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ANTIOXIDANT AND ANTI-INFLAMMATORY

PROPERTIES OF CURCUMIN

Venugopal P. Menon and Adluri Ram Sudheer

Abstract: Curcumin, a yellow pigment from Curcuma longa, is a major com-

ponent of turmeric and is commonly used as a spice and food-coloring agent. It
is also used as a cosmetic and in some medical preparations. The desirable pre-
ventive or putative therapeutic properties of curcumin have also been considered
to be associated with its antioxidant and anti-inflammatory properties. Because
free-radical-mediated peroxidation of membrane lipids and oxidative damage of
DNA and proteins are believed to be associated with a variety of chronic pathologi-
cal complications such as cancer, atherosclerosis, and neurodegenerative diseases,
curcumin is thought to play a vital role against these pathological conditions. The
anti-inflammatory effect of curcumin is most likely mediated through its ability to
inhibit cyclooxygenase-2 (COX-2), lipoxygenase (LOX), and inducible nitric ox-
ide synthase (iNOS). COX-2, LOX, and iNOS are important enzymes that mediate
inflammatory processes. Improper upregulation of COX-2 and/or iNOS has been
associated with the pathophysiology of certain types of human cancer as well as
inflammatory disorders. Because inflammation is closely linked to tumor promo-
tion, curcumin with its potent anti-inflammatory property is anticipated to exert
chemopreventive effects on carcinogenesis. Hence, the past few decades have wit-
nessed intense research devoted to the antioxidant and anti-inflammatory properties
of curcumin. In this review, we describe both antioxidant and anti-inflammatory
properties of curcumin, the mode of action of curcumin, and its therapeutic usage
against different pathological conditions.

1. CURCUMIN: THE SPICE OF LIFE–UNLOCKING THE

SECRETS OF CURCUMIN

–“Imagine if the key to disease prevention was as close as your kitchen shelf. It’s not
the product of someone’s imagination, but the product of years of medical research.
Scientists are beginning to take notice of a well-known spice as a potent new pre-
ventive therapy against disease, especially cancer—John C. Martin, LE Magazine,
September 2001”

More than one billion people consume curcumin regularly in their diets. Cur-
cumin has long been used in Eastern medicine and is gaining attention in Western
medicine, not only as a nonsteroidal anti-inflammatory drug (NSAID) but also

105
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106 MENON AND SUDHEER

for its chemopreventive properties. Essentially, curcumin is believed to possess

generalized protective properties.
Curcumin, a yellow pigment from Curcuma longa, is a major component of
turmeric and is commonly used as a spice and food-coloring material. It exhibits
anti-inflammatory,1 antitumor, and antioxidant2 properties. Curcumin is a low-
molecular-weight polyphenol, first chemically characterized in 1910, with the
molecular formula of C21 H20 O6 . It is generally regarded as the most active con-
stituent of and comprises 2–8% of most turmeric preparations. It has long been
used as the yellow spice in Indian food and as a naturally occurring medicine for
the treatment of inflammatory diseases.3
The desirable preventive or putative therapeutic properties of curcumin have
also been considered to be associated with its antioxidant property.4 Because free
radical-mediated peroxidation of membrane lipids and oxidative damage of DNA
and proteins are believed to be associated with a variety of chronic pathologi-
cal complications such as cancer, atherosclerosis, neurodegenerative diseases, and
aging,5 curcumin is thought to play a vital role against oxidative-stress-mediated
pathological conditions. Hence, the past few decades have witnessed intense re-
search devoted to the antioxidant activity of curcumin. Before pointing out the
potential antioxidant property of curcumin, it is worthwhile to outline the role of
free radicals and antioxidants in health and disease.

2. ROLE OF FREE RADICALS IN HEALTH AND DISEASE

It has been nearly 50 years since Denham Harman6 suggested that free radicals
produced during aerobic respiration cause cumulative oxygen damage, resulting
in aging and death.
Oxygen is an essential molecule for all aerobic forms; however, oxygen plays
univalent roles. Although oxygen is indispensable for all cells for chemical energy
production (ATP), it is also often transformed into highly reactive forms: reactive
oxygen species (ROS), which are often very toxic to the cells.7,8 Approximately
2% of the oxygen reduced by the mitochondria then forms superoxide (O−. 2 ) or
the dismutation product H2 O2 . Superoxide and peroxide reacts with metal ions
(Heiber-Weiss and Fenton’s reactions) to promote additional radical generation,
particularly with the generation of hydroxyl radicals. The hydroxyl radical reacts
with all components of the cell, including lipid membrane, DNA and proteins.9
Nitric oxide (NO) has an unpaired electron and is therefore a free-radical species.
It is a short-lived, lipophilic molecule generated from l-arginine by NO synthase
(NOS). NO is involved physiologically in vasorelaxation, neurotransmission, inhi-
bition of platelet aggregation, immune defense, and intracellular signaling. How-
ever, NO reacts with O−. −
2 to form peroxynitrite (ONOO ), which is a powerful
oxidant. NO bioactivity is related to the production of many reactive intermedi-
ates, but many of these reactive nitrogen species (RNS) are capable of damaging
DNA or hindering DNA repair.10 It is now beyond doubt that oxidants are generated
in vivo and can cause significant damage to cells.
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ANTIOXIDANT AND ANTI-INFLAMMATORY PROPERTIES 107

When an imbalance occurs between oxidants and defense systems, in favor of

oxidants, oxidative stress occurs. This oxidative stress in cells results in severe
metabolic dysfunctions, including loss of cell integrity, enzyme function, genomic
stability, and so forth, which ultimately lead to pathogenesis of many human dis-
eases (e.g., inflammation, ischemia, atherosclerosis, arthritis, cancer, Parkinson’s
disease, Alzheimer’s disease, and so forth).

3. ANTIOXIDANTS: WHY ARE THEY NEEDED?

To deal with the threat of oxidant-induced damage, biological antioxidants were

evolved. Cells are equipped with an impressive repertoire of antioxidant enzymes,
as well as small antioxidant molecules, the later being mostly ingested from fruits
and vegetables. The antioxidant defenses include the following:
1. Superoxide dismutase (SOD), which hastens the dismutation of O.− 2 to H2 O2 ,
catalase, and glutathione peroxidase (GPx), which converts H2 O2 to water
2. Hydrophilic radical scavengers such as ascorbate, urate, and glutathione (GSH)
3. Lipophilic radical scavengers such as tocopherols, flavonoids, carotenoids, and
ubiquinol
4. Enzymes involved in the reduction of oxidized form of small-molecule antiox-
idants (GSH reductase and ascorbate reductase) or responsible for the mainte-
nance of protein thiols (thioredoxin reductase)
Antioxidant systems are complex and act in concert to decrease ROS load. It also
helps to divert ROS to other reaction pathways that form less reactive products, to
selectively inactivate (in redox terms) transition metal ions, and, when all of these
fails, to provide sacrificial molecules that act as a replicable or recyclable “buffer”
to absorb oxidative hits and excess energy.11
Human antioxidant defenses are effective, but they are not infallible and oxida-
tive damage to key biological sites occurs, accumulates with age, and contributes
to senescence and age-related disease. This means that oxidative stress, which is
an oxidant:antioxidant imbalance in favor of oxidation, remains a real and constant
threat.
The evolution of our endogenous antioxidant system has not progressed beyond
the breakeven point of cost-effectiveness. This has led to the attention of dietary
antioxidants. Wood and Brooks12 suggested that “we are what we ate,” and al-
though many geographical and environmental factors undoubtedly determined the
evolutionary development of our species, our future health as individuals might
well depend on what we eat today.

4. CURCUMIN: ANTIOXIDANT MECHANISM

The antioxidant mechanisms of curcumin have recently been the focus of interest
of free-radical chemists and biologists.
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108 MENON AND SUDHEER

O OH

H CO OCH
3 3

HO OH

Figure 1. Curcumin.

Curcumin is known to protect biomembranes against peroxidative damage.

Peroxidation of lipids is known to be a free-radical-mediated chain reaction, lead-
ing to the damage of the cell membranes, and the inhibition of peroxidation by cur-
cumin is mainly attributed to the scavenging of the reactive free radicals involved
in the peroxidation. Most of the antioxidants have either a phenolic functional
group or a -diketone group. Curcumin is an unique antioxidant, which contains a
variety of functional groups, including the B-diketo group, carbon–carbon double
bonds, and phenyl rings containing varying amounts of hydroxyl and methoxy
substituents (Figure 1).13
The central argument is whether the phenolic or the central methylenic hydrogen
in the heptadienone moiety is responsible for its antioxidant activity. Jovanovic and
collaborators14 concluded that curcumin is a superb H-atom donor by donating the
H-atom from the central methylenic group rather than from the phenolic group in
acidic and neutral aqueous and acetonitrile solutions. On the other hand, Barclay
et al.15 proposed that curcumin is a classical phenolic chain-breaking antioxidant,
donating H-atoms from the phenolic group. Priyadarsini et al.16 have also claimed
that the phenolic group is essential for the free-radical-scavenging activity and that
the presence of the methoxy group further increased the activity.
Theoretical calculations by the density functional theory (DFT) demonstrated
that the enol form of curcumin is significantly more stable than the diketo form and
that the bond dissociation enthalpy (BDE) of the phenolic O:H bond is significantly
lower than the BDE of the central O:H bond, suggesting that the hydrogen atom
abstraction takes place in the phenolic group.13,16,17 It was also pointed out that
the relative contribution of the phenolic group and the central methylenic group on
the antioxidant activity depends on the activity of attacking radical and the reac-
tion medium.13,18 Litwinienko and Ingold19 recently compared the rate constants
of the reaction of 1,1-Diphenyl-2-picrylhydrazyl (DPPH) radical with curcumin
in ionizing solvents and nonionizing solvents and resolved the curcumin antiox-
idant controversy by the mechanism of sequential proton loss electron transfer
(SPLET); that is, in solvents that support ionization, curcumin reacts with elec-
trophilic radicals initially at ionized keto-enol moiety and the resulting neutral
radicals lose a phenolic photon, thus yielding the same phenoxyl radical, as would
have been formed by H-atom transfer (HAT) from the phenolic hydroxyl group of
the curcumin anion to the radicals. However, in nonionizing solvent, the SPLET
mechanism cannot occur and the reactions involve only HAT from a phenolic
hydroxyl group of the neutral curcumin to the radical.19
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ANTIOXIDANT AND ANTI-INFLAMMATORY PROPERTIES 109

Another important mechanism is that curcumin can degrade into trans-6-(4’-

hydroxy-3’-methoxyphenyl)-2,4-dioxo-5-hexanal, ferulic acid, ferruloylmethane,
and vanillin at basic pH within 30 min.3 Among these, ferrulic acid and vannilin
are well-established antioxidants.

5. ANTI-INFLAMMATORY PROPERTY OF CURCUMIN

Curcumin was found to have a miraculous power in anti-inflammatory response.

The natural anti-inflammatory activity of curcumin is on a par with steroidal drugs
and nonsteroidal drugs as indomethacin and phenylbutazone, which have danger-
ous side effects. Its anti-inflammatory property appears to be mediated through the
inhibition of induction of COX-2, LOX, iNOS and production of cytokines such
as interferon- and tumor necrosis factor, and activation of transcription factors
like NF-κB, and AP-1.

5.1. Effect of Curcumin on Cyclooxygenases and Lipoxygenases

The anti-inflammatory properties of curcumin have been attributed, at least in part,
to suppression of prostaglandins (PGs) synthesis.20 The involvement of PGs and
other eicosanoids in the development of human cancer has been known for over two
decades. Importantly, an increase in PG synthesis might influence tumor growth
in human beings and experimental animals, and numerous studies have illustrated
the effect of PG synthesis on carcinogen metabolism, tumor cell proliferation, and
metastatic potential.21 Cyclooxygenase (COX) is a key enzyme responsible for the
conversion of arachidonic acid to PGs. It consists of two different isoforms, desig-
nated COX-1 and COX-2. COX-1 is a constitutive isoform present in most tissues
and is generally regarded as a “housekeeping” enzyme22 and its inhibition results
in serious effects such as peptic ulceration or impairment of renal blood flow. In
contrast, COX-2 is constitutively expressed only in brain and spinal cord tissue and
it can also be induced in a wide variety of normal tissues by the hormones of ovula-
tion and pregnancy, cytokines, growth factors, oncogenes, and tumor promoters.23
COX-2 overexpression has been implicated in the carcinogenesis of tumors of
the colon, rectum, breast, head and neck, lung, pancreas, stomach, and prostate.24
There is growing evidence that inhibitors of COX-2 activity are useful for treating
inflammation and preventing or treating cancer.25 Therefore, agents that interfere
with the signaling mechanisms governing the transcription of COX-2 should also
inhibit inflammation and tumorigenesis. Further investigations suggest that arachi-
donic acid (AA) metabolites derived from lipoxygenase (LOX) pathways play an
important role in growth-related signal transduction, implying that intervention
through these pathways should be useful for arresting cancer progression.
An expanding body of evidence suggests that curcumin inhibits the expression
of COX-2. Kawamori et al.26 have demonstrated that dietary curcumin significantly
inhibits phospholipase A2 in colonic mucosa and tumors, leading to the release of
arachidonic acid from phospholipids, alters COX and LOX activities, and modifies
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110 MENON AND SUDHEER

PGE2 levels. Unlike selective COX-2 inhibitors, which inhibit the catalytic activity
of the COX enzyme, curcumin decreases COX-2 expression at the transcriptional
level.27 Several lines of evidence also indicate that the mechanism of action of
curcumin is not limited to PG inhibition. They have also observed that dietary
curcumin inhibits LOX activity and the production of the LOX metabolites in the
colonic mucosa and in tumors. LOX metabolites have also been shown to promote
tumor cell adhesion, stimulate the spreading of tumor cells, and augment metastatic
potential.28
In one study, Zhang and colleagues27 from the Cornell University campus in
New York City, exposed gastrointestinal cells to two known tumor promoters: bile
acids (BA) and phorbol esters (PMA). The team found COX-2 to be induced in
several of the cell lines, accompanied by a 10-fold increase in the synthesis of
inflammatory-causing PGE2 . However, dose-dependent treatment of the cells with
curcumin suppressed both BA- and PMA-mediated induction of COX-2 protein,
genetic COX-2 expression (as measured by mRNA), and the synthesis of PGE2 .
Most impressive, however, was the discovery that curcumin directly inhibited the
enzymatic activity of COX-2.
An additional study presented at the 1999 American Association for Cancer
Research (AACR) conference also examined the pain-relieving properties of cur-
cumin. Researchers at the University of California, San Diego and the Veterans
Administration Medical Center, San Diego29 investigated whether curcumin could
suppress COX-2 expression in human colon cancer cells. After exposing such cells
to curcumin, the researchers found the compound not only inhibited cell growth
but also reduced the expression of COX-2 mRNA in a time- and dose-dependent
manner.
Therefore, curcumin would appear to be a safe, natural COX-2 inhibitor in
humans, given its safety profiles and demonstrated anti-inflammatory activity.

5.2. Effect of Curcumin on Inducible Nitric Oxide Synthase

Another enzyme that plays a pivotal role in mediating inflammation is inducible ni-
tric oxide synthase (iNOS). iNOS catalyzes the oxidative deamination of l-arginine
to produce NO, a potent pro-inflammatory mediator. NO has multifaceted roles in
mutagenesis and carcinogenesis.30 In addition to acting as an initiator of carcino-
genesis, NO is involved in the promotional stage of tumorigenesis or neoplastic
transformation. NO is also known to affect tumor progression by regulating the an-
giogenesis, possibly by stimulating the production of vascular endothelial growth
factor (VEGF).31 NO reacts rapidly with superoxide anion to produce the extremely
powerful oxidant peroxynitrite (ONOO− ).32 Peroxynitrite can cause various DNA
modifications and other types of cellular injury, contributing to genotoxicity or
initiation of multistage carcinogenesis. One of the secondary processes that might
follow DNA damage by NO or peroxynitrite includes activation of the tumor
suppressor gene p53 or the DNA repair enzyme poly(ADP-ribose)polymerase
(PARP).33 It is known that activation of p53 or PARP is often associated with apop-
totic cell death. There are numerous reports on the NO- or peroxynitrite-induced
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ANTIOXIDANT AND ANTI-INFLAMMATORY PROPERTIES 111

apoptosis.34 Increased expression of iNOS and/or its catalytic activity has been
observed in several human tumor tissues and also in chemically induced animal
tumors as well as in inflammatory disorders.35−37 Human breast tumor biopsies in
higher grades exhibited elevated levels of iNOS, compared with those in lower-
grade ones.38 Thus, aberrant or excessive expression of iNOS, as in the case of
COX-2, is considered to be implicated in the pathogenesis of cancer, and com-
pounds that can selectively inhibit abnormal expression of iNOS can act as a po-
tential candidate for chemoprevention. iNOS has been shown to be involved in the
regulation of COX-2 and, hence, the subsequent production of pro-inflammatory
PGs.39
In addition to COX-2, iNOS also appears to be a target for the anti-inflammatory
effect of curcumin. Curcumin is reported to inhibit the NO production and expres-
sion of iNOS protein and mRNA in RAW 264.7 cells stimulated with lipopolysac-
charides (LPSs) or interferon-γ.40 Downregulation of the iNOS gene by curcumin
in RAW 264.7 cells might be attributed to suppression of c-Jun/AP-1 activation,
because it is a known fact that the consensus AP-1-binding sequence is present in
the promoter region of the iNOS gene and it can be attenuated by curcumin.40 Chan
et al.41 have reported that curcumin can inhibit the iNOS gene expression in isolated
BALB/c mouse peritoneal macrophages and in the livers of LPS-injected mice.

5.3. Effect of Curcumin on Nuclear Factor-κB

One of the most ubiquitous eukaryotic transcription factors that regulate expres-
sion of genes involved in controlling cellular proliferation/growth, inflammatory
responses, cell adhesion, and so forth is nuclear factor-κB (NF-κB).42,43 The func-
tionally active NF-κB exists mainly as a heterodimer consisting of subunits of
the Rel family (e.g., Rel A or p65, p50, p52, c-Rel, v-Rel, and Rel B), which
is normally sequestered in an inactive cytoplasmic complex by binding to an
inhibitory protein, IκB. Exposure of cells to such external stimuli as mitogens,
inflammatory cytokines, ultraviolet radiation, ionizing radiation, viral proteins,
bacterial LPSs, and ROS causes rapid phosphorylation of IκB with subsequent
degradation by proteosomes. Dissociation of IκB from NF-κB allows the acti-
vated free dimer to translocate to the nucleus, where it induces, through binding
the cis-acting κB element, the transcription of a large variety of target genes
that normally encode cytokines, cell adhesion molecules, growth factors, and so
forth. The transcriptional activity of NF-κB is regulated via an elaborate series of
intracellular signal transduction events in response to external stimuli.30 In addi-
tion to its central roles in mediating inflammation, NF-κB is important in control
via cell proliferation, oncogenesis, and cell transformation.44 Thus, aberrant con-
stitutive activation of NF-κB/Rel has been observed in an array of human and
experimentally induced tumors and transformed cells in culture. There is increas-
ing evidence that constitutive activation of this transcription factor is associated
with the proliferation and survival of certain tumor cells and causes resistance to
apoptosis.45
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112 MENON AND SUDHEER

The data from experimental studies have demonstrated that curcumin inhibits the
activation of NF-κB in different cancer cell lines.46 It has been found that oxidative
stress activates NF-κB DNA-binding activity. Because curcumin has been known
as an antioxidant, its inhibitory effects on oxidative stress might be mediated
through the suppression of NF-κB DNA-binding activity. It has been reported that
curcumin inhibited IKB kinase (IKK), suppressed both constitutive and inducible
NF-κB activation and potentiated tumor necrosis factor (TNF)-induced apoptosis.
Curcumin treatment reduced the amount of phosphorylated IKK, which ultimately
prevents the translocation of NF-κB to the nucleus. Curcumin also showed strong
antioxidant and anticancer properties through regulating the expression of genes
that require the activation of activator protein (AP1) and NF-κB.47

5.4. Effect of Curcumin on Tumor Necrosis Factor

Tumor necrosis factor (TNF) has been shown to mediate tumor initiation,
promotion, and metastasis.48 Moore et al.49 have reported that TNF-deficient
mice have been shown to be resistant to skin carcinogenesis. The induction of
pro-inflammatory genes by TNF has been linked to most diseases. The pro-
inflammatory effects of TNF are primarily due to its ability to activate NF-κB.
Almost all cell types, when exposed to TNF, activate NF-κB, leading to the ex-
pression of inflammatory genes. These include COX-2, LOX-2, cell adhesion
molecules, inflammatory cytokines, chemokines, and iNOS. TNF has been found
to be a growth factor for most tumor cells.50
Because of the critical role of TNF in mediating tumorigenesis, agents that
can suppress TNF activity have the potential for therapy of TNF-linked dis-
eases. Curcumin was found to have a spellbound effect in the suppression of
TNF production.51 The constitutive activation of NF-κB in mantle cell lymphoma
(MCL) cells is due to autocrine expression of TNF. TNF mRNA is constitutively
expressed in the MCL cell lines; curcumin inhibits the expression of both TNF
mRNA and TNF protein in MCL cell lines.51 Suppression of TNF by curcumin led
to inhibition of NF-κB and cell proliferation, as was the case when TNF secretion
was neutralized using anti-TNF antibody.51
Thus, curcumin exerts a protective role against inflammatory diseases through
the suppression of COX, LOX, iNOS, NF-κB, TNF and some other inflammatory
mediators.

6. THERAPEUTIC USE OF CURCUMIN

6.1. Cancer
Curcumin has proved its credentials as a wonderful chemopreventive agent against
a variety of cancers. Oxidative stress induced by ROS has been linked to tu-
mor promotion in mouse skin and other tissues.52−54 Hydrogen peroxide pro-
motes the transformation of chemically initiated mouse epidermal cells.52 When
different types of tumor promoter were applied topically to mouse skin, there
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ANTIOXIDANT AND ANTI-INFLAMMATORY PROPERTIES 113

was a distinct increase in the production of hydrogen peroxide in the epidermis,

which correlated with their promoting potential.55 Superoxide anion radicals were
also formed in keratinocytes stimulated with the tumor promoter such as 12-O-
tetradecanoylphorbol-13-acetate (TPA).56 Further support for the association be-
tween pro-oxidant status and tumor promotion derives from the observation that
many structurally unrelated antioxidants and radical scavengers exert antipromo-
tional activity.52,53 Exogenous superoxide dismutase (SOD) inhibited the promo-
tion by TPA of JB6 mouse epidermal cell transformation, providing additional
evidence for a critical role of ROS in tumor promotion.57 Similarly, the lipophilic
biomimetic SOD cupric 3,5-diidopropylsalicylic acid inhibited tumor promotion
in mouse epidermis.58 Ornithine decarboxylase (ODC), a rate-limiting enzyme
in polyamine biosynthesis, has been utilized as a biochemical marker for tumor
promotion. ODC induction was found to be suppressed by SOD and catalase in
murine mammary tumor cells and by butylated hydroxytoluene in mouse epider-
mal cells, suggesting the intermediacy of Reactive oxygen intermediates (ROIs)
in the tumor promotion.52
Persistent, local inflammation has been considered to contribute to multistage
carcinogenesis. ROS produced during the inflammatory tissue damage can trigger
a series of reactions responsible for malignant transformation, particularly in the
stage of promotion.52 . There is accumulating evidence that ROS influence the
intracellular signaling cascades mediating cell proliferation. Activity or expression
of several protein kinases have been shown to be regulated by the pro-oxidant state
of cells. ROS are typical by-products of eicosanoid metabolism.59 ROS are released
from the cells of the inflammatory skin infiltrate. A correlation exists between the
ability of a compound to induce PG release in vitro and its ability to promote
papilloma formation in mouse skin in vivo. Verma et al.60 suggests that PGs play a
crucial role in the induction of ODC activity and mouse skin tumor promotion by
TPA. Both ROI generation by inflammatory cells and skin tumor promotion are
efficiently inhibited by protease inhibitors, indicating an interrelationship between
the two processes.54
Chemopreventive properties of curcumin have been extensively investigated
and well documented.61,62 One of the most plausible mechanisms underlying the
chemopreventive effects of curcumin involves suppression of tumor promotion.
Thus, topical application of curcumin strongly inhibited TPA-induced inflam-
mation, hyperplasia, proliferation, ODC activity, ODC mRNA expression, gen-
eration of ROIs, oxidized DNA base modification, and papilloma formation in
mouse skin.62−63 Curcumin inhibited COX-2 and LOX activities in TPA-treated
mouse epidermis.20 Treatment of several human gastrointestinal cell lines with
curcumin suppressed expression of COX-2 protein and mRNA, PGE2 production,
and AP-1 DNA binding induced by TPA or chenodeoxycholate.27 Suppression of
TPA-induced activation of c-Jun/AP-1 in cultured NIH3T3 cells has been proposed
to be responsible for the antitumor-promoting activity that curcumin retains.64
In conclusion, the anticancer potential of curcumin stems from its ability to
suppress proliferation of a wide variety of tumor cells, downregulate transcription
factors NF-κB, AP-1, and Egr-1, downregulate the expression of COX-2, LOX,
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114 MENON AND SUDHEER

iNOS, MMP-9, uPA, TNF, chemokines, cell surface adhesion molecules, and cy-
clin D1, downregulate growth factor receptors (such as EGFR and HER2), and
inhibit the activity of c-Jun N-terminal kinase, protein tyrosine kinases, and pro-
tein serine/threonine kinases. It also influences the free-radical production during
the activation of carcinogen and helps in detoxification of carcinogens.

6.2. Atherosclerosis
The most common form of heart disease is atherosclerosis. Atherosclerosis in-
volves the deposition of fatty substances, cholesterol, complex carbohydrates and
fibrin (a clotting material in the blood), and so forth in the inner lining of the
major artery. The deposition that results (referred to as plaque) can partially or
totally block the flow of blood through the artery. This can lead to the forma-
tion of a blood clot (thrombus) on the surface of the plaque. If either of these
events occurs and blocks the coronary artery, a heart attack might result. Some
controllable mechanisms that are involved in the development of atherosclerosis
are oxidation of low-density lipoprotein-cholesterol (LDL-C), abnormal platelet
aggregation, and inflammation.65,66 Curcumin has gained importance because of
its antioxidant and antiplatelet aggregating qualities. Curcumin’s ability to control
platelet aggregation appears directly to be related to thromboxane inhibition (a
promoter of aggregation) and an increase in prostacyclin activity, an inhibitor of
aggregation.67,68 Curcumin, being a powerful antioxidant, quenches free radicals,
thereby decreasing the cellular damage. It also helps in reducing blood lipid levels,
particularly cholesterol. Rats fed 0.1% curcumin, along with a cholesterol diet, had
about one-half of the blood cholesterol as rats fed equal amounts of cholesterol
but without curcumin.66
Curcumin, with its potent anti-inflammatory activity, reduces the inflammation,
promotes fibrinolysis, and inhibits the leukotriene formation,69,70 which are im-
portant steps in the prevention of atherosclerosis.

6.3. Aging
A number of theories have been proposed to explain the nature of aging and one
such is the free-radical theory.71 According to the free-radical theory of aging,
these very reactive species, produced continuously during normal metabolism,
eventually accumulates, damaging DNA and other macromolecules. This is due to
progressive defects in the defense systems against reactions that generate free rad-
icals. The result is the appearance of degenerative lesions and cellular death. Then
the organism ages and, finally dies. Different observations support the hypothesis
of the major role of free radicals in aging. The potential life span of a species is
determined genetically. However, it can be altered by environmental conditions
such as diet. Harman72,73 has demonstrated, for example, that life expectation of
many species is increased by 20% by adding antioxidants to the diet. It has also
been shown that animals, which live longer or with longer life spans, present higher
SOD levels.74 Curcumin might have been delaying the aging of human beings with
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ANTIOXIDANT AND ANTI-INFLAMMATORY PROPERTIES 115

its effective antioxidant property, as it is known that billions of people consume

curcumin daily in their diets.

6.4. Neurodegenerative disease

Oxidative stress has been implicated in mechanisms leading to neuronal cell in-
jury in various pathological states of the brain. Alzheimer’s disease (AD) is a
progressive disorder with cognitive and memory decline, speech loss, personality
changes, and synapse loss.75 Many approaches have been undertaken to understand
AD, but the heterogeneity of the etiologic factors makes it difficult to define the
clinically most important factor determining the onset and progression of the dis-
ease. However, increasing evidence indicates that factors such as oxidative stress
and disturbed protein metabolism and their interaction in a vicious cycle are central
to AD pathogenesis.
Increasing interest has been focused on identifying dietary compounds that can
inhibit, retard, or reverse the multistage pathophysiological events underlying AD
pathology. AD, in fact, involves a chronic inflammatory response associated with
both brain injury and β-amyloid associated pathology. All of the above evidence
suggests that stimulation of various repair pathways by mild stress has significant
effects on delaying the onset of various age-associated alterations in cells, tissues,
and organisms.
Curcumin has emerged as a strong inducer of the heat shock response. In light of
this finding, curcumin supplementation has recently been considered an alternative,
nutritional approach to reduce oxidative damage and amyloid pathology associated
with AD.
The potential neuroprotective action of curcumin was discovered during a
screening of its potential to protect against the adverse effects from high doses
of alcohol, which revealed positive results. Since then, studies have indicated po-
tential benefits for AD and Parkinson’s disease, based on laboratory animal models;
clinical work is now beginning. In addition, studies in animal models of AD in-
dicate a direct effect of curcumin in decreasing the amyloid pathology of AD. As
the widespread use of curcumin as a food additive and relatively small short-term
studies in humans suggest safety, curcumin is a promising agent in the treatment
and/or prevention of AD. Just as in AD, inflammation and oxidative damage play
a strong role in the neurodegenerative process of Hodgkin’s disease (HD): Oxida-
tive damage helps to degrade nerve cells in the basal ganglia and cerebral cortex
and chronic inflammation in the brains of people with HD is believed to play a
significant role in the progression of the disease. As shown previously, curcumin
was able to reduce inflammation and oxidative damage in mouse models of AD.76

6.5. Liver Fibrosis

Liver fibrosis and cirrhosis result from the majority of chronic liver insults and
represent a common and difficult clinical challenge of worldwide importance.
At present, the only curative treatment for end-stage cirrhosis is transplantation.
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116 MENON AND SUDHEER

Hence, there is a considerable imperative to develop antifibrotic strategies that are

applicable to liver fibrosis. Development of liver fibrosis entails major alterations
in both the quantity and quality of the extracellular matrix (ECM).77,78 The re-
modeling of ECM both in normal and pathological conditions is controlled by a
group of enzymes called matrix metalloproteinases (MMPs).79
Curcumin has been extensively investigated for its hepatoprotective potential.
Normally, oxidative stress and inflammation play an important role in the develop-
ment of alcohol and heated polyunsaturated fatty acids (PUFAs) and CCL4 -induced
liver fibrosis.80 Curcumin, due to its effective antioxidant and anti-inflammatory
properties, inhibits liver fibrosis.81 Curcumin is also reported to influence the
hepatic expression patterns of MMPs.82 Thus, curcumin emerged as an potent
antifibrotic compound.

6.6. Diabetes
Environmental factors play an important role in the etiology and management of
diabetes, and antioxidants in food and medicinal plants are potential modulators
of diabetes onset, progression, and complications. Among the naturally occurring
compounds, curcumin has received the most attention as an antidiabetic compound.
Oxidative stress as a consequence of hyperglycemia and changes in energy
metabolism and inflammatory mediators play an important role in the pathophys-
iology of diabetes in association with depleted cellular antioxidant defense sys-
tems and enhanced production of ROS.82 Oxidative stress associated with hyper-
glycemia impairs cellular function and alters vascular and neural function. High
glucose concentrations promote free-radical production via the following three
biochemical pathways: advanced glycation end products (AGEs),83 protein ki-
nase C activation,84 and aldose reductase pathway.85 Another important factor
that increases ROS is TNF86 ; it forms a possible connection between obesity and
diabetes87 and has been linked to insulin resistance88 and diabetic complications.
Curcumin generally improves oxidative status, protects and enhances endoge-
nous defenses, and directly mediates various mechanics of pathology. Many stud-
ies have shown that curcumin prevents AGE-induced complications in rats.89
Curcumin might act by sparing or enhancing the function of the endogenous
antioxidants.90 Antioxidant activities of curcumin might occur synergistically with
glucose-lowering activity.90 The antidiabetic action of curcumin seems to be me-
diated through (1) stimulation of the pancreas to produce and secrete insulin, (2)
interference with dietary glucose absorption, (3) insulin-sparing action of the con-
stituent bioactive compounds, and (4) antioxidant and anti-inflammataory proper-
ties of curcumin.

6.7. AIDS
More recently, curcumin has been shown to inhibit HIV replication,91 and currently
it is in clinical trials. Mazumder et al.92 have shown that curcumin inhibits p24
antigen production and Tat-mediated transcription. They also shown that curcumin
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inhibits purified HIV-l integrase, suggesting that the anti-HIV activity of curcumin
could be due to several mechanisms. Energy minimization studies suggest that the
anti-integrase activity of curcumin could be due to an intramolecular stacking of
two phenyl rings that brings the hydroxyl groups into close proximity (antioxidant
property). The present data suggest that HIV-l integrase inhibition might contribute
to the antiviral activity of curcumin. These observations suggest new strategies for
antiviral drug development that could be based on curcumin as a lead compound
for the development of inhibitors of HIV-l integrase.92

6.8. Autoimmune Disease

The immune system has evolved to discriminate self from nonself antigens, thereby
protecting the host from microbial pathogens and malignant tumors.93 Neverthe-
less, a breakdown in this fundamental immunoregulatory process often results
in the development of chronic infectious diseases, malignant tumors, and organ-
specific autoimmune diseases. Recent studies have used nutraceuticals (human
diets of plant origin, containing many hundreds of biologically active compounds
called nutraceuticals) to successfully target organ-specific autoimmune diseases.94
The pathogenesis of autoimmune diseases involves complex immune mechanisms
in which the pro-inflammatory cytokines contribute to manifestation of the dis-
eases.
The anti-inflammatory action of curcumin is associated with its ability to in-
hibit reactive-oxygen-generating enzymes such as COX, LOX, xanthine dehydro-
genase, and iNOS.95 The involvement of interleukin (IL)-12 in the pathogenesis
of rheumatoid arthritis and myocarditis has been well established, and inhibition
of IL-12 has decreased the clinical symptoms of these autoimmune diseases.96
In view of the central role played by IL-12 in Th1 differentiation, the IL-12/Th1
axis has become a novel molecular target in the treatment of Th1 cell-mediated
autoimmune diseases.
Many studies suggest that nutraceuticals ameliorate autoimmune diseases by
blocking Th1 cell-mediated inflammation and/or by promoting the progenitor cell
growth and differentiation in the repair process.

6.9. Psoriasis
Curcumin, by its immune-modulating, anti-inflammatory, and antioxidant proper-
ties, shows a favorable effect on a mouse model of psoriasis.97 Heng et al.98 showed
that topical treatment with curcumin results in resolution of the psoriatic activity as
assessed by clinical, histological, and immunological criteria in patients. Accord-
ing to them, this antipsoriatic effect is linked to a curcumin-caused modulation of
phosphorylase-kinase (Phk) activity that integrates multiple calcium/calmodulin-
dependent signaling pathways. These pathways are coupled to glycogenolysis and
ATP-dependent phosphorylation, thus ensuring the required energy supply for cell
proliferation and migration.
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118 MENON AND SUDHEER

The effectiveness of curcumin is shown by the fact that the raised Phk activity
found in untreated psoriasis, that was decreased by the vitamin D3 analogue (and
indirect inhibitor of Phk) calcipotriol, was even more decreased to near-normal
values by the curcumin treatment.
Previous reports suggest additional mechanisms for the antipsoriatic effects
of the antioxidants from C. longa.99,100 Thus, in vitro exposure of human ker-
atinocytes of the HaCaT line to a hydroalcoholic extract of the rhizome of this
plant was as effective for inhibition of the ultraviolet-induced secretion of IL-6
and IL-8 as medium supplementation with betamethasone-17-valerate. This ob-
served downregulation of pro-inflammatory cytokines supports the view that the
curcumin might exert a favorable effect on psoriasis-linked inflammation.
Curcumin, by its effective antioxidant and anti-inflammatory properties, was
evaluated as a remarkable antipsoriatic compound.

6.10. Drug/Environmental Carcinogen-Induced Toxicity

The two most commonly abused substances in the general population are alcohol
and nicotine.
Alcohol is considered to be an important recreational beverage, which is non-
toxic at lower concentrations, but it is toxic at higher concentrations. Alcohol-
related problems are one of the world’s major public health concerns. Alcoholism
is seen in all races, ethnic groups, and socioeconomic strata. Oxidative stress plays
an important role in the development of alcohol-induced tissue injury.101 Antioxi-
dant compounds are important in treating this condition. Curcumin received much
attention as a hepatoprotective agent. It is well established that curcumin pro-
tects experimental rats from chronic alcohol toxicity by its effective antioxidant
property.102
Nicotine, a major toxic component of cigarette smoke, plays an important role
in the development of cardiovascular disease and lung cancer in smokers.103 Nico-
tine damages the system through the production of free radicals and inflammatory
mediators.104 Curcumin was found to offer significant protection to the experi-
mental rats from nicotine-induced toxicity.105
Benzo(a)pyrene [B(a)P] is a classical environmental carcinogen present in
cigarette smoke and generally regarded to be involved in the development of lung
cancer. Curcumin is reported to inhibit the B(a)P-induced DNA mutations and
thus protects the host organism from the development of lung cancer.106

7. CONCLUSION

Curcumin, with its impressive antioxidant and anti-inflammatory properties, was

found to be a genuine natural product in treating a wide array of diseases. Its antiox-
idant property is believed to be due to the presence of different functional groups,
including methoxy, phenoxy, and carbon–carbon double bonds in its structure. Its
remarkable anti-inflammatory property kept it in the limelight over the decades
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ANTIOXIDANT AND ANTI-INFLAMMATORY PROPERTIES 119

in treating inflammatory-mediated diseases including cancer, atherosclerosis, dia-

betes, rheumatoid arthritis, and so forth. Its anti-inflammatory property appears to
be mediated through the inhibition of induction of COX-2, LOX, and iNOS and
the production of cytokines such as interferon-γ, tumor necrosis factor, and many
other transcription factors such as NF-κB.

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