / Heme oxygenase / Neurodegenerative disorders /
Received: August 10, 2007; revised: April 29, 2008; accepted: May 1, 2008
1 Introduction
Curcumin (1,7-bis(4-hydroxy 3-methoxy phenyl)-1,6-hep-
tadiene-3,5-dione) (Fig. 1) is a phenolic compound
extracted from the rhizome of Curcuma longa L. (family
Zingiberaceae) and it is commonly used in the Asian conti-
nent, especially in India, as a spice to make food colored
and flavored. Furthermore, traditional Indian medicine has
considered curcumin a drug effective on several disorders
including anorexia, coryza, cough, hepatic diseases, and
sinusitis [1, 2]. Recently, several studies have substantiated
and provided scientific evidence regarding the potential
prophylactic or therapeutic use of curcumin, unraveling the
anti-inflammatory, anticarcinogenic, and anti-infectious
activities of this compound [3–6]. In the field of neuropro-
tection, especially exciting are the findings of Cole and his
colleagues who demonstrated that curcumin inhibits forma-
tion of amyloid boligomers and fibrils at submicromolar
concentrations, crosses the blood–brain barrier, and
reduces amyloid levels and plaque burden in a mouse model
of Alzheimer's disease (AD) [7].
2 Pharmacokinetics of curcumin
Curcumin is quite stable at acidic pH and upon ingestion
almost 40–80% of this compound remains in the gastroin-
Correspondence: Professor Vittorio Calabrese, Department of Chem-
istry, Biochemistry and Molecular Biology Section, University of Cat-
ania, Via Andrea Doria 95100 Catania, Italy
E-mail: calabres@mbox.unict.it
Fax: +39-095-580138
Abbreviations: AD, Alzheimer's disease; APP, amyloid precursor
protein; ARE, antioxidant response element; BM, bone marrow; BR,
bilirubin; BV, biliverdin; GST, glutathione S-transferase; HIF-1, hypo-
xia-inducible factor-1; HO-1, heme oxygenase-1; Hsp70, heat shock
protein70; IkB, inhibitory kappa B; Keap1, Kelch-like ECH-associ-
ated protein 1; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine;
NFkB, nuclear factor kB; NO, nitric oxide; NOS, nitric oxide syn-
thase; Nrf2, nuclear factor-erythroid 2-related factor 2; PD, Parkin-
son's disease; RNS, reactive nitrogen species; ROS, reactive oxygen
species; THC, tetrahydrocurcumin; Trx, thioredoxin; TrxR, thiore-
doxin reductase; UPR, unfolded protein response; UPS, ubiquitin–
proteasome system
i2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com
DOI 10.1002/mnfr.200700316 Mol. Nutr. Food Res. 2008, 52, 1062 –1073
Mol. Nutr. Food Res. 2008, 52, 1062 – 1073
testinal tract [1]. However, curcumin undergoes a marked
first-pass metabolism which limits its systemic bioavail-
ability (l60%) as demonstrated in humans and rodents [8 –
10]. Interestingly, in order to increase its bioavailability, the
co-administration of curcumin with piperine or its com-
plexation with phospholipids to form a curcumin–phos-
pholipid complex have been proposed [8, 11, 12]. Preclini-
cal studies have shown that administration of 1 g/kg of cur-
cumin to the rat allows the polyphenol to reach plasma con-
centrations around 0.5 lg/mL; on the other hand, patients
affected by malignant or premalignant conditions of the
bladder, skin, cervix, stomach, or oral mucosa, treated with
doses of curcumin in the range of 0.5–8 g/day for 3 months
had a plasma concentration of this compound of
1.75 l0.8 lM [8, 13]. In the rat, the volume of distribution
of curcumin is around 190 L suggesting that this polyphe-
nol may accumulate in many organs including colorectal
tissue, liver, and brain [8, 11, 14]. Studies in rodents and
humans demonstrated that, after oral dosing, curcumin is
conjugated to curcumin glucuronide and curcumin sulfate
as well as reduced into dihydrocurcumin (DHC), tetrahy-
drocurcumin (THC), hexahydrocurcumin, octahydrocurcu-
min, and hexahydrocurcuminol [1, 15, 16]; curcumin,
DHC, and THC can be further converted in monoglucuro-
nide conjugates [15, 17]. These metabolic changes seem to
occur not only in the liver, the main organ deputed to bio-
transformation, but also in the intestinal tract [1, 16]. Inter-
estingly, the metabolism of curcumin generates products
such as THC which retains anti-inflammatory activity com-
parable to that of the parental compound [1, 16]. In rodents
and humans curcumin inhibits cytochrome P450 enzymes,
glutathione S-transferase (GST) and UDP-glucuronosyl-
transferases, therefore the ingestion of this spice may alter
the metabolism of drugs thus increasing their plasma con-
centrations and initiating potential toxic effects [18–21]. In
the rat, curcumin is mainly excreted into the bile and elimi-
nated in the feces, only a small amount is excreted in the
urine [9, 10] with a half-life of elimination of l1.5 h [11].
The urinary elimination of curcumin and its metabolites
seems to increase if curcumin is administered at large doses
(e.g., 3.6 g/day for up to 4 months) [8, 22]. With regard to
the toxicity profile of curcumin, studies in rodents and pri-
mates have shown that doses of up to 3.5 g/kg body weight
administered for up to 3 months were well tolerated by the
animals [8]. In humans, curcumin at doses ranging from 2.1
to 8 g/day for up to 3 months did not originate any toxic
effects [13, 23]. However, patients affected by advanced
colorectal cancer treated with curcumin (3.6 g/day) devel-
oped diarrhea whereas a dose of 0.9 g/day was associated
with nausea, which resolved spontaneously. In the same
patients, blood test abnormalities related to curcumin
administration were a rise in serum alkaline phosphatase
and lactate dehydrogenase, but the possibility that they
resulted from the progression of cancer rather than curcu-
min toxicity can not be excluded [8, 22].
3 Pharmacodynamics of curcumin
Early studies have shown that curcumin and related prod-
ucts such as THC, have a strong antioxidant activity. In fact,
these compounds have been shown to reduce free radical-
or copper-induced lipid peroxidation in several experimen-
tal systems [24–26]. Furthermore, structure – activity stud-
ies clearly demonstrated the importance of the b-diketone
moiety and especially the phenolic hydroxyl group, for the
antioxidant activity of curcumin and its analogues [24, 27].
Very recently, many papers have appeared in the literature
demonstrating that curcumin and its metabolites affect
numerous intracellular systems such as transcription factor
nuclear factor kB (NFkB), inducible nitric oxide synthase
(iNOS), hypoxia-inducible factor-1 (HIF-1), nuclear factor-
erythroid 2-related factor 2 (Nrf2), and members of the vita-
gene family (e.g., heat shock protein70 (Hsp70), heme oxy-
genase-1 (HO-1), thioredoxin (Trx)). This complex array of
interactions is in agreement with the well-known ability of
curcumin to serve not only as an antioxidant but also as
anti-inflammatory and anticarcinogenic molecule.
Reyes-Gordillo et al. [28], in an elegant paper, have shown
that curcumin reduced the CCl4-induced liver toxicity in the
rat; in particular, curcumin reduced the CCl4-related
increase in proinflammatory cytokines and blocked the
nuclear translocation of NFkB [28]. Similarly, curcumin pre-
vented the dinitrochlorobenzene-induced colitis in the rat by
downregulating both NFkB and iNOS [29]. In lung epithelial
cells, curcumin exerted anticarcinogenic activity and pre-
vented the cigarette smoke-induced NFkB activation
through the inhibition of inhibitory kappa B (IkB)akinase
activation, IkBaphosphorylation, and degradation [30]. The
inhibition of the NFkB activation was paralleled bythe sup-
pression of many NFkB-related genes, including cyclin D1,
cyclooxygenase-2, and matrix metalloproteinase-9 (MMP-
9) [30]. Comparable results have been found in a macro-
phage cell line (RAW 264.7) challenged with bacterial endo-
toxin. In these cells, curcumin and its reduced metabolites
blocked the activation of NFkB, and the downstream activa-
tion of iNOS, via inhibition of the IkB kinases 1 and 2, thus
providing further evidence about the importance of the
effects on NFkB in the anti-inflammatory and anticarcino-
genic activity of this phenolic compound [31]. Through
interaction with NFkB, curcumin exerts protective function
also in the regulation of T-cell-mediated immunity. In fact,
overexpression of NFkB in T-cells confers protection against
tumor-induced apoptosis, whereas when NFkB is inhibited,
the cell becomes much more vulnerable and undergoes apop-
tosis [32]. By so doing, NFkB plays an important role in the
regulation of T-cell apoptosis and the related thymic atrophy
which occurs during carcinogenesis. In this experimental
model, curcumin prevented the tumor-induced apoptosis
and the following thymic atrophy by restoring the activity of
NFkB [32].
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V. Calabrese et al. Mol. Nutr. Food Res. 2008, 52, 1062 –1073
Another transcription factor involved in the anticarcino-
genic effect of curcumin is HIF-1. HIF-1 is composed of
two proteins, HIF-1aand the aryl hydrocarbon receptor
nuclear translocator (ARNT) and plays a major role in the
development of hypoxic tumors [33]. Curcumin has been
demonstrated to inactivate HIF-1 in several cell lines and
this effect has been related to its ability to promote ARNT
degradation [33]. As a consequence of HIF-1 inactivation,
several proteins downstream to HIF-1 were downregulated,
such as erythropoietin and the vascular endothelial growth
factor (VEGF) [33].
Particularly interesting is the interaction of curcumin
with the vitagene system. The term vitagenes refers to an
integrated network of protective mechanisms involved in
preserving cellular homeostasis during stress conditions,
which are under control of redox-sensitive genes and
related signaling pathways that result in increased expres-
sion of specific genes, such as those responding to antioxi-
dant compounds [34 –36]. The vitagene family is composed
of the Hsps HO-1, Hsp70 and by the Trx/thioredoxin reduc-
tase (TrxR) system [34–36]. HO-1, also referred to as
Hsp32, degrades heme, which is toxic if produced in excess,
into ferrous iron, carbon monoxide, and biliverdin (BV);
BV is the precursor of bilirubin (BR), a linear tetrapyrrole
which has been shown to effectively counteract oxidative
and nitrosative stress due to its ability to interact with reac-
tive oxygen species (ROS), nitric oxide (NO), and reactive
nitrogen species (RNS) [34, 35, 37–40]. Hsp70 is a func-
tional chaperone and acts by inhibiting key effectors of the
apoptotic machinery [34, 37]. Finally, Trx is responsible for
the reduction of protein disulfide bonds whereas TrxR
serves to maintain Trx in a reduced form [34]. Very
recently, curcumin was shown to have cytoprotective effects
by interacting with all members of the vitagene family. In
particular, curcumin increased the expression of HO-1 in
human cardiac myoblasts, hepatocytes, monocytes, and
endothelial cells [41– 44], rat neurons and astrocytes [45]
as well as porcine endothelial cells [46]. In several rodents
and human cells, the curcumin-induced HO-1 overexpres-
sion was correlated with production of mitochondrial ROS,
activation of transcription factors Nrf2 and NFkB, induc-
tion of mytogen activated protein kinase (MAPK) p38, and
inhibition of phosphatase activity [44, 47, 48]. Moreover,
curcumin upregulated Hsp70 in human colorectal carci-
noma cells, proximal tubule cells [49–52], and rat glioma
cells [53]. Quite different is the effect of curcumin on TrxR,
as it has been shown that curcumin irreversibly inhibits
TrxR activity. As a consequence, there was increased
NADPH oxidase activity, which in turn, produced an abun-
dance of ROS [54]. This latter paradoxical effect may
explain, at least in part, the cancer chemopreventive activity
of curcumin [54].
Having two Michael acceptor functionalities on its mole-
cule (Fig. 1), curcumin and its structural analogues induce
the gene expression of a battery of cytoprotective proteins
in a process known as “the phase 2 response” [55] or the
“electrophile counterattack response” [56]. The designation
“phase 2” historically comes from the fact that many of
these proteins are involved in the second step of the metab-
olism of xenobiotics, e.g., the diverse families of gluta-
thione transferases and UDP-glucuronosyltransferases
[57]. However, the understanding of the common molecular
regulation of the basal and inducible levels of their gene
expression has placed many other proteins, e.g., HO-1 and
c-glutamylcysteine synthetase, in this category of cytopro-
tective proteins [58, 59]. There are three essential cellular
components in the general scheme of induction of the phase
2 response (Fig. 2): (i) the antioxidant response elements
(AREs), (ii) transcription factor Nrf2, and (iii) the sensor
for inducers Kelch-like ECH-associated protein 1 (Keap1).
The AREs represent single or multiple copies of upstream
regulatory sequences present on all genes encoding for
phase 2 cytoprotective proteins [60, 61]. Binding to the
AREs is Nrf2, a 66-kDa transcription factor [62], the princi-
pal transcription factor that determines the levels of expres-
sion of these cytoprotective genes [63]. Nrf2 is a cap ,n'-col-
lar (CNC) transcription factor that has a highly conserved
basic region-leucine zipper (bZIP) domain [64]. In order to
bind to the AREs, Nrf2 has to form a heterodimer first with
a small Maf protein [65]. Binding of the dimeric complex
so formed to the ARE and subsequent recruitment of the
general transcriptional machinery ultimately results in the
activation of transcription of ARE-dependent genes and
correlates with protection against a wide array of electro-
philes and oxidants [66 – 68]. A great body of genetic evi-
dence utilizing nrf2-knockout mice reveled that Nrf2 serves
as a master regulator of the ARE-driven cellular defense
systems against electrophiles and oxidants. Indeed, nrf2-
knockout mice have low and uninducible levels of gluta-
thione and phase 2 proteins compared to otherwise geneti-
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Figure 1. Schematic diagram showing the main molecular tar-
gets of curcumin. Curcumin inhibits pathways that could lead
to neurodegeneration and upregulates cytoprotective (phase
2) enzymes and vitagenes thus counteracting free radical-
induced damage and exerting a neuroprotective role. By mod-
ulating the activation of various transcription factors, curcumin
regulates the expression of inflammatory enzymes, cytokines,
adhesion molecules, and cell survival proteins. Curcumin also
downregulates cyclin D1, COX-2, and MMP-9, and upregu-
lates p21, p27, and p53. Straight arrows, stimulation; dashed
arrows, inhibition.
Mol. Nutr. Food Res. 2008, 52, 1062 – 1073
cally identical wild-type mice and are much more sensitive
to toxic challenges of many different types [66– 68].
The entry of Michael acceptors like curcumin into the
cell is “sensed” by the cysteine-rich sensor protein Keap1
[69], a dimeric cytosolic repressor protein that binds and
targets Nrf2 for ubiquitination and subsequent proteasomal
degradation via association with Cullin 3 to form an E3
ubiquitin– ligase complex [70]. Inducers chemically mod-
ify specific highly reactive cysteine residues of Keap1 [71,
72]. Direct sulfhydryl-addition reaction of the structurally
related to curcumin synthetic bis(2-hydroxybenzylidene)a-
cetone with purified recombinant murine Keap1 has been
observed spectroscopically [71]. Such reaction with the
cysteine sulfhydryls of Keap1 leads to loss of its ability to
repress Nrf2 which then undergoes nuclear translocation
and activates the transcription of ARE-dependent genes
[66– 73]. Murine Keap1 has 25 cysteine residues (its human
homologue has 27) and amino acid replacements of C273
and C288, either individually or in combination, result in
loss of the repressor function of Keap1 and constitutive
expression of ARE-dependent genes [73].
Notably, the gene expression of HO-1, Trx, and TrxR can
be upregulated in a manner dependent on Nrf2 and ARE.
To our knowledge, there are no reports of a similar type of
regulation of the third member of the vitagene family,
Hsp70. However, curcumin as well as several other com-
pounds (e.g., hydrogen peroxide [74], the cyclopentenone
prostaglandin 15-deoxy-D12,14-prostaglandin J2, and the
vicinal dithiol reagent phenylarsine oxide [75, 76]), all of
which can react with sulfhydryl groups, have been reported
to increase the protein levels of Hsp70. Indeed, the tran-
scriptional activation of both Nrf2 and heat shock factor 1
(HSF1), the major activator of Hsp70 gene expression,
depend on cysteine modification, in one case within the
Nrf2 regulator Keap1 [72, 76], and in the other, within
HSF1 [77].
4 Curcumin and neurodegenerative
disorders
Neurodegenerative disorders, such as AD and Parkinson's
disease (PD), belong to the family of the protein conforma-
tional diseases (PCD) and affect a large portion of our aging
population [78]. In general, PCD are conditions that arise
from the dysfunctional aggregation of proteins in non
native conformations. It is known that the b-conformation
in proteins is particularly susceptible to perturbations in the
quality control system and that ROS play an important role
in the development and/or pathogenetic progression of
aging and neurodegenerative diseases [79– 81]. Chaperones
can rescue misfolded proteins by breaking up aggregates
and assisting the refolding process [80, 82]. Proteins that
cannot be rescued by refolding can be delivered to the pro-
teasome by chaperones to be recycled [82, 59]. If the cell is
not able to eliminate misfolded proteins multiple metabolic
derangements resulting in the excessive production of ROS
and RNS occur [83]. The ability of a cell to deal with oxida-
tive and nitrosative stress requires functional chaperones,
antioxidant production, protein degradation, and a cascade
of intracellular events collectively known as unfolded pro-
tein response (UPR), a form of cell stress response [84, 85].
As the cell's quality control system becomes overwhelmed
(see below), conformational changes occur to amyloid pol-
ypeptide intermediates, generating stable oligomers with an
antiparallel crossed b-pleated sheet structure that eventu-
ally accumulate as space-occupying lesions within neurons
[81]. Although it is clear why mutant proteins form amy-
loid, it is hard to rationalize why a wild-type protein adopts
a native conformation in most individuals, but it misfolds in
a minority of others, in what should be a common extracel-
lular environment. This discrepancy suggests that other
events most likely trigger misfolding processes in sporadic
amyloid disease. One possibility is that an abnormal metab-
olite, generated only in some individuals, covalently modi-
fies the protein or peptide and causes it to misfold. Candi-
date metabolites are suggested by the recently recognized
links between AD and atherosclerosis, in which known
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Figure 2. Model for induction of phase 2 cytoprotective genes.
Nrf2 is a transcription factor responsible for the induction of
several genes related to the cellular stress response, including
phase 2 enzymes, such as GST and NAD(P)H:quinone oxidor-
eductase 1 (NQO1); antioxidants, such as glutathione reduc-
tase (GR), glutathione peroxidase (GPx), and catalase; and
vitagenes such as Heme oxygenase-1 (HO-1) and Hsp70. At
basal conditions the cysteine rich sensor metalloprotein
Keap1 binds and targets transcription factor Nrf2 for ubiquiti-
nation and proteasomal degradation via association with the
Cullin 3 (Cul3)-based E3 ubiquitin– ligase complex. Inducers,
by promoting mild oxidative stress (hormesis) react and
chemically modify specific highly reactive cysteine residues of
the sensor Keap1. Consequently, Keap1 loses its ability to
repress transcription factor Nrf2. This leads to increased stabi-
lization of Nrf2, its nuclear translocation, binding to the ARE
(in heterodimeric combinations with members of the small Maf
family of transcription factors), and ultimately transcriptional
activation of phase 2 cytoprotective genes.
V. Calabrese et al. Mol. Nutr. Food Res. 2008, 52, 1062 –1073
chronic inflammatory metabolites, may play a critical
pathogenic role. If this holds true, then new targets are dis-
closed for a prevention strategy brought about through
nutritional antioxidants.
AD is characterized by a subtly impaired cognitive func-
tion or a disturbance of behavior. With time there is a grad-
ual memory loss and disorientation which eventually prog-
ress into dementia. Although, most cases are sporadic, 5–
10% or more are familial [86]. Families that have an autoso-
mal dominant pattern for AD constitute about 13% of early
cases and less than 0.01% of the total number of patients.
Molecular analysis of families with early onset AD has
made it possible to identify mutations in three different
genes that are responsible for the disease: the gene encoding
for the amyloid precursor protein (APP) peptide, and the
presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes. Yet,
these genes are involved in less than 5% of the total number
of cases of AD [86]. Gross examination of the brain in AD
shows a variable degree of cortical atrophy with narrowed
gyri and widened sulci most apparent in the frontal, parietal,
and temporal lobes. Microscopically, the features include
neurofibrillary tangles, neurite (senile) plaques, the central
core of which is amyloid-bpeptide (Ab) derived from the
transmembrane APP, amyloid angiopathy, granulovacuolar
degeneration, and Hirano bodies. Importantly, all of these
changes are present in the brains of nondemented older indi-
viduals but to a much lesser extent [87, 88].
Recent studies have suggested that neuronal death in AD
could arise from dysfunction of the ER. Proteins in the ER
require an efficient system of molecular chaperones whose
role is to assure their proper folding and to prevent accumu-
lation of unfolded proteins. The response of cells to the
accumulation of unfolded proteins in the ER is termed
UPR. UPR is a functional mechanism by which cells
attempt to protect themselves against ER stress, resulting
from the accumulation of the unfolded/misfolded proteins.
Inhibition of protein glycosylation, perturbation of calcium
homeostasis, and reduction of disulfide bonds provoke
accumulation of unfolded protein in the ER, and are called
ER stress. Normal cells respond to ER stress by increasing
transcription of genes encoding ER-resident chaperones
such as GRP78/BiP, to facilitate protein folding or by sup-
pressing the mRNA translation to synthesize proteins.
These systems are termed the UPR. Familial AD-linked
PSEN1 (PS1) mutation downregulates the UPR and leads to
vulnerability to ER stress [89]. Given that AD involves
accumulation of aggregates of two different proteins, the
potential involvement of the UPR and ER dysfunction has
been suggested to lead to cell death. In actively dividing
cells, activation of the UPR is accompanied by decreased
cell cycle protein expression and an arrest in the G1 phase
of the cell cycle [90]. It has been shown that amyloidogenic
proteins can give rise to amyloid fibrils in vitro when a seg-
ment of one of its b-sheets undergoes a conformational
change, exposing an Hsp70 binding site. While normal pro-
teins are rapidly oxidized and subsequently secreted,
mutated proteins remain in the reduced state. Most of these
protein molecules are dislocated out of the ER into the cyto-
sol, where they are ubiquitinylated and degraded by protea-
somes. A parallel pathway for molecules that are not
degraded is condensation into perinuclear aggresomes that
are surrounded by vimentin- or tubulin-containing inter-
mediate filaments and are dependent upon intact microtu-
bules. Inhibition of proteasome activity shifts the balance
toward aggresome formation. Intracellular aggregation is
decreased and targeting to proteasomes improved by over-
expression of the cytosolic chaperone Hsp70. Importantly,
transduction into the cell of an Hsp70 target peptide,
derived from the mutated protein sequence, also reduces
aggresome formation and increases amyloid degradation.
These results demonstrate that amyloidogenic proteins can
aggregate intracellularly despite the common presentation
of extracellular aggregates, and that a similar molecular
surface mediates both in vitro fibril formation and in vivo
aggregation. Furthermore, rationally designed peptides can
be used to suppress this aggregation and may provide a fea-
sible therapeutic approach [91]. Aggresomes are associated
with many neurodegenerative disorders, including AD, PD,
and polyglutamine disorders such as Huntington's disease.
These inclusions commonly contain ubiquitylated proteins.
The stage at which these proteins are ubiquitylated remains
unclear. A malfunction of the ubiquitin–proteasome sys-
tem (UPS) may be associated with their formation. Con-
versely, it may reflect an unsuccessful attempt by the cell to
remove them. The 26S proteasome system is involved in
eliminating ubiquitinated misfolded/unfolded proteins, and
its inhibition results in cellular accumulation of protein
aggregates. Accordingly, proteasome dysfunction in AD
neurons may play a role in the accumulation of misfolded,
potentially cytotoxic proteins and may be induced by
increased intracellular AbetaPP/Abeta. Moreover, a role of
microglia recruited from bone marrow (BM) into the CNS
during the progression of AD has been considered and
emerging evidence suggests that infiltration of BM-derived
monocytic cells into the brain contributes to the develop-
ment of microglial reaction in AD, where APP enhances
BM-derived macrophage-mediated clearance of Abeta
[92].
Several lines of evidence support a fundamental role for
calcium, ROS, and RNS secondary to ER, oxidative and
nitrosative stress, respectively, in the pathogenesis of AD
[34, 87, 93]. In particular, neurofibrillary Abhas been
shown to generate both superoxide anion and a-carbon-cen-
tered radicals; in addition the upregulation of iNOS
increases the formation of NO and RNS [94]. Finally, Ab
increases intracellular calcium levels via both the ER rya-
nodine and inositol 1,4,5-trisphosphate receptors thus
inducing ER stress which culminates with the apoptotic
death of neuronal cells [95, 96]. All these prooxidant path-
ways activated by Abcontribute to the massive destruction
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Mol. Nutr. Food Res. 2008, 52, 1062 – 1073
of brain cells in AD. As mentioned above, antioxidant
enzymes such as HO-1 and TrxR along with the chaperone
Hsp70, are well known intracellular antioxidant systems
which contribute to the “UPR” and guarantee an important
cytoprotective effect against free radical-mediated injury in
AD.
The first evidence of a protective role of curcumin in the
onset of AD derived from epidemiological studies. Ganguli
et al. [97] demonstrated that Indian population, who have a
curcumin-enriched diet, has a reduced prevalence of AD
compared to United States. Following this initial observa-
tion, many basic studies were conducted and the neuropro-
tective role of curcumin was corroborated. In vitro studies
have shown that curcumin protects neuron-like PC12 cells
from b-amyloid toxicity and, interestingly, the polyphenol
displayed a neuroprotective effect greater than a well known
antioxidant such as a-tocopherol [98]. By using an Alz-
heimer transgenic APPSw mouse model (Tg2576), Lim et
al. [99] have shown that dietary curcumin suppressed
inflammation and oxidative damage in the brain of these
mice. More recently, Garcia-Alloza et al. [14] in transgenic
APPswe/PS1dE9 mice demonstrated that curcumin, given
intravenously for 7 days, crosses the blood– brain barrier,
binds to b-amyloid deposits in the brain and accelerates
their rate of clearance. These latter results are in good
agreement with previous findings which demonstrated that
curcumin disaggregates and inhibits b-amyloid aggregation
at submicromolar concentrations in vitro, and more impor-
tantly, reduces amyloid levels and plaque burden in vivo in
Tg2576 mice [100, 101]. Curcumin has an important
impact on ER stress biology, as its apoptosis-induced effect
is associated with its ability to cause ER stress. Removing
two double bonds in curcumin, which was speculated to
form Michael adducts with thiols in secretory proteins,
resulted in a loss of the ability of curcumin to induce apop-
tosis as well as ER stress. Inhibition of caspase-4 activity by
z-LEVD-FMK, blockage of survival molecules such as
CAAT/enhancer binding protein homologous protein
(CHOP) expression by small interfering RNA, and treat-
ment with salubrinal, an ER inhibitor, significantly reduced
curcumin-induced apoptosis [102]. In addition to this,
impairment of UPS has been demonstrated to mediate cur-
cumin proapoptotic effects. Curcumin disrupts UPS func-
tion by directly inhibiting the enzyme activity of the protea-
some's 20S core catalytic component. Like other protea-
some inhibitors, curcumin exposure induces neurite out-
growth and the stress response, as evident from the induc-
tion of various cytosolic and ER chaperones as well as
induction of transcription factor CHOP/GADD153. The
direct inhibition of proteasome activity also causes an
increase in half-life of IkBathat ultimately leads to the
downregulation of NF-kappaB activation. These results
suggest that curcumin-induced proteasomal malfunction
might be linked with both antiproliferative and anti-inflam-
matory activities [103].
PD, whose cardinal features include tremor, slowness of
movement, stiffness, and poor balance, is attributed to a
profound deficit in dopamine that follows the loss of dopa-
minergic neurons in the substantia nigra pars compacta
and dopaminergic nerve terminals in the striatum [34, 104].
Although the mechanisms of PD are still uncertain, a large
amount of experimental evidence implicates oxidative and
nitrosative stress as one of the crucial factors in the patho-
genesis of PD [105, 106]. Considerable insights into the
pathogenesis of PD, indeed, have been achieved by use of
the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri-
dine (MPTP), which is commonly used to induce an experi-
ment model of PD [105, 107]. Excessive free radical forma-
tion or antioxidant deficiency and the resulting oxidative
stress are all mechanisms involved in MPTP neurotoxicity
[108]. Rajeswari [109] has shown that curcumin protects rat
brain from MPTP-induced neurotoxicity by virtue of its
scavenger activity. On the other hand, curcumin has been
shown to protect PC12 cells from MPP+(the active metabo-
lite of MPTP) by inducing the anti-apoptotic protein bcl-2,
preventing the dissipation of mitochondrial membrane
potential and reducing the intracellular iNOS levels [3].
The importance of mitochondria in the neuroprotective
effect of curcumin has been also stressed by Mythri et al.
[110] who demonstrated that curcumin prevents the forma-
tion of peroxynitrite which is responsible for the complex I
damage which is a common feature in PD.
Transient forebrain ischemia is a common cause of
stroke and occurs in people suffering from cardiovascular
diseases [111]. As a consequence of ischemia and the fol-
lowing reperfusion, a cascade of events such as increased
calcium release, the overexpression of cycloxygenase-2
(COX-2) and iNOS both of which are important free-radical
generators and trigger neuronal cell death in selected brain
areas including the hippocampal cornu ammonis 1 (CA1)
[35, 38, 111, 112]. Curcumin exerted a neuroprotective
effect in rats who underwent ischemia/reperfusion injury
and this effect has been related to the direct scavenger effect
of curcumin as well as to a curcumin-induced interference
with the apoptotic machinery, increase in antioxidant mole-
cules (reduced glutathione (GSH)) and enzymes (catalase,
superoxide dismutase) [111, 113, 114].
The mechanism(s) underlying these neuroprotective
effects of curcumin are still debated. Although it is clear
that the free-radical scavenging activity of curcumin plays a
main role in its antioxidant activity, new lines of evidence
propose that curcumin is neuroprotective because of its
ability to induce vitagenes (Figs. 2 and 3). As mentioned
above, curcumin induced HO-1 in rat neurons and astro-
cytes and, consequently the heme-degrading activity of
HO-1 increased [45]. Keeping in mind that through the HO
activity heme is degraded into BV which is then reduced
into BR by biliverdin reductase (BVR) and that BR is a very
efficient scavenger of ROS, NO, and RNS [38, 39, 115–
117], it is possible to conclude that the strong antioxidant
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V. Calabrese et al. Mol. Nutr. Food Res. 2008, 52, 1062 –1073
and anti-inflammatory activities of curcumin could be
mediated by the induction of HO-1.
5 Curcumin and diabetes
Compelling evidence has been provided that both insulin
dependent and noninsulin dependent diabetic patients are
under conditions of oxidative stress and that the complica-
tions of diabetes mellitus could be partially mediated by
oxidative stress [118, 119]. Several mechanisms seem to be
involved in the genesis of oxidative stress in diabetic
patients, including glucose autoxidation, protein glycation,
as well as the formation of advanced-glycation end-prod-
ucts [119, 120].
Recent findings have shown that curcumin can reduce
the degree of systemic oxidative stress as well as retinal
inflammation and diabetic nephropathy in streptozocin-
treated rats, an animal model for diabetes [121 – 123]. The
protective effect of curcumin and THC in diabetes and its
complications seems to be due to the inhibition of proin-
flammatory cytokines (IL-1b) and growth factors (VEGF),
to the blockade of the NFkB signaling and the increasing
activity of chaperone molecules [122, 124]. Remarkably,
the cytoprotective effect of curcumin in diabetic complica-
tions could be related to the interaction of this spice with
the vitagene system. In fact, type 2 diabetic patients with or
without nephropathy have an increased level of both HO-1
and Hsp70 in lymphocytes and this is considered as an
attempt of the immune system to react to oxidative insults
[125]. The possibility that curcumin may further upregulate
HO-1 and Hsp70 in diabetic patients thus contributing to
counteract prooxidant conditions allows to hypothesize a
potential role of curcumin in the prevention of diabetes and
its complications.
6 Curcumin and other oxidative stress-
related conditions
Oxidative stress plays an important role in the pathogenesis
of lung and liver diseases, both of which recognize oxida-
tive stress as a main pathogenetic factor.
The pharmacological therapy of both asthma and chronic
obstructive pulmonary disease (COPD) is based on the
administration of corticosteroids. Unfortunately, in some
cases, these drugs are ineffective and this is often due to the
development of steroid resistance. Histone deacetylase is
involved in the mechanism of action of corticosteroid and
its activity is often reduced in case of steroid insensitivity
[126]. Curcumin has been shown to restore histone deacety-
lase activity and therefore its use can be hypothesized in the
treatment of lung disease unresponsive to corticosteroids
[126]. However, the concomitant administration of curcu-
min with systemic corticosteroids should be discouraged
because curcumin may inhibit cytochrome P450 and UDP-
glucuronosyltransferases (see above), two enzymatic routes
through which corticosteroids are metabolized.
Curcumin reduces both thioacetamide- and endotoxin-
induced liver dysfunction in rodents and this effect is attrib-
uted to the inhibition of the expression of proinflammatory
cytokines (tumor necrosis factor-aand IL-1b), transcription
factors (NFkB), and enzymes (iNOS) [127– 129].
The long term use of some drugs is associated with the
development of organ toxicity often due to increased oxida-
tive stress. Curcumin and THC reduced the kidney toxicity
of chloroquine, gentamicin, and cyclosporin A in the rat [2,
130, 131]. Furthermore, curcumin reduced the indometha-
cin-induced intestinal damage in the rat and the ritonavir-
related vascular dysfunction in porcine coronary arteries
[132, 133]. All these reports agree that the protective effects
of curcumin were due to the well-known ability of this com-
pound to increase both the enzymatic and nonenzymatic
intracellular antioxidant molecules.
Recent evidence highlighted the potential use of curcu-
min in the treatment of cancer [134]. In animal models, cur-
cumin demonstrated an anticancer activity against skin,
colon, lung, and gastrointestinal tumors [134]. Notably, a
phase II clinical trial on patients affected by advanced pan-
creatic cancer and treated with 8 g of curcumin per os for
2 months has shown a biologic activity of this spice in the
therapy of pancreatic cancer [134].
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Figure 3. Curcumin and cellular stress response mediated by
vitagenes. Under conditions of oxidative/nitrosative stress,
there is an increased formation of ROS or RNS. They play a
key role in the pathogenesis of free radical-induced diseases,
such as neurodegenerative disorders. Vitagenes (HO-1 and
Hsp70) contribute to counteract the ROS/RNS-mediated neu-
rotoxic insult, thus initiating a neuroprotective response. In
addition, curcumin by inducing ER stress, disrupting UPS and
downregulating NF-kappaB activation exerts antiproliferative
and anti-inflammatory activities resulting in cytoprotection.
Straight arrows, stimulation; dashed arrows, inhibition.
Mol. Nutr. Food Res. 2008, 52, 1062 – 1073
7 Conclusions and perspectives
As highlighted in this review, the cytoprotective role of cur-
cumin in several experimental systems is well established.
Commercial grade curcumin contains 10– 20% curcumi-
noids, desmethoxycurcumin, and bisdesmethoxycurcumin
and they are as effective as purecurcumin. Based on a num-
ber of clinical studies in carcinogenesis, a daily oral dose of
3.6 g curcumin has been efficacious for colorectal cancer
and advocates its advancement into Phase II clinical stud-
ies. In addition to the anticancer effects, curcumin has been
effective against a variety of disease conditions in both in
vitro and in vivo preclinical studies [135]. Interestingly,
nanodelivery biotechnology, using primarily composed
phospholipids coated with prostate membrane specific anti-
gen specific antibodies, has been developed to enhance tar-
geted delivery of curcumin as an anticancer agent showing
that treatment of human prostate cancer cell lines with lip-
osomal curcumin resulted in at least 70– 80% inhibition of
cellular proliferation at ten-fold lower doses compared to
free curcumin [136].
Although curcumin has been described in Ayurveda, as a
treatment for inflammatory diseases and is referred by
different names in different cultures, extensive research
over the last half century has revealed several important
functions, as it binds to a variety of proteins and inhibits the
activity of various kinases. By modulating the activation of
various transcription factors, curcumin regulates the
expression of inflammatory enzymes, cytokines, adhesion
molecules, and cell survival proteins. Curcumin also down-
regulates cyclin D1, cyclin E, and MDM2; and upregulates
p21, p27, and p53. Various preclinical cell culture and ani-
mal studies suggest that curcumin has potential as an anti-
proliferative, anti-invasive, and anti-angiogenic agent; as a
mediator of chemoresistance and radioresistance; as a che-
mopreventive agent; and as a therapeutic agent in wound
healing, diabetes, AD, PD, cardiovascular disease, pulmo-
nary disease, and arthritis. Pilot phase I clinical trials have
shown curcumin to be safe even when consumed at a daily
dose of 12 g for 3 months. Other clinical trials suggest a
potential therapeutic role for curcumin in diseases such as
familial adenomatous polyposis, inflammatory bowel dis-
ease, ulcerative colitis, colon cancer, pancreatic cancer,
hypercholesteremia, atherosclerosis, pancreatitis, psoriasis,
chronic anterior uveitis, and arthritis. Thus, curcumin is
emerging into the clinic and may prove to be “Curecumin”
[137]. However, the potential use of dietary or supplemental
curcumin in the treatment of human pathologies remains to
be refined. Some concern derive from the pharmacokinetics
of curcumin and in particular its poor bioavailability and
metabolic fate [8, 138]. Also, no conclusive data are avail-
able regarding the concentrations of curcumin in the nerv-
ous system as well as the molecular targets of nanomolar
concentrations of curcumin, which are most likely the con-
centrations attained in vivo after regular dietary intake. In
this regard, the possible effects on vitagenes [34, 139] and
related signal transduction pathways which ultimately can
provide cytoprotective and chemopreventive effects open
new targeted strategies for its clinical use. Once better phar-
macodynamics will be achieved then the inhibitory effects
on cytochrome P450 enzymes, GST and UDP-glucurono-
syltransferases elicited by curcumin should be taken into
consideration because many drugs are metabolised by these
enzymes in the liver and gastrointestinal tract and therefore
their inhibition could increase the plasma concentrations
potentiating toxic effects. Keeping all this in mind, it is pos-
sible to conclude that clinical research on curcumin and its
potential use in human diseases needs to be expanded and
therapeutic use of curcumin in several human oxidant stress
pathologies has to be considered a promising strategy.
The authors have declared no conflict of interest.
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