December 22, 200616:34
CURCUMIN: THE INDIAN SOLID GOLD
Bharat B. Aggarwal, Chitra Sundaram, Nikita Malani,
and Haruyo Ichikawa
Abstract: Turmeric, derived from the plant Curcuma longa, is a gold-colored
spice commonly used in the Indian subcontinent, not only for health care but
also for the preservation of food and as a yellow dye for textiles. Curcumin,
which gives the yellow color to turmeric, was first isolated almost two centuries
ago, and its structure as diferuloylmethane was determined in 1910. Since the
time of Ayurveda (1900 bc) numerous therapeutic activities have been assigned
to turmeric for a wide variety of diseases and conditions, including those of
the skin, pulmonary, and gastrointestinal systems, aches, pains, wounds, sprains,
and liver disorders. Extensive research within the last half century has proven
that most of these activities, once associated with turmeric, are due to cur-
cumin. Curcumin has been shown to exhibit antioxidant, anti-inflammatory, an-
tiviral, antibacterial, antifungal, and anticancer activities and thus has a poten-
tial against various malignant diseases, diabetes, allergies, arthritis, Alzheimer’s
disease, and other chronic illnesses. These effects are mediated through the reg-
ulation of various transcription factors, growth factors, inflammatory cytokines,
protein kinases, and other enzymes. Curcumin exhibits activities similar to re-
cently discovered tumor necrosis factor blockers (e.g., HUMIRA, REMICADE,
human epidermal growth factor receptor blockers (e.g., ERBITUX, ERLOTINIB,
and GEFTINIB), and a HER2 blocker (e.g., HERCEPTIN). Considering the
recent scientific bandwagon that multitargeted therapy is better than monotar-
geted therapy for most diseases, curcumin can be considered an ideal “Spice for
The questions of whether medicines discovered today are safer, more efficacious,
and more affordable than generic medicines (whose patents have expired) or
medicines that are centuries old could be answered “no” for most of the mod-
ern medicines. If so, then it is logical to revisit and revive these age-old medicines
for the welfare of mankind. Curcumin is one such medicine. Its history goes
back over 5000 years, to the heyday of Ayurveda (which means the science of
long life). Turmeric derived from the rhizome of the plant Curcuma longa has
December 22, 2006 16:34
2 AGGARWAL ET AL.
been used by the people of the Indian subcontinent for centuries with no known
side effects, not only as a component of food but also to treat a wide variety of
Turmeric is a spice of golden color that is used in cooking in the Indian sub-
continent. Because of its color and taste, turmeric was named “Indian saffron”
in Europe. Today, India is the primary exporter of turmeric (known as haldi in
India). Although its ability to preserve food through its antioxidant mechanism,
to give color to food, and to add taste to the food is well known, its health-
promoting effects are less well recognized or appreciated. It was once considered
a cure for jaundice, an appetite suppressant, and a digestive. In Indian and Chinese
medicines, turmeric was used as an anti-inflammatory agents to treat gas, colic,
toothaches, chest pains, and menstrual difficulties. This spice was also used to
help with stomach and liver problems, to heal wounds and lighten scars, and as a
Turmeric was mentioned in the writings of Marco Polo concerning his 1280
journey to China and India and it was first introduced to Europe in the 13th
century by Arab traders. Although Vasco de Gama (a Portugeese sailor) dur-
ing 15th century, after his visit to India, truly introduced spices to the West, it
was during the rule of British in India that turmeric was combined with vari-
ous other spices and renamed “curry powder,” as it is called in the West. What
is there in turmeric that has therapeutic potential, how does this substance me-
diates its effects, with what types of receptor does it interact, and for what
type of diseases is it effective? All of these questions will be addressed in this
2. COMPOSITION OF TURMERIC
Turmeric contains a wide variety of phytochemicals, including curcumin,
demethoxycurcumin, bisdemethoxycurcumin, zingiberene, curcumenol, curcu-
mol, eugenol, tetrahydrocurcumin, triethylcurcumin, turmerin, turmerones, and
turmeronols.1Curcumin, demethoxycurcumin, and bisdemethoxycurcumin have
Curcuma xanthorrhiza,4Curcuma aromatica,5Cucruma phaeocaulis,5Etlingera
elatior,6and Zingiber cassumunar7(Figure 1; see Table 1). Curcumin is the phy-
tochemical that gives a yellow color to turmeric and is now recognized as being
is curcumin. Curcumin was first isolated from turmeric in 1815, and the structure
of curcumin contain approximately 77% diferuloylmethane, 18% demethoxycur-
cumin, and 5% bisdemethoxycurcumin. Curcumin is hydrophobic in nature and
frequently soluble in dimethylsulfoxide, acetone, ethanol, and oils. It has an ab-
sorption maxima around 420 nm. When exposed to acidic conditions, the color
of turmeric/curcumin turns from yellow to deep red, the form in which it is used
routinely for various religious ceremonies.
December 22, 2006 16:34
CURCUMIN: THE INDIAN SOLID GOLD3
(White turmeric, Zedoary root)
(Haldi, Turmeric, Ukon, Woolgum, Kunyit, Oendre,
Rame, Temu kuning, Temu kunyit, Goeratji, Kakoenji,
Koenjet, Kondin, Tius, Kunir, Gianghuang)
(Wild turmeric, Vanarishta,
Jangali Haldi, Aranyaharidra)
(Temu Lawak, Ubat Jamu,
(Cane Reed, Crepe ginger,
Wild ginger, Keokand)
(Torch ginger, eka,
opuhi, pua vao)
(Ezhu, Zedoary rhizome,
Figure 1. Sources of curcuminoids. (See also Plate 1 in the Color Plate Section.)
3. CURCUMIN ANALOGUES
As indicated earlier, turmeric contains three different analogues of curcumin (i.e.,
diferuloylmethane, also called curcumin, demethoxycurcumin, and bisdemothy-
curcumin (Figure 2). Whether all three analogues exhibit equal activity is not
clear. Although in most systems curcumin was found to be most potent,8,9in some
systems bisdemethoxycurcumin was found to exhibit higher activity.3,10There
are also suggestions that the mixture of all three is more potent than either one
When administered orally, curcumin is metabolized into curcumin glucuronide
and curcumin sulfonate.13However, when administered systemically or intraperi-
toneally, it is metabolized into tetrahydrocurcumin, hexhyrdrocurcumin, and hex-
hydrocurcuminol. Tetrahydrocurcumin has been shown to be active in some
systems14–18and not in others.13,19Whether other metabolites of curcumin ex-
hibit biological activity is not known.
4. USES OF CURCUMIN
The use of turmeric for health purposes is nothing new. As a folklore medicine, its
December 22, 2006 16:34
4 AGGARWAL ET AL.
Table 1. List of various species of curcuma.
Note: Curcuma is indicated by C.
∗Curcuminoids have been isolated from the plant indicated in bold.
Source: Modified from http://en.wikipedia.org/wiki/Curcuma.
include antiseptic, analgesic, anti-inflammatory, antioxidant, antimalarial, insect-
repellant, and other activities associated to turmeric.4,20–27(Figure 3). Perhaps
one of the most often prescribed uses is for wound-healing.28This activity is well
known to people from the Indian subcontinent. Modern research has provided
considerable evidence, and the mechanism by which turmeric/curcumin could
accelerate wound-healing has been described.29–36
It is now well recognized that most chronic diseases are the result of dis-
regulated inflammation,37,38Turmeric has been traditionally described as an
anti-inflammatory agent. Recent scientific evidence has indeed demonstrated that
turmeric, and curcumin in particular, exhibits potent anti-inflammatory activities
as determined by a wide variety of systems.39–49Therefore, it is not too surprising
that turmeric displays activities against a variety of diseases. Because curcumin
also exhibits potent antioxidant activity, whether the anti-inflammatory activity
of curcumin is mediated through its antioxidant mechanism is not clear. Since
December 22, 2006 16:34
CURCUMIN: THE INDIAN SOLID GOLD5
Figure 2. Chemical structures of curcumin and its analogues.
most well-characterized antioxidants do not exhibit antinflammatory activity, it is
unlikely that the anti-inflammatory activity of curcumin is due to its antioxidant
5. MOLECULAR TARGETS OF TURMERIC/CURCUMIN
Most molecular targets established in modern biology were discovered within
the last three decades. The effect of curcumin on most of these targets has
December 22, 200616:34
6AGGARWAL ET AL.
Figure 3. Traditional uses of curcmin. (See also Plate 2 in the Color Plate Section.)
been examined10,12,45,50–201(Figure 4). The results have revealed that curcumin
can modulate several different transcription factors,50–96,113,114cytokines,45,97–112
growth factors,202–215kinases,115–128and other enzymes.91,129–159Although most
diseases are caused by dysregulated inflammation, to find a safe and efficacious
anti-inflammatory agent is a real challenge in modern medicine. Steroids are per-
haps the best known anti-inflammatory agents. However, there are numerous side
flamatory drugs (NSAIDs) have been discovered within the last century, and these
include salicylates, ibuprofen, sulindac, phenylbutazone, naproxen, diclofenac,
indomethacin, and coxibs.216Experience over the years has indicated that most
of these NSAIDs are associated with a constellation of side effects. Perhaps the
best example is the cardiovascular system-related side effects recently identified
with most coxibs.217–219Although the intake of such anti-inflammatory agents
can be justified for chronic conditions, they are not appropriate as chemopreven-
tive agents under normal conditions, because that purpose requires long periods
of time. Thus, there is a great need for safer and efficacious anti-inflammatory
agent (see Figure 5). First, curcumin suppresses the activation of the transcrip-
tion factor NF–?B, which regulates the expression of pro-inflammatory gene
products.50–81Second, curcumin downregulates the expression of COX-2, an
December 22, 2006 16:34
CURCUMIN: THE INDIAN SOLID GOLD7
Figure 4. Molecular targets of curcumin. Abbreviations used: NF-?B, nuclear factor-?B;
AP-1, activating protein-1; STAT, signal transducers and activators of transcription; Nrf-
2, nuclear factor erythroid 2-related factor; Egr-1, early growth response gene-1; PPAR?,
peroxisome preoliferator-activated receptor-?; CBP, CREB-binding protein; EpRE, elec-
trophile response element; CTGF, connective tissue growth factor; EGF, epidermal growth
factor; EGFRK, EGF receptor-kinase; FGF, fibroblast growth factor; HGF, hepatocyte
growth factor; NGF, nerve growth factor; PDGF, platelet-derived growth factor; TGF-?1,
ceptor; Arh-R, aryl hydrocarbon receptor; DR-5, death receptor-5; EGF-R, EGF-receptor;
EPC-R, endothelial protein C-receptor; ER-?, estrogen receptor-?; Fas-R, Fas receptor;
H2-R, histamine (2)-receptor; InsP3-R, inositol 1,4,5-triphosphate receptor; IR, integrin
receptor; IL-8-R, interleukin-8-receptor; LDL-R, low-density lipoprotein-receptor; MMP,
ligase; NAT, arylamine N-acetyltransferases; IAP, inhibitory apoptosis protein; HSP-70,
heat shock protein 70; MDR, multidrug resistance; TNF-?, tumor necrosis factor-?; IL,
interleukin; MCP, monocyte chemoattractant protein; MIF, migration inhibition protein;
MIP, macrophage inflammatory protein; cAK, autophosphorylation-activated protein ki-
nase; CDPK, Ca2+-dependent protein kinase; cPK, protamine kinase; ERK, extracellular
receptor kinase; FAK, focal adhesion kinase; IARK, IL-1 receptor-associated kinase; JAK,
phosphorylase kinase; PKA, protein kinase A; PKB, protein kinase B; PKC, protein kinase
C; pp60c-src, c-Src; TK, protein tyrosine kinase; FPTase, farnesyl protein transferase;
GST, gluthathione-S-transferase; HO, hemeoxygenase; ICAM-1, intracellular adhesion
molecule-1; VCAM-1, vascular cell adhesion molecule-1; ELAM-1, endothelial leukocyte
adhesion molecule-1; Bcl-2, B-cell lymphoma protein 2; SHP-2, Src homology 2 domain-
containing tyrosine phosphatase 2, uPA, urokinase-type plasminogen activator, DFF40;
DNA fragmentation factor, 40-kd subunit. (See also Plate 3 in the Color Plate Section.)
December 22, 200616:34
8AGGARWAL ET AL.
Hyaline membrane disease
Lewy body disease
Figure 5. Potential uses of curcumin based on modern technology. (See also Plate 4 in the
Color Plate Section.)
enzyme linked with most types of inflammations.75,177–181,183Third, curcumin
inhibits the expression of another pro-inflammatory enzyme: 5-LOX.177,182–184
Additionally, curcumin has been shown to bind to the active site of 5-LOX and
inhibit its activity183Fourth, curcumin downregulates the expression of various
cell surface adhesion molecules that have been linked with inflammation.220–222
Fifth, curcumin downregulates the expression of various inflammatory cytokines,
including TNF, IL-1, IL-6, IL-8, and chemokines.45,97–112Sixth, curcumin has
been shown to inhibit the action of TNF, one of the most pro-inflammatory of the
to its anti-inflammatory action.16,19,31,159,223–279All of this recent evidence con-
firms the anti-inflammatory action of curcumin, known for thousands of years. Its
pharmacological safety combined with its anti-inflammatory action, makes it an
ideal agent to explore for preventive and therapeutic situations.
Whereas pro-oxidants are considerd mediators of numerous diseases, antioxi-
dants are generally believed to delay or halt the disease. However, this paradigm
is not always valid, as most cytokines mediate their effects through pro-oxidant
mechanisms. Reactive oxygen species (ROS) also play an important role in cell-
mediated cytotoxicity (CMC) of the immune system. Numerous reports indicate
that curcumin could mediate both pro-oxidant and antioxidant roles. First, cur-
cumin could induce the expression of ROS,8,280–282which plays an important
role in the antiproliferative effects of this molecule.283Second, curcumin binds
December 22, 200616:34
CURCUMIN: THE INDIAN SOLID GOLD9
PPARγ γ γ γ
NF-κ κ κ κB
β β β β-catenin
β β β β-catenin
γ γ γ γ-Radiation
Agents & antioxidants
⇑ ⇑ ⇑ ⇑
⇓ ⇓ ⇓ ⇓
⇓ ⇓ ⇓ ⇓
⇓ ⇓ ⇓ ⇓
⇓ ⇓ ⇓ ⇓
⇓ ⇓ ⇓ ⇓
⇓ ⇓ ⇓ ⇓
⇓ ⇓ ⇓ ⇓
⇓ ⇓ ⇓ ⇓
⇓ ⇓ ⇓ ⇓
⇓ ⇓ ⇓ ⇓
⇓ ⇓ ⇓ ⇓
⇓ ⇓ ⇓ ⇓
⇓ ⇓ ⇓ ⇓
⇑ ⇑ ⇑ ⇑
⇓ ⇓ ⇓ ⇓
⇓ ⇓ ⇓ ⇓
⇓ ⇓ ⇓ ⇓
⇑ ⇑ ⇑ ⇑
⇑ ⇑ ⇑ ⇑
⇑ ⇑ ⇑ ⇑
⇑ ⇑ ⇑ ⇑
⇑ ⇑ ⇑ ⇑
⇓ ⇓ ⇓ ⇓
⇓ ⇓ ⇓ ⇓
⇓ ⇓ ⇓ ⇓
⇓ ⇓ ⇓ ⇓
⇓ ⇓ ⇓ ⇓
PDGF PDGF-β β β β-R
HIF-1 ⇓ ⇓ ⇓ ⇓
⇓ ⇓ ⇓ ⇓
⇓ ⇓ ⇓ ⇓
Figure 6. Signaling pathway modulated by curcumin. Intermediates upregulated by cur-
cumin are indicated as ⇑ and those downregulated by curcumin are indicated as ⇓.
curcumin kills tumor cells through this mechanism. Third, curcumin suppresses
creases the expression of intracellular glutathione.139,140,142,143,146,290–294Fifth,
curcumin could also play an antioxidant role through its ability to bind iron.229All
of these reports combined suggest the ability of curcumin to modulate the redox
factors and cytokines has also been demonstrated (Figure 6). First, curcumin has
been shown to downregulate the effect of epidermal growth factor (EGF) through
downregulation of expression and activity of EGF receptors (EGFR).203,210–212
Second, curcumin has been shown to downregulate the activity of human EGFR-
2 (called HER2/neu),127a growth factor receptor closely linked with cancer of
the breast, lung, kidney, and prostate. Third, curcumin suppresses the action of
interleukin (IL)-6 through the downregulation of STAT3 activation.296Fourth,
curcumin modulates the action of TNF, a growth factor for tumor cells.297Fifth,
curcumin negatively regulates the action of IL-2,298a growth factor for T cells.
Thus, curcumin can affect the action of a wide variety of growth factors.202–215
December 22, 2006 16:34
10AGGARWAL ET AL.
Angiogenesis is a process of vascularization of the tissue, which is critical
for the growth of solid tumors. Numerous molecules have been linked with an-
giogenesis. These include vascular endothelial growth factor (VEGF), COX-2,
fibroblast growth factor (FGF), and TNF. Evidence suggests that curcumin could
suppress angiogenesis.113,205,208,299–303Curcumin includes its ability to down-
regulate the expression of VEGF.208Likewise, it downregulates FGF-mediated
angiogenesis.205Curcumin was found to negatively regulate the expression of
COX-2.74,177–181and suppresses both the expression and action of TNF.97–100
6. CURCUMIN RECEPTORS
Receptors are cellular proteins to which a molecule binds, leading to secondary
cellular responses. Whether there are any authentic receptors for curcumin is not
known. However, numerous molecules to which curcumin binds have been identi-
fied. These include serum albumin,304,305,3065-LOX,183,307xanthine oxidase,159
tein kinase,115pp60c-src tyrosine kinase,115Ca2+-dependent protein kinase
(CDPK),116Ca2+-ATPase of sarcoplasmic reticulum,131aryl hydrocarbon
receptor,186rat river cytochrome p450s,291Topo II isomerase,312inositol 1,4,5-
triphosphate receptor,313and glutathione.143
7. DISEASE TARGETS OF CURCUMIN
Extensive research within the last half a decade has revealed that curcumin
has potential against a wide variety of diseases, both malignant and nonma-
lignant (see Figure 5). The potential of curcumin, however, has not been sys-
tematically examined through the modern multicenter, randomized, double-
blind, placebo-controlled clinical trial.314–335Its potential in humans is indi-
cated either through preclinical studies, some pilot studies in humans, anec-
dotal studies in patients, or epidemiological studies. Curcumin has been
shown to exhibit activity against numerous inflammatory diseases, includ-
ing pancreatitis,100,214,261,336,337arthritis,105,338–341inflammatory bowel disease
through the downregulation of inflammatory markers, as indicated earlier. The
effect of curcumin against various autoimmune diseases has also been demon-
strated; they include scleroderma,351psoriasis,352multiple sclerosis,111,353and
diabetes.354–362Again, these effects of curcumin are through the regulation of
Although once thought to be distinct, the molecular targets for both the
prevention and therapy of cancer are now considered the same,363,364. Nu-
merous lines of evidence suggest the potential of curcumin against various
types of cancer11,56,76,83,95,145,153,155,273,283,298,309,365–462(see Table 2). First,
December 22, 2006 16:34
CURCUMIN: THE INDIAN SOLID GOLD 11
Table 2. Chemopreventive and anticancer effects of curcumin.
External cancerous lesion405
Human basal cell carcinoma469
Human epidermal carcinoma415
Prevention from azoxymethanol407
Prevention from benz[a]pyrene and
Prevention from 12-O-tetradecanoylphorbol-
Prevention from 4-nitroquinoline 1-oxide417
Prevention from benzo[a]pyrene406,422,423
Prevention from Min/+ mouse
(a model of familial adenomatous
Colon adeno carcinoma95,435–440
Prevention from azoxymethane427–433
Prevention from 1,2-dimethylhydrazine
Prevention from 7,12-
Prevention from diethylstilbestrol444
Prevention from radiation365,455
Prevention from diethylnitrosamine366,367,369
Prevention from N-nitrosodiethylamine and
Prevention from 3,2’-dimethyl-4-aminobiphenol
(DMAB) and 2-amino-1-
Blood and Bone Marrow
B-cell non-Hodgkin’s lymphoma385,386
Human multiple myeloma83,309,388
Primary effusion lymphoma389
Ehrlich’s ascites carcinoma456,480
Gastric signet ring carcinoma400
Head and Neck
Head and neck squamous cell carcinoma76,200,401
curcumin has been shown to suppress the proliferation of a wide variety
of tumor cells through the downregulation of antiapoptotic gene prod-
ucts, activation of caspases, and induction of tumor suppressor genes such
December 22, 2006 16:34
12 AGGARWAL ET AL.
Second, curcumin has also been to shown to suppress the invasion of tumors
adhesion molecules134,208,220,301,302,340,346,500–507Third, curcumin suppresses the
angiogenesis of tumors through the suppression of angiogeneic cytokines.508–512
Fourth, the anti-inflammatory effects of curcumin contribute to its antitumor
activity as well.39–49
Curcumin has also been shown to play a role in diabetes mellitus type II,
in which the patient develops a resistance to insulin.354,356,359–361,513Both NF–
?B and TNF have been linked with the induction of resistance to insulin. Be-
cause curcumin can downregulate the activation of NF–?B and downregulate
TNF expression and TNF signaling,97–100it can be exploited in diabetic patients.
Several animal studies have demonstrated that curcumin can overcome insulin
has also been demonstrated.202,516–524The effects of curcumin in cardiovascular
diseases are linked to its ability to (1) inhibit platelet aggregation,215,525–529(2)
(4) inhibit fibrinogen synthesis,539and (5) inhibit oxidation of LDL.288,531,540–542
curcumin can suppress amyloid-induced inflammation, curcumin has also been
linked to the suppression of Alzheimer’s disease.150,297,327,543–554
The above description and various other chapters in this volume prove that cur-
cumin has enormous potential for a variety of diseases. There are, however, still
several unanswered questions. First, phase I clinical trials have indicated that
as high as 12 g of curcumin per day for over 3 months is well tolerated in
humans.334What the optimum dose of curcumin is for the treatment of a given
disease is not clear. Serum levels of curcumin tend to be low,334which might
be responsible for its pharmacological safety, These data have led to the no-
tion that curcumin has low bioavailability. Second, the tissue concentration of
curcumin and how it compares to what is seen in cell culture conditions are
not known. There are studies, however, that suggest that agents such as piper-
ine (a component of black pepper) can enhance the bioavailability of curcumin
through suppression of its glucuronidation occurring primarily in the liver and in
the intestine.317Third, whether there are components of turmeric other than cur-
cumin that have beneficial effects either alone or in combination with curcumin
needs to be determined. For instance, numerous activities have been assigned to
turmeric oil.307,555–559Fourth, what effect do other spices have on the pharmacol-
of curcumin that are more bioavailable and efficacious are needed. However, this
December 22, 2006 16:34
CURCUMIN: THE INDIAN SOLID GOLD 13
might compromise the safety of curcumin. Sixth, well-controlled large clinical
trials are required to determine the potential of curcumin both in the prevention
and therapy of a disease. All of these studies should further add to the usefulness
of curcumin. Overall, the biological safety, combined with its cost and efficacy,
and thousands of years of experimentation justify calling curcumin “Indian Solid
This research was supported by The Clayton Foundation for Research (to BBA)
and by a P50 Head and Neck SPORE grant from the National Institutes of Health
(to BBA). We would like to thank Walter Pagel for a careful review of the
EGF, epidermal growth factor; EGFR, EGF receptor; NF-?B, nuclear factor-?B;
TNF, tumor necrosis factor; H2O2; AP-1, activating protein-1; JNK, c-jun N-
terminal kinase; MMP, matrix metalloprotease; COX-2, cyclooxygenase 2; iNOS,
inducible nitric oxide synthase; PBMC; VSMC; HDL, high-density lipoprotein;
TBARS; LDL, low-density lipoprotein; VLDL; ASA; PGI2; AA; GSH; MDA;
SOD; LDH; ISO; NAG; TGF-?1, transforming growth factor beta 1; IL, inter-
leukin; MS; CNS; EAE; STAT, signal transducers and activators of transcription;
HIV; LTR; LMW proteins, low molecular weight proteins; NSAIDs, nonsteroidal
anti-inflammatory drugs; APP, amyloid precursor; 4-HNE; GST, gluthathione-S–
transferase; ADR; LDH; BLM; BAL; ACE; and PQ.
1. I. Chattopadhyay, K. Biswas, U. Bandyopadhyay, and R. K. Banerjee, Turmeric
and curcumin: Biological actions and medicinal applications. Curr Sci 87, 44–50
2. F. Abas, N. H. Lajis, K. Shaari, D. A. Israf, J. Stanslas, U. K. Yusuf, and S. M. Raof,
A labdane diterpene glucoside from the rhizomes of Curcuma mangga. J Nat Prod
68, 1090–1093 (2005).
3. W. J. Syu, C. C. Shen, M. J. Don, J. C. Ou, G. H. Lee, and C. M. Sun, Cytotoxicity
of curcuminoids and some novel compounds from Curcuma zedoaria. J Nat Prod 61,
4. J. A. Duke, CRC Handbook of Medicinal Spices, 137–144 (2002). CRC Press.
5. C. Tohda, N. Nakayama, F. Hatanaka, and K. Komatsu, Comparison of anti-
December 22, 2006 16:34
14 AGGARWAL ET AL.
Med 3, 255–260 (2006).
6. H. Mohamad, N. H. Lajis, F. Abas, A. M. Ali, M. A. Sukari, H. Kikuzaki, and N.
Nakatani, Antioxidative constituents of Etlingera elatior. J Nat Prod 68, 285–288
7. T. Dechatowongse, Isolation of constituents from the rhizome of plai (Zingiber cas-
sumunar Rpxb.). Bull Dept Med Sci 18, 75 (1976).
8. H. Ahsan, N. Parveen, N. U. Khan, and S. M. Hadi, Pro-oxidant, anti-oxidant and
cleavage activities on DNA of curcumin and its derivatives demethoxycurcumin and
bisdemethoxycurcumin. Chem Biol Interact 121, 161–175 (1999).
9. N. Sreejayan and M. N. Rao, Free radical scavenging activity of curcuminoids.
Arzneimittelforschung 46, 169–171 (1996).
10. R. Thapliyal and G. B. Maru, Inhibition of cytochrome P450 isozymes by curcumins
in vitro and in vivo. Food Chem Toxicol 39, 541–547 (2001).
11. M. T. Huang, Y. R. Lou, J. G. Xie, W. Ma, Y. P. Lu, P. Yen, B. T. Zhu, H. Newmark,
and C. T. Ho, Effect of dietary curcumin and dibenzoylmethane on formation of 7,12-
dimethylbenz[a]anthracene-induced mammary tumors and lymphomas/leukemias in
Sencar mice. Carcinogenesis 19, 1697–1700 (1998).
12. Sreejayan and M. N. Rao, Nitric oxide scavenging by curcuminoids. J Pharm Phar-
macol 49, 105–107 (1997).
13. C. Ireson, S. Orr, D. J. Jones, R. Verschoyle, C. K. Lim, J. L. Luo, L. Howells, S.
Plummer, R. Jukes, M. Williams, W. P. Steward, and A. Gescher, Characterization
of metabolites of the chemopreventive agent curcumin in human and rat hepatocytes
and in the rat in vivo, and evaluation of their ability to inhibit phorbol ester-induced
prostaglandin E2 production. Cancer Res 61, 1058–1064 (2001).
15. S. M. Khopde, K. I. Priyadarsini, S. N. Guha, J. G. Satav, P. Venkatesan, and M.
N. Rao, Inhibition of radiation-induced lipid peroxidation by tetrahydrocurcumin:
possible mechanisms by pulse radiolysis. Biosci Biotechnol Biochem 64, 503–509
16. K. Okada, C. Wangpoengtrakul, T. Tanaka, S. Toyokuni, K. Uchida, and T. Osawa,
Curcumin and especially tetrahydrocurcumin ameliorate oxidative stress-induced re-
nal injury in mice. J Nutr 131, 2090–2095 (2001).
17. L. Pari and P. Murugan, Protective role of tetrahydrocurcumin against erythromycin
estolate-induced hepatotoxicity. Pharmacol Res 49, 481–486 (2004).
18. L. Pari and D. R. Amali, Protective role of tetrahydrocurcumin (THC) an active prin-
ciple of turmeric on chloroquine induced hepatotoxicity in rats. J Pharm Pharm Sci
8, 115–123 (2005).
species generation in leukocytes in vitro and in vivo. Jpn J Cancer Res 89, 361–370
20. K. R. Chaudhri, Turmeric, haldi or haridra, in eye diseases., Antiseptic. 1950 Jan;
December 22, 2006 16:34
CURCUMIN: THE INDIAN SOLID GOLD 15
22. C. Niederau and E. Gopfert, [The effect of chelidonium- and turmeric root extract on
upper abdominal pain due to functional disorders of the biliary system. Results from
a placebo-controlled double-blind study]. Med Klin (Munich) 94, 425–430 (1999).
23. C. Li, L. Li, J. Luo, and N. Huang, [Effect of turmeric volatile oil on the respiratory
tract]. Zhongguo Zhong Yao Za Zhi 23, 624–625, inside back cover (1998).
24. Curcuma longa (turmeric). Monograph. Altern Med Rev 6(Suppl), S62–S66 (2001).
25. A. Tawatsin, S. D. Wratten, R. R. Scott, U. Thavara, and Y. Techadamrongsin, repel-
lency of volatile oils from plants against three mosquito vectors. J Vector Ecol 26,
26. G. Bouvier, M. Hergenhahn, A. Polack, G. W. Bornkamm, and H. Bartsch, Validation
of two test systems for detecting tumor promoters and EBV inducers: comparative
responses of several agents in DR-CAT Raji cells and in human granulocytes. Car-
cinogenesis 14, 1573–1578 (1993).
27. A. P. Saikia, V. K. Ryakala, P. Sharma, P. Goswami. and U. Bora, Ethnobotany of
medicinal plants used by Assamese people for various skin ailments and cosmetics. J
Ethnopharmacol 106, 149–157 (2006).
28. T. K. Biswas and B. Mukherjee, Plant medicines of Indian origin for wound healing
activity: A review. Int J Low Extrem Wounds 2, 25–39 (2003).
R. K. Maheshwari, Enhancement of wound healing by curcumin in animals. Wound
Repair Regen 6, 167–177 (1998).
30. G. S. Sidhu, H. Mani, J. P. Gaddipati, A. K. Singh, P. Seth, K. K. Banaudha, G. K.
Patnaik, and R. K. Maheshwari, Curcumin enhances wound healing in streptozotocin
induced diabetic rats and genetically diabetic mice. Wound Repair Regen 7, 362–374
31. T. T. Phan, P. See, S. T. Lee, and S. Y. Chan, Protective effects of curcumin against
oxidative damage on skin cells in vitro: its implication for wound healing. J Trauma
51, 927–931 (2001).
32. T. R. Fray, A. L. Watson, J. M. Croft, C. D. Baker, J. Bailey, N. Sirel, A. Tobias,
and P. J. Markwell, A combination of aloe vera, curcumin, vitamin C, and taurine
increases canine fibroblast migration and decreases tritiated water diffusion across
canine keratinocytes in vitro. J Nutr 134, 2117S–2119S (2004).
33. D. Gopinath, M. R. Ahmed, K. Gomathi, K. Chitra, P. K. Sehgal, and R. Jayaku-
mar, Dermal wound healing processes with curcumin incorporated collagen films.
Biomaterials 25, 1911–1917 (2004).
34. G. C. Jagetia and G. K. Rajanikant, Role of curcumin, a naturally occurring phenolic
compound of turmeric in accelerating the repair of excision wound, in mice whole-
body exposed to various doses of gamma-radiation. J Surg Res 120, 127–138 (2004).
35. G. C. Jagetia and G. K. Rajanikant, Effect of curcumin on radiation-impaired healing
of excisional wounds in mice. J Wound Care 13, 107–109 (2004).
eration of wounds in mice exposed to hemibody gamma-irradiation. Plast Reconstr
Surg 115, 515–528 (2005).
37. A. Kumar, Y. Takada, A. M. Boriek, and B. B. Aggarwal, Nuclear factor-kappaB: Its
role in health and disease. J Mol Med 82, 434–448 (2004).
Y. Baba, and A. Kumar, Nuclear transcription factor NF-kappa B: Role in biology and
medicine. Indian J Exp Biol 42, 341–353 (2004).
December 22, 2006 16:34
16 AGGARWAL ET AL.
A potent inhibitor of leukotriene B4 formation in rat peritoneal polymorphonuclear
neutrophils (PMNL). Planta Med 58, 226 (1992).
40. Y. Fujiyama-Fujiwara, R. Umeda, and O. Igarashi, Effects of sesamin and curcumin
in primary cultured rat hepatocytes. J Nutr Sci Vitaminol (Tokyo) 38, 353–363 (1992).
42. H. P. Ammon, H. Safayhi, T. Mack, and J. Sabieraj, Mechanism of antiinflammatory
actions of curcumine and boswellic acids. J Ethnopharmacol 38, 113–119 (1993).
and dietary n-3 polyunsaturated fatty acids on carrageenan-induced inflammation in
rats. Ann Nutr Metab 38, 349–358 (1994).
44. B. Joe and B. R. Lokesh, Effect of curcumin and capsaicin on arachidonic acid
metabolism and lysosomal enzyme secretion by rat peritoneal macrophages. Lipids
32, 1173–1180 (1997).
45. Y. X. Xu, K. R. Pindolia, N. Janakiraman, C. J. Noth, R. A. Chapman, and S. C.
Gautam, Curcumin, a compound with anti-inflammatory and anti-oxidant properties,
46. B. Joe and B. R. Lokesh, Dietary n-3 fatty acids, curcumin and capsaicin lower the
release of lysosomal enzymes and eicosanoids in rat peritoneal macrophages. Mol
Cell Biochem 203, 153–161 (2000).
47. E.A. Jones,A.Shahed,andD.A.Shoskes,Modulationofapoptoticandinflammatory
genes by bioflavonoids and angiotensin II inhibition in ureteral obstruction. Urology
56, 346–351 (2000).
48. M. Banerjee, L. M. Tripathi, V. M. Srivastava, A. Puri, and R. Shukla, Modulation of
inflammatory mediators by ibuprofen and curcumin treatment during chronic inflam-
mation in rat. Immunopharmacol Immunotoxicol 25, 213–224 (2003).
49. R. C. Lantz, G. J. Chen, A. M. Solyom, S. D. Jolad, and B. N. Timmermann, The
effect of turmeric extracts on inflammatory mediator production. Phytomedicine 12,
50. S. Singh and B. B. Aggarwal, Activation of transcription factor NF-kappa B is sup-
pressed by curcumin (diferuloylmethane) [corrected]. J Biol Chem 270, 24,995–
factor gene expression by inhibiting binding of AP-1 to the DNA and activation of
NF-kappa B. Thromb Haemost 77, 772–782 (1997).
52. A. Munzenmaier, C. Lange, E. Glocker, A. Covacci, A. Moran, S. Bereswill, P. A.
Baeuerle, M. Kist, and H. L. Pahl, A secreted/shed product of Helicobacter pylori ac-
in cultured endothelial cells by curcumin. Suppression of activation of transcription
factors Egr-1, AP-1, and NF-kappa B. Arterioscler Thromb Vasc Biol 17, 3406–3413
in bone marrow stromal cells. Hematopathol Mol Hematol 11, 49–62 (1997).
December 22, 2006 16:34
CURCUMIN: THE INDIAN SOLID GOLD 17
55. P. Brennan and L. A. O’Neill, Inhibition of nuclear factor kappaB by direct modifica-
tion in whole cells: Mechanism of action of nordihydroguaiaritic acid, curcumin and
thiol modifiers. Biochem Pharmacol 55, 965–973 (1998).
56. S. S. Han, S. T. Chung, D. A. Robertson, D. Ranjan, and S. Bondada, Curcumin
causes the growth arrest and apoptosis of B cell lymphoma by downregula-
tion of egr-1, c-myc, bcl-XL, NF-kappa B, and p53. Clin Immunol 93, 152–161
57. C. Jobin, C. A. Bradham, M. P. Russo, B. Juma, A. S. Narula, D. A. Brenner, and
R. B. Sartor, Curcumin blocks cytokine-mediated NF-kappa B activation and proin-
flammatory gene expression by inhibiting inhibitory factor I-kappa B kinase activity.
J Immunol 163, 3474–3483 (1999).
58. S. M. Plummer, K. A. Holloway, M. M. Manson, R. J. Munks, A. Kaptein, S. Farrow,
and L. Howells, Inhibition of cyclo-oxygenase 2 expression in colon cells by the
chemopreventive agent curcumin involves inhibition of NF-kappaB activation via the
NIK/IKK signalling complex. Oncogene 18, 6013–6020 (1999).
and capsaicin on phorbol ester-induced activation of eukaryotic transcription factors,
NF-kappaB and AP-1. Biofactors 12, 107–112 (2000).
60. S. E. Chuang, P. Y. Yeh, Y. S. Lu, G. M. Lai, C. M. Liao, M. Gao, and A. L. Cheng,
Basal levels and patterns of anticancer drug-induced activation of nuclear factor-
in carcinoma cells. Biochem Pharmacol 63, 1709–1716 (2002).
and M. Guenounou, Relative contribution of NF-kappaB and AP-1 in the modulation
by keratinocytes. Cytokine 18, 168–177 (2002).
62. S. S. Han, Y. S. Keum, H. J. Seo, and Y. J. Surh, Curcumin suppresses activation
of NF-kappaB and AP-1 induced by phorbol ester in cultured human promyelocytic
leukemia cells. J Biochem Mol Biol 35, 337–342 (2002).
63. T. C. Hour, J. Chen, C. Y. Huang, J. Y. Guan, S. H. Lu, and Y. S. Pu, Curcumin
Prostate 51, 211–218 (2002).
64. K. S. Chun, Y. S. Keum, S. S. Han, Y. S. Song, S. H. Kim, and Y. J. Surh, Cur-
cumin inhibits phorbol ester-induced expression of cyclooxygenase-2 in mouse skin
through suppression of extracellular signal-regulated kinase activity and NF-kappaB
activation. Carcinogenesis 24, 1515–1524 (2003).
65. S. Philip and G. C. Kundu, Osteopontin induces nuclear factor kappa B-mediated
promatrix metalloproteinase-2 activation through I kappa B alpha /IKK signaling
pathways, and curcumin (diferulolylmethane) down-regulates these pathways. J Biol
Chem 278, 14,487–14,497 (2003).
66. S. Shishodia, P. Potdar, C. G. Gairola, and B. B. Aggarwal, Curcumin (diferuloyl-
methane) down-regulates cigarette smoke-induced NF-kappaB activation through
inhibition of IkappaBalpha kinase in human lung epithelial cells: correlation with
suppression of COX-2, MMP-9 and cyclin D1. Carcinogenesis 24, 1269–1279
blocks NF-kappaB and the motogenic response in Helicobacter pylori-infected ep-
ithelial cells. Biochem Biophys Res Commun 316, 1065–1072 (2004).
December 22, 2006 16:34
18AGGARWAL ET AL.
68. I. A. Leclercq, G. C. Farrell, C. Sempoux, A. dela Pena, and Y. Horsmans, Curcumin
in mice. J Hepatol 41, 926–934 (2004).
69. B. van’t Land, N. M. Blijlevens, J. Marteijn, S. Timal, J. P. Donnelly, T. J. de Witte
and L. M’Rabet, Role of curcumin and the inhibition of NF-kappaB in the onset of
chemotherapy-induced mucosal barrier injury. Leukemia 18, 276–284 (2004).
70. B. B. Aggarwal, S. Shishodia, Y. Takada, S. Banerjee, R. A. Newman, C. E. Bueso-
Ramos and J. E. Price, Curcumin suppresses the paclitaxel-induced nuclear factor-
kappaB pathway in breast cancer cells and inhibits lung metastasis of human breast
cancer in nude mice. Clin Cancer Res 11, 7490–7498 (2005).
71. S. K. Biswas, D. McClure, L. A. Jimenez, I. L. Megson, and I. Rahman, Curcumin
induces glutathione biosynthesis and inhibits NF-kappaB activation and interleukin-
8 release in alveolar epithelial cells: mechanism of free radical scavenging activity.
Antioxid Redox Signal 7, 32–41 (2005).
72. M. Farid, M. B. Reid, Y. P. Li, E. Gerken, and W. J. Durham, Effects of dietary
curcumin or N-acetylcysteine on NF-kappaB activity and contractile performance in
ambulatory and unloaded murine soleus. Nutr Metab (Lond) 2, 20 (2005).
73. G. Y. Kim, K. H. Kim, S. H. Lee, M. S. Yoon, H. J. Lee, D. O. Moon, C. M. Lee, S.
C. Ahn, Y. C. Park, and Y. M. Park, Curcumin inhibits immunostimulatory function
of dendritic cells: MAPKs and translocation of NF-kappa B as potential targets. J
Immunol 174, 8116–8124 (2005).
74. K. W. Lee, J. H. Kim, H. J. Lee, and Y. J. Surh, Curcumin inhibits phorbol ester-
induced up-regulation of cyclooxygenase-2 and matrix metalloproteinase-9 by block-
ing ERK1/2 phosphorylation and NF-kappaB transcriptional activity in MCF10A
human breast epithelial cells. Antioxid Redox Signal 7, 1612–1620 (2005).
75. J. Lee, Y. H. Im, H. H. Jung, J. H. Kim, J. O. Park, K. Kim, W. S. Kim, J. S. Ahn,
C. W. Jung, Y. S. Park, W. K. Kang, and K. Park, Curcumin inhibits interferon-alpha
induced NF-kappaB and COX-2 in human A549 non-small cell lung cancer cells.
Biochem Biophys Res Commun 334, 313–318 (2005).
of head and neck squamous cell carcinoma. Clin Cancer Res 11, 6994–7002 (2005).
inhibits constitutive NF-kappaB activation, induces G1/S arrest, suppresses prolifera-
78. S. Wessler, P. Muenzner, T. F. Meyer, and M. Naumann, The anti-inflammatory com-
pound curcumin inhibits Neisseria gonorrhoeae-induced NF-kappaB signaling, re-
lease of pro-inflammatory cytokines/chemokines and attenuates adhesion in late in-
fection. Biol Chem 386, 481–490 (2005).
79. S. Aggarwal, H. Ichikawa, Y. Takada, S. K. Sandur, S. Shishodia, and B. B. Aggar-
wal, Curcumin (diferuloylmethane) down-regulates expression of cell proliferation
and antiapoptotic and metastatic gene products through suppression of IkappaBalpha
kinase and Akt activation. Mol Pharmacol 69, 195–206 (2006).
80. M. Tomita, H. Kawakami, J. N. Uchihara, T. Okudaira, M. Masuda, N. Takasu, T.
T-cell leukemia virus type I-infected T-cell lines and primary adult T-cell leukemia
cells. Int J Cancer 118, 765–772 (2006).
December 22, 2006 16:34
CURCUMIN: THE INDIAN SOLID GOLD 19
81. W. M. Weber, L. A. Hunsaker, C. N. Roybal, E. V. Bobrovnikova-Marjon, S. F.
Abcouwer, R. E. Royer, L. M. Deck, and D. L. Vander Jagt, Activation of NFkap-
paB is inhibited by curcumin and related enones. Bioorg Med Chem 14, 2450–2461
82. W. Q. Li, F. Dehnade, and M. Zafarullah, Oncostatin M-induced matrix metallo-
proteinase and tissue inhibitor of metalloproteinase-3 genes expression in chondro-
cytes requires Janus kinase/STAT signaling pathway. J Immunol 166, 3491–3498
83. A. C. Bharti, Y. Takada, and B. B. Aggarwal, Curcumin (diferuloylmethane) inhibits
receptor activator of NF-kappa B ligand-induced NF-kappa B activation in osteoclast
precursors and suppresses osteoclastogenesis. J Immunol 172, 5940–5947 (2004).
84. H. Y. Kim, E. J. Park, E. H. Joe, and I. Jou, Curcumin suppresses Janus kinase-STAT
inflammatory signaling through activation of Src homology 2 domain-containing ty-
rosine phosphatase 2 in brain microglia. J Immunol 171, 6072–6079 (2003).
growth-arrest and apoptosis in association with the inhibition of constitutively active
JAK-STAT pathway in T cell leukemia. Biochem Biophys Res Commun 340, 359–368
confers radiosensitizing effect in prostate cancer cell line PC-3. Oncogene 23, 1599–
87. D. A. Dickinson, K. E. Iles, H. Zhang, V. Blank, and H. J. Forman, Curcumin al-
ters EpRE and AP-1 binding complexes and elevates glutamate-cysteine ligase gene
expression. FASEB J 17, 473–475 (2003).
88. B. K. Prusty and B. C. Das, Constitutive activation of transcription factor AP-1 in
cervical cancer and suppression of human papillomavirus (HPV) transcription and
AP-1 activity in HeLa cells by curcumin. Int J Cancer 113, 951–960 (2005).
89. M. Tomita, H. Kawakami, J. N. Uchihara, T. Okudaira, M. Masuda, N. Takasu, T.
30, 313–321 (2006).
90. U. R. Pendurthi and L. V. Rao, Suppression of transcription factor Egr-1 by curcumin.
Thromb Res 97, 179–189 (2000).
91. E. Balogun, M. Hoque, P. Gong, E. Killeen, C. J. Green, R. Foresti, J. Alam, and R.
Motterlini, Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and
the antioxidant-responsive element. Biochem J 371, 887–895 (2003).
92. J. Xu, Y. Fu, and A. Chen, Activation of peroxisome proliferator-activated receptor-
gamma contributes to the inhibitory effects of curcumin on rat hepatic stellate cell
growth. Am J Physiol Gastrointest Liver Physiol 285, G20–G30 (2003).
93. S. Zheng and A. Chen, Activation of PPAR? is required for curcumin to induce
apoptosis and to inhibit the expression of extracellular matrix genes in hepatic stellate
cells in vitro. Biochem J 384, 149–157 (2004).
94. A. Chen and J. Xu, Activation of PPAR? by curcumin inhibits Moser cell growth
and mediates suppression of gene expression of cyclin D1 and EGFR. Am J Physiol
Gastrointest Liver Physiol 288, G447–G456 (2005).
induced growth arrest and apoptosis in colon cancer cells. Oncogene 21, 8414–8427
December 22, 2006 16:34
20AGGARWAL ET AL.
of curcumin and its derivative against beta-catenin/Tcf signaling. FEBS Lett 579,
97. M. M. Chan, Inhibition of tumor necrosis factor by curcumin, a phytochemical.
Biochem Pharmacol 49, 1551–1556 (1995).
of macrophage TNF-alpha release from Curcuma zedoaria. Planta Med 67, 550–552
99. H. Matsuda, S. Tewtrakul, T. Morikawa, A. Nakamura, and M. Yoshikawa, Anti-
allergic principles from Thai zedoary: structural requirements of curcuminoids for
inhibition of degranulation and effect on the release of TNF-alpha and IL-4 in RBL-
2H3 cells. Bioorg Med Chem 12, 5891–5898 (2004).
100. A. Gulcubuk, K. Altunatmaz, K. Sonmez, D. Haktanir-Yatkin, H. Uzun, A. Gurel and
late phase of experimental acute pancreatitis. J Vet Med A Physiol Pathol Clin Med
53, 49–54 (2006).
101. J. P. Gaddipati, S. V. Sundar, J. Calemine, P. Seth, G. S. Sidhu, and R. K. Maheshwari,
Differential regulation of cytokines and transcription factors in liver by curcumin
following hemorrhage/resuscitation. Shock 19, 150–156 (2003).
of baicalein, berberine, curcumin and hesperidin on mucin release from airway goblet
cells. Planta Med 69, 523–526 (2003).
103. N. Jurrmann, R. Brigelius-Flohe and G. F. Bol, Curcumin blocks interleukin-1 (IL-1)
signaling by inhibiting the recruitment of the IL-1 receptor-associated kinase IRAK
in murine thymoma EL-4 cells. J Nutr 135, 1859–1864 (2005).
104. Y. Moon, W. C. Glasgow, and T. E. Eling, Curcumin suppresses interleukin 1beta-
mediated microsomal prostaglandin E synthase 1 by altering early growth response
gene 1 and other signaling pathways. J Pharmacol Exp Ther 315, 788–795 (2005).
expression and activation of caspase-3: An immunomorphological study. Ann Anat
187, 487–497 (2005).
106. T. Kobayashi, S. Hashimoto and T. Horie, Curcumin inhibition of Dermatophagoides
farinea-induced interleukin-5 (IL-5) and granulocyte macrophage-colony stimulating
factor (GM-CSF) production by lymphocytes from bronchial asthmatics. Biochem
Pharmacol 54, 819–824 (1997).
107. Y. Abe, S. Hashimoto, and T. Horie, Curcumin inhibition of inflammatory cytokine
production by human peripheral blood monocytes and alveolar macrophages. Phar-
macol Res 39, 41–47 (1999).
108. H. Hidaka, T. Ishiko, T. Furuhashi, H. Kamohara, S. Suzuki, M. Miyazaki, O. Ikeda,
S. Mita, T. Setoguchi, and M. Ogawa, Curcumin inhibits interleukin 8 production and
enhances interleukin 8 receptor expression on the cell surface:impact on human pan-
creatic carcinoma cell growth by autocrine regulation. Cancer 95, 1206–1214 (2002).
109. B. Y. Kang, S. W. Chung, W. Chung, S. Im, S. Y. Hwang, and T. S. Kim, Inhibition of
interleukin-12 production in lipopolysaccharide-activated macrophages by curcumin.
Eur J Pharmacol 384, 191–195 (1999).
110. B. Y. Kang, Y. J. Song, K. M. Kim, Y. K. Choe, S. Y. Hwang and T. S. Kim, Curcumin
in macrophages. Br J Pharmacol 128, 380–384 (1999).
December 22, 2006 16:34
CURCUMIN: THE INDIAN SOLID GOLD 21
J Immunol 168, 6506–6513 (2002).
112. M. Tomita, B. J. Holman, C. P. Santoro, and T. J. Santoro, Astrocyte production of
the chemokine macrophage inflammatory protein-2 is inhibited by the spice principle
curcumin at the level of gene transcription. J Neuroinflammation 2, 8 (2005).
113. M. K. Bae, S. H. Kim, J. W. Jeong, Y. M. Lee, H. S. Kim, S. R. Kim, I. Yun, S. K. Bae,
of HIF-1. Oncol Rep 15, 1557–1562 (2006).
inducible factor-1 by degrading aryl hydrocarbon receptor nuclear translocator: A
mechanism of tumor growth inhibition. Mol Pharmacol 70(5), 1664–1671 (2006).
115. S. Reddy and B. B. Aggarwal, Curcumin is a non-competitive and selective inhibitor
of phosphorylase kinase. FEBS Lett 341, 19–22 (1994).
116. M. Hasmeda and G. M. Polya, Inhibition of cyclic AMP-dependent protein kinase by
curcumin. Phytochemistry 42, 599–605 (1996).
117. Y. R. Chen and T. H. Tan, Inhibition of the c-Jun N-terminal kinase (JNK) signaling
pathway by curcumin. Oncogene 17, 173–178 (1998).
118. M. S. Squires, E. A. Hudson, L. Howells, S. Sale, C. E. Houghton, J. L. Jones,
L. H. Fox, M. Dickens, S. A. Prigent, and M. M. Manson, Relevance of mitogen
activated protein kinase (MAPK) and phosphotidylinositol-3-kinase/protein kinase B
(PI3K/PKB) pathways to induction of apoptosis by curcumin in breast cells. Biochem
Pharmacol 65, 361–376 (2003).
120. M. Hu, Q. Du, I. Vancurova, X. Lin, E. J. Miller, H. H. Simms, and P. Wang, Proapop-
protein kinase pathway. Crit Care Med 33, 2571–2578 (2005).
121. L. R. Chaudhary and K. A. Hruska, Inhibition of cell survival signal protein kinase
B/Akt by curcumin in human prostate cancer cells. J Cell Biochem 89, 1–5 (2003).
122. J. Y. Liu, S. J. Lin, and J. K. Lin, Inhibitory effects of curcumin on protein kinase
C activity induced by 12-O-tetradecanoyl-phorbol-13-acetate in NIH 3T3 cells. Car-
cinogenesis 14, 857–861 (1993).
protein kinase C by phenolic compounds. Cancer Lett 121, 99–104 (1997).
124. P. Varadkar, P. Dubey, M. Krishna, and N. Verma, Modulation of radiation-induced
protein kinase C activity by phenolics. J Radiol Prot 21, 361–370 (2001).
action mechanisms of cancer chemoprevention by Curcumin. Arch Pharm Res 27,
126. S. A. Rushworth, R. M. Ogborne, C. A. Charalambos, and M. A. O’Connell, Role of
protein kinase C delta in curcumin-induced antioxidant response element-mediated
127. R. L. Hong, W. H. Spohn, and M. C. Hung, Curcumin inhibits tyrosine kinase activity
of p185neu and also depletes p185neu. Clin Cancer Res 5, 1884–1891 (1999).
cancer. II. Curcumin inhibits tyrosine kinase activity of epidermal growth factor re-
ceptor and depletes the protein. Mol Urol 4, 1–6 (2000).
December 22, 2006 16:34
22AGGARWAL ET AL.
129. S. Kaul and T. P. Krishnakanth, Effect of retinol deficiency and curcumin or turmeric
feeding on brain Na(+)−K+ adenosine triphosphatase activity. Mol Cell Biochem
137, 101–107 (1994).
130. J. G. Bilmen, S. Z. Khan, M. H. Javed, and F. Michelangeli, Inhibition of the SERCA
Ca2+ pumps by curcumin. Curcumin putatively stabilizes the interaction between
the nucleotide-binding and phosphorylation domains in the absence of ATP. Eur J
Biochem 268, 6318–6327 (2001).
131. M. J. Logan-Smith, P. J. Lockyer, J. M. East and A. G. Lee, Curcumin, a molecule
that inhibits the Ca2+-ATPase of sarcoplasmic reticulum but increases the rate of
accumulation of Ca2+. J Biol Chem 276, 46,905–46.911 (2001).
132. Y. A. Mahmmoud, Curcumin modulation of Na,K-ATPase: phosphoenzyme accumu-
lation, decreased K+ occlusion, and inhibition of hydrolytic activity. Br J Pharmacol
145, 236–245 (2005).
133. J. Kang, J. Chen, Y. Shi, J. Jia, and Y. Zhang, Curcumin-induced histone hypoacetyla-
tion: The role of reactive oxygen species. Biochem Pharmacol 69, 1205–1213 (2005).
134. W. H. Liu, X. M. Chen, and B. Fu, Thrombin stimulates MMP-9 mRNA expression
through AP-1 pathway in human mesangial cells. Acta Pharmacol Sin 21, 641–645
135. S. Shimizu, S. Jareonkitmongkol, H. Kawashima, K. Akimoto, and H. Yamada, In-
hibitory effect of curcumin on fatty acid desaturation in Mortierella alpina 1S-4 and
rat liver microsomes. Lipids 27, 509–512 (1992).
136. H. Kawashima, K. Akimoto, S. Jareonkitmongkol, N. Shirasaka, and S. Shimizu,
Inhibition of rat liver microsomal desaturases by curcumin and related compounds.
Biosci Biotechnol Biochem 60, 108–110 (1996).
137. X. Chen, T. Hasuma, Y. Yano, T. Yoshimata, Y. Morishima, Y. Wang, and S. Otani,
Inhibition of farnesyl protein transferase by monoterpene, curcumin derivatives and
gallotannin. Anticancer Res 17, 2555–2564 (1997).
Inhibitory activity of diarylheptanoids on farnesyl protein transferase. Nat Prod Res
18, 295–299 (2004).
139. M. Susan and M. N. Rao, Induction of glutathione S-transferase activity by curcumin
in mice. Arzneimittelforschung 42, 962–964 (1992).
140. M. L. Iersel, J. P. Ploemen, I. Struik, C. van Amersfoort, A. E. Keyzer, J. G.
Schefferlie, and P. J. van Bladeren, Inhibition of glutathione S-transferase activity
in human melanoma cells by alpha,beta-unsaturated carbonyl derivatives. Effects
of acrolein, cinnamaldehyde, citral, crotonaldehyde, curcumin, ethacrynic acid, and
trans-2-hexenal. Chem Biol Interact 102, 117–132 (1996).
141. J. T. Piper, S. S. Singhal, M. S. Salameh, R. T. Torman, Y. C. Awasthi, and S. Awasthi,
Mechanisms of anticarcinogenic properties of curcumin: The effect of curcumin on
glutathione linked detoxification enzymes in rat liver. Int J Biochem Cell Biol 30,
142. S. S. Singhal, S. Awasthi, U. Pandya, J. T. Piper, M. K. Saini, J. Z. Cheng, and Y.
C. Awasthi, The effect of curcumin on glutathione-linked enzymes in K562 human
leukemia cells. Toxicol Lett 109, 87–95 (1999).
143. S. Awasthi, U. Pandya, S. S. Singhal, J. T. Lin, V. Thiviyanathan, W. E. Seifert, Jr.,
Y. C. Awasthi, and G. A. Ansari, Curcumin-glutathione interactions and the role of
human glutathione S-transferase P1-1. Chem Biol Interact 128, 19–38 (2000).
144. R. A. Sharma, C. R. Ireson, R. D. Verschoyle, K. A. Hill, M. L. Williams, C. Leuratti,
M. M. Manson, L. J. Marnett, W. P. Steward, and A. Gescher, Effects of dietary
December 22, 2006 16:34
CURCUMIN: THE INDIAN SOLID GOLD 23
curcumin on glutathione S-transferase and malondialdehyde-DNA adducts in rat liver
and colon mucosa: Relationship with drug levels. Clin Cancer Res 7, 1452–1458
145. A. Duvoix, F. Morceau, S. Delhalle, M. Schmitz, M. Schnekenburger, M. M. Gal-
teau, M. Dicato, and M. Diederich, Induction of apoptosis by curcumin: mediation
by glutathione S-transferase P1-1 inhibition. Biochem Pharmacol 66, 1475–1483
146. R. Blasius, A. Duvoix, F. Morceau, M. Schnekenburger, S. Delhalle, E. Henry, M.
P1-1 mRNA expression in K562 cells. Ann N Y Acad Sci 1030, 442–448 (2004).
147. N. Hill-Kapturczak, V. Thamilselvan, F. Liu, H. S. Nick and A. Agarwal, Mechanism
of heme oxygenase-1 gene induction by curcumin in human renal proximal tubule
cells. Am J Physiol Renal Physiol 281, F851–F859 (2001).
terlini, Caffeic acid phenethyl ester and curcumin: a novel class of heme oxygenase-1
inducers. Mol Pharmacol 61, 554–561 (2002).
149. E. Balogun, R. Foresti, C. J. Green, and R. Motterlini, Changes in temperature mod-
ulate heme oxygenase-1 induction by curcumin in renal epithelial cells. Biochem
Biophys Res Commun 308, 950–955 (2003).
150. V. Calabrese, D. A. Butterfield, and A. M. Stella, Nutritional antioxidants and the
heme oxygenase pathway of stress tolerance: Novel targets for neuroprotection in
Alzheimer’s disease. Ital J Biochem 52, 177–181 (2003).
151. J. Gaedeke, N. A. Noble, and W. A. Border, Curcumin blocks fibrosis in anti-Thy 1
glomerulonephritis through up-regulation of heme oxygenase 1. Kidney Int 68, 2042–
152. H. Yamamoto, K. Hanada, K. Kawasaki, and M. Nishijima, Inhibitory effect
on curcumin on mammalian phospholipase D activity. FEBS Lett 417, 196–198
12-O-tetradecanoylphorbol-13-acetate-induced increase in ornithine decarboxylase
mRNA in mouse epidermis. Carcinogenesis 14, 293–297 (1993).
and aberrant crypt foci formation in the rat colon. Carcinogenesis 14, 2219–2225
155. C. Ishizaki, T. Oguro, T. Yoshida, C. Q. Wen, H. Sueki, and M. Iijima, Enhancing
effect of ultraviolet A on ornithine decarboxylase induction and dermatitis evoked by
12-O-tetradecanoylphorbol-13-acetate and its inhibition by curcumin in mouse skin.
Dermatology 193, 311–317 (1996).
156. Y. Okazaki, M. Iqba,l and S. Okada, Suppressive effects of dietary curcumin
on the increased activity of renal ornithine decarboxylase in mice treated with
a renal carcinogen, ferric nitrilotriacetate. Biochim Biophys Acta 1740, 357–366
157. C. Ramachandran, H. B. Fonseca, P. Jhabvala, E. A. Escalon, and S. J. Melnick,
in MCF-7 breast cancer cell line. Cancer Lett 184, 1–6 (2002).
158. S. Chakraborty, U. Ghosh, N. P. Bhattacharyya, R. K. Bhattacharya, and M. Roy,
Inhibition of telomerase activity and induction of apoptosis by curcumin in K-562
cells. Mutat Res 596, 81–90 (2006).
December 22, 2006 16:34
24AGGARWAL ET AL.
159. J. K. Lin and C. A. Shih, Inhibitory effect of curcumin on xanthine dehydroge-
nase/oxidase induced by phorbol-12-myristate-13-acetate in NIH3T3 cells. Carcino-
genesis 15, 1717–2171 (1994).
agent, inhibits induction of nitric oxide synthase in activated macrophages. Biochem
Biophys Res Commun 206, 533–540 (1995).
161. M. M. Chan, H. I. Huang, M. R. Fenton, and D. Fong, In vivo inhibition of nitric
anti-inflammatory properties. Biochem Pharmacol 55, 1955–1962 (1998).
162. K. F. Soliman and E. A. Mazzio, In vitro attenuation of nitric oxide production in
C6 astrocyte cell culture by various dietary compounds. Proc Soc Exp Biol Med 218,
163. M. Onoda and H. Inano, Effect of curcumin on the production of nitric oxide by
cultured rat mammary gland. Nitric Oxide 4, 505–515 (2000).
164. M. H. Pan, S. Y. Lin-Shiau and J. K. Lin, Comparative studies on the suppression of
nitric oxide synthase by curcumin and its hydrogenated metabolites through down-
regulation of IkappaB kinase and NFkappaB activation in macrophages. Biochem
Pharmacol 60, 1665–1676 (2000).
165. H. Narang and M. Krishna, Inhibition of radiation induced nitration by curcumin and
nicotinamide in mouse macrophages. Mol Cell Biochem 276, 7–13 (2005).
166. A. Mukhopadhyay, S. Banerjee, L. J. Stafford, C. Xia, M. Liu, and B. B. Aggarwal,
Curcumin-induced suppression of cell proliferation correlates with down-regulation
Oncogene 21, 8852–8861 (2002).
167. T. Choudhuri, S. Pal, T. Das, and G. Sa, Curcumin selectively induces apoptosis in
deregulated cyclin D1-expressed cells at G2 phase of cell cycle in a p53-dependent
manner. J Biol Chem 280, 20,059–20,068 (2005).
168. Y. K. Kwon, J. M. Jun, S. W. Shin, J. W. Cho, and S. I. Suh, Curcumin decreases cell
proliferation rates through BTG2-mediated cyclin D1 down-regulation in U937 cells.
Int J Oncol 26, 1597–1603 (2005).
169. D. Bech-Otschir, R. Kraft, X. Huang, P. Henklein, B. Kapelari, C. Pollmann, and W.
ubiquitin system. Embo J 20, 1630–1639 (2001).
170. P. J. Moos, K. Edes, J. E. Mullally, and F. A. Fitzpatrick, Curcumin impairs tu-
mor suppressor p53 function in colon cancer cells. Carcinogenesis 25, 1611–1617
171. P. Tsvetkov, G. Asher, V. Reiss, Y. Shaul, L. Sachs, and J. Lotem, Inhibition of
NAD(P)H:quinone oxidoreductase 1 activity and induction of p53 degradation by
the natural phenolic compound curcumin. Proc Natl Acad Sci USA 102, 5535–5540
172. S. S. Kakar and D. Roy, Curcumin inhibits TPA induced expression of c-fos, c-jun
and c-myc proto-oncogenes messenger RNAs in mouse skin. Cancer Lett 87, 85–59
173. M. T. Huang, W. Ma, Y. P. Lu, R. L. Chang, C. Fisher, P. S. Manchand, H. L. New-
mark, and A. H. Conney, Effects of curcumin, demethoxycurcumin, bisdemethoxy-
curcumin and tetrahydrocurcumin on 12-O-tetradecanoylphorbol-13-acetate-induced
tumor promotion. Carcinogenesis 16, 2493–2497 (1995).
December 22, 2006 16:34
CURCUMIN: THE INDIAN SOLID GOLD 25
B light-induced expression of c-Jun and c-Fos in JB6 cells and in mouse epidermis.
Carcinogenesis 15, 2363–2370 (1994).
175. P. Limtrakul, S. Anuchapreeda, S. Lipigorngoson and F. W. Dunn, Inhibition of car-
cinogen induced c-Ha-ras and c-fos proto-oncogenes expression by dietary curcumin.
BMC Cancer 1, 1 (2001).
176. K. Nakamura, Y. Yasunaga, T. Segawa, D. Ko, J. W. Moul, S. Srivastava, and J. S.
cell lines. Int J Oncol 21, 825–830 (2002).
effects of curcumin on in vitro lipoxygenase and cyclooxygenase activities in mouse
epidermis. Cancer Res 51, 813–819 (1991).
178. F. Zhang, N. K. Altorki, J. R. Mestre, K. Subbaramaiah, and A. J. Dannenberg, Cur-
cumin inhibits cyclooxygenase-2 transcription in bile acid- and phorbol ester-treated
human gastrointestinal epithelial cells. Carcinogenesis 20, 445–451 (1999).
179. A. Goel, C. R. Boland, and D. P. Chauhan, Specific inhibition of cyclooxygenase-2
(COX-2) expression by dietary curcumin in HT-29 human colon cancer cells. Cancer
Lett 172, 111–118 (2001).
180. J. W. Cho, K. Park, G. R. Kweon, B. C. Jang, W. K. Baek, M. H. Suh, C. W. Kim, K.
S. Lee, and S. I. Suh, Curcumin inhibits the expression of COX-2 in UVB-irradiated
human keratinocytes (HaCaT) by inhibiting activation of AP-1: p38 MAP kinase and
JNK as potential upstream targets. Exp Mol Med 37, 186–192 (2005).
intestinal adenomas: Modification by dietary curcumin and implications for clinical
trials. Eur J Cancer 42, 415–421 (2006).
acid (5-HETE) formation in intact human neutrophils by naturally-occurring diaryl-
heptanoids: inhibitory activities of curcuminoids and yakuchinones. Prostaglandins
Leukot Med 22, 357–360 (1986).
183. J. Hong, M. Bose, J. Ju, J. H. Ryu, X. Chen, S. Sang, M. J. Lee, and C. S. Yang, Mod-
ulation of arachidonic acid metabolism by curcumin and related beta-diketone deriva-
tives: effects on cytosolic phospholipase A(2), cyclooxygenases and 5-lipoxygenase.
Carcinogenesis 25, 1671–1679 (2004).
184. N. S. Prasad, R. Raghavendra, B. R. Lokesh, and K. A. Naidu, Spice phenolics inhibit
185. P. F. Firozi, V. S. Aboobaker, and R. K. Bhattacharya, Action of curcumin on the
100, 41–51 (1996).
hydrocarbon receptor and cytochrome P450 1A1 in MCF-7 human breast carcinoma
cells. Biochem Pharmacol 56, 197–206 (1998).
187. R. Thapliyal, S. S. Deshpande, and G. B. Maru, Effects of turmeric on the activities of
20, 59–63 (2001).
K. Umegaki, Selective protection of curcumin against carbon tetrachloride-induced
inactivation of hepatic cytochrome P450 isozymes in rats. Life Sci 78, 2188–2193
December 22, 2006 16:34
26AGGARWAL ET AL.
189. M. J. Van Erk, E. Teuling, Y. C. Staal, S. Huybers, P. J. Van Bladeren, J. M. Aarts, and
B. Van Ommen, Time- and dose-dependent effects of curcumin on gene expression
in human colon cancer cells. J Carcinog 3, 8 (2004).
190. C. Yan, M. S. Jamaluddin, B. Aggarwal, J. Myers, and D. D. Boyd, Gene expres-
sion profiling identifies activating transcription factor 3 as a novel contributor to the
proapoptotic effect of curcumin. Mol Cancer Ther 4, 233–241 (2005).
191. H. M. Wortelboer, M. Usta, A. E. van der Velde, M. G. Boersma, B. Spenkelink, J. J.
van Zanden, I. M. Rietjens, P. J. van Bladeren, and N. H. Cnubben, Interplay between
MRP inhibition and metabolism of MRP inhibitors: the case of curcumin. Chem Res
Toxicol 16, 1642–1651 (2003).
192. W. Chearwae, S. Anuchapreeda, K. Nandigama, S. V. Ambudkar, and P. Limtrakul,
Biochemical mechanism of modulation of human P-glycoprotein (ABCB1) by cur-
resistance MDR-1 gene by natural curcuminoids. BMC Cancer 4, 13 (2004).
194. W. Chearwae, C. P. Wu, H. Y. Chu, T. R. Lee, S. V. Ambudkar, and P. Limtrakul, Cur-
cuminoids purified from turmeric powder modulate the function of human multidrug
resistance protein 1 (ABCC1). Cancer Chemother Pharmacol 57, 376–388 (2006).
in resistant human gastric carcinoma cell line SGC7901/VCR. Acta Pharmacol Sin
26, 1009–1016 (2005).
196. J. Lee, H. H. Jung, Y. H. Im, J. H. Kim, J. O. Park, K. Kim, W. S. Kim, J. S. Ahn,
C. W. Jung, Y. S. Park, W. K. Kang, and K. Park, Interferon-alpha resistance can be
activation in A549 cells. Oncol Rep 15, 1541–1549 (2006).
197. C. Park, G. Y. Kim, G. D. Kim, B. T. Choi, Y. M. Park, and Y. H. Choi, Induction
of G2/M arrest and inhibition of cyclooxygenase-2 activity by curcumin in human
bladder cancer T24 cells. Oncol Rep 15, 1225–1231 (2006).
198. W. J. Durham, S. Arbogast, E. Gerken, Y. P. Li, and M. B. Reid, Progressive nuclear
factor-kappaB activation resistant to inhibition by contraction and curcumin in mdx
mice. Muscle Nerve 34(3), 298–303 (2006).
199. C. C. Su, G. W. Chen, J. G. Lin, L. T. Wu, and J. G. Chung, Curcumin inhibits cell
kappa B /p65 and down-regulates cyclooxygenase-2 and matrix metalloproteinase-2
expressions. Anticancer Res 26, 1281–1288 (2006).
200. N. Chakravarti, J. N. Myers, and B. B. Aggarwal, Targeting constitutive and
interleukin-6-inducible signal transducers and activators of transcription 3 pathway in
head and neck squamous cell carcinoma cells by curcumin (diferuloylmethane). Int J
Cancer 119(6), 1268–1275 (2006).
201. A. M. Siddiqui, X. Cui, R. Wu, W. Dong, M. Zhou, M. Hu, H. H. Simms, and P.
Wang, The anti-inflammatory effect of curcumin in an experimental model of sepsis
is mediated by up-regulation of peroxisome proliferator-activated receptor-gamma*.
Crit Care Med 34(7), 1874–1882 (2006).
202. H. C. Huang, T. R. Jan, and S. F. Yeh, Inhibitory effect of curcumin, an anti-
inflammatory agent, on vascular smooth muscle cell proliferation. Eur J Pharmacol
221, 381–384 (1992).
203. L. Korutla and R. Kumar, Inhibitory effect of curcumin on epidermal growth factor
receptor kinase activity in A431 cells. Biochim Biophys Acta 1224, 597–600 (1994).
December 22, 2006 16:34
CURCUMIN: THE INDIAN SOLID GOLD 27
204. J. F. Santibanez, M. Quintanilla, and J. Martinez, Genistein and curcumin block TGF-
beta 1-induced u-PA expression and migratory and invasive phenotype in mouse epi-
dermal keratinocytes. Nutr Cancer 37, 49–54 (2000).
Chem 275, 10,405–10,512 (2000).
activation of VEGF expression. Growth Factors 19, 19–34 (2001).
207. H. Mani, G. S. Sidhu, R. Kumari, J. P. Gaddipati, P. Seth and R. K. Maheshwari,
Curcumin differentially regulates TGF-beta1, its receptors and nitric oxide synthase
during impaired wound healing. Biofactors 16, 29–43 (2002).
297, 934–942 (2002).
209. J. Gaedeke, N. A. Noble, and W. A. Border, Curcumin blocks multiple sites of the
TGF-beta signaling cascade in renal cells. Kidney Int 66, 112–120 (2004).
210. P. C. Smith, J. F. Santibanez, J. P. Morales, and J. Martinez, Epidermal growth factor
lasts. Possible modulation by genistein and curcumin. J Periodontal Res 39, 380–387
by suppressing gene expression of epidermal growth factor receptor through reducing
the activity of the transcription factor Egr-1. Oncogene 25, 278–287 (2006).
212. J. H. Kim, C. Xu, Y. S. Keum, B. Reddy, A. Conney, and A. N. Kong, Inhibition of
EGFR signaling in human prostate cancer PC-3 cells by combination treatment with
beta-phenylethyl isothiocyanate and curcumin. Carcinogenesis 27, 475–482 (2006).
213. S. Zheng and A. Chen, Curcumin suppresses the expression of extracellular matrix
genes in activated hepatic stellate cells by inhibiting gene expression of connective
214. A. Masamune, N. Suzuki, K. Kikuta, M. Satoh, K. Satoh, and T. Shimosegawa, Cur-
cumin blocks activation of pancreatic stellate cells. J Cell Biochem 97, 1080–1093
215. X. Yang, D. P. Thomas, X. Zhang, B. W. Culver, B. M. Alexander, W. J. Murdoch,
M. N. Rao, D. A. Tulis, J. Ren, and N. Sreejayan, Curcumin inhibits platelet-derived
growth factor-stimulated vascular smooth muscle cell function and injury-induced
neointima formation. Arterioscler Thromb Vasc Biol 26, 85–90 (2006).
216. Y. Takada, A. Bhardwaj, P. Potdar, and B. B. Aggarwal, Nonsteroidal anti-
inflammatory agents differ in their ability to suppress NF-kappaB activation, inhi-
bition of expression of cyclooxygenase-2 and cyclin D1, and abrogation of tumor cell
proliferation. Oncogene 23, 9247–9258 (2004).
217. J. M. Dogne, J. Hanson, C. Supuran, and D. Pratico, Coxibs and cardiovascular side-
effects: from light to shadow. Curr Pharm Des 12, 971–975 (2006).
218. A. T. Chan, J. E. Manson, C. M. Albert, C. U. Chae, K. M. Rexrode, G. C. Curhan,
E. B. Rimm, W. C. Willett, and C. S. Fuchs, Nonsteroidal antiinflammatory drugs,
acetaminophen, and the risk of cardiovascular events. Circulation 113, 1578–1587
219. M. Hermann and F. Ruschitzka, Coxibs, non-steroidal anti-inflammatory drugs and
cardiovascular risk. Intern Med J 36, 308–319 (2006).
December 22, 2006 16:34
28AGGARWAL ET AL.
220. B. Gupta and B. Ghosh, Curcuma longa inhibits TNF-alpha induced expression of ad-
hesion molecules on human umbilical vein endothelial cells. Int J Immunopharmacol
21, 745–757 (1999).
221. B. Madan and B. Ghosh, Diferuloylmethane inhibits neutrophil infiltration and im-
proves survival of mice in high-dose endotoxin shock. Shock 19, 91–96 (2003).
mulate during donor liver cold preservation: A study on increased adhesion molecule
expression and abrogation by curcumin in cultured endothelial cells. Cryobiology 46,
223. O. P. Sharma, Antioxidant activity of curcumin and related compounds. Biochem
Pharmacol 25, 1811–1812 (1976).
224. V. K. Shalini and L. Srinivas, Lipid peroxide induced DNA damage: protection by
turmeric (Curcuma longa). Mol Cell Biochem 77, 3–10 (1987).
as inhibitors of nitrosation in vitro. Mutat Res 202, 163–169 (1988).
226. I. A. Donatus, Sardjoko, and N. P. Vermeulen, Cytotoxic and cytoprotective activi-
ties of curcumin. Effects on paracetamol-induced cytotoxicity, lipid peroxidation and
glutathione depletion in rat hepatocytes. Biochem Pharmacol 39, 1869–1875 (1990).
227. S. C. Sahu and M. C. Washington, Effect of ascorbic acid and curcumin on quercetin-
induced nuclear DNA damage, lipid peroxidation and protein degradation. Cancer
Lett 63, 237–241 (1992).
228. K. K. Soudamini, M. C. Unnikrishnan, K. B. Soni, and R. Kuttan, Inhibition of lipid
peroxidation and cholesterol levels in mice by curcumin. Indian J Physiol Pharmacol
36, 239–243 (1992).
formation. FEBS Lett 301, 195–196 (1992).
230. B. Joe and B. R. Lokesh, Role of capsaicin, curcumin and dietary n-3 fatty acids in
lowering the generation of reactive oxygen species in rat peritoneal macrophages.
Biochim Biophys Acta 1224, 255–263 (1994).
231. D. V. Rajakumar and M. N. Rao, Antioxidant properties of dehydrozingerone and
curcumin in rat brain homogenates. Mol Cell Biochem 140, 73–79 (1994).
232. A. C. Reddy and B. R. Lokesh, Effect of dietary turmeric (Curcuma longa) on iron-
induced lipid peroxidation in the rat liver. Food Chem Toxicol 32, 279–283 (1994).
233. A. C. Reddy and B. R. Lokesh, Studies on the inhibitory effects of curcumin and
eugenol on the formation of reactive oxygen species and the oxidation of ferrous iron.
Mol Cell Biochem 137, 1–8 (1994).
234. Sreejayan and M. N. Rao, Curcuminoids as potent inhibitors of lipid peroxidation. J
Pharm Pharmacol 46, 1013–1016 (1994).
235. R. Selvam, L. Subramanian, R. Gayathri, and N. Angayarkanni, The anti-oxidant
activity of turmeric (Curcuma longa). J Ethnopharmacol 47, 59–67 (1995).
236. M. K. Unnikrishnan and M. N. Rao, Inhibition of nitrite induced oxidation of
hemoglobin by curcuminoids. Pharmazie 50, 490–492 (1995).
237. M. K. Unnikrishnan and M. N. Rao, Curcumin inhibits nitrogen dioxide induced
oxidation of hemoglobin. Mol Cell Biochem 146, 35–37 (1995).
Cell Biochem 175, 43–48 (1997).
239. A. Nogaki, K. Satoh, K. Iwasaka, H. Takano, M. Takahama, Y. Ida, and H. Sakagami,
Radical intensity and cytotoxic activity of curcumin and gallic acid. Anticancer Res
18, 3487–3491 (1998).
December 22, 2006 16:34
CURCUMIN: THE INDIAN SOLID GOLD 29
240. S. Bhaumik, M. D. Jyothi, and A. Khar, Differential modulation of nitric oxide pro-
241. S. Kapoor and K. I. Priyadarsini, Protection of radiation-induced protein damage by
curcumin. Biophys Chem 92, 119–126 (2001).
242. M. R. Kelly, J. Xu, K. E. Alexander, and G. Loo, Disparate effects of similar phenolic
phytochemicals as inhibitors of oxidative damage to cellular DNA. Mutat Res 485,
243. T. Masuda, T. Maekawa, K. Hidaka, H. Bando, Y. Takeda, and H. Yamaguchi, Chem-
ical studies on antioxidant mechanism of curcumin: analysis of oxidative coupling
products from curcumin and linoleate. J Agric Food Chem 49, 2539–2547 (2001).
244. K. C. Das and C. K. Das, Curcumin (diferuloylmethane), a singlet oxygen ((1)O(2))
quencher. Biochem Biophys Res Commun 295, 62–66 (2002).
245. G. K. Jayaprakasha, B. S. Jena, P. S. Negi, and K. K. Sakariah, Evaluation of an-
tioxidant activities and antimutagenicity of turmeric oil: a byproduct from curcumin
production. Z Naturforsch [C] 57, 828–835 (2002).
246. R. Toniolo, F. Di Narda, S. Susmel, M. Martelli, L. Martelli, and G. Bontempelli,
Quenching of superoxide ions by curcumin. A mechanistic study in acetonitrile. Ann
Chim 92, 281–288 (2002).
247. M. Balasubramanyam, A. A. Koteswari, R. S. Kumar, S. F. Monickaraj, J. U.
Maheswari, and V. Mohan, Curcumin-induced inhibition of cellular reactive oxygen
species generation: novel therapeutic implications. J Biosci 28, 715–721 (2003).
248. A. Betancor-Fernandez, A. Perez-Galvez, H. Sies, and W. Stahl, Screening pharma-
ceutical preparations containing extracts of turmeric rhizome, artichoke leaf, devil’s
claw root and garlic or salmon oil for antioxidant capacity. J Pharm Pharmacol 55,
249. S. M. Chauhan, A. S. Kandadai, N. Jain, and A. Kumar, Biomimetic oxidation of cur-
chlorides in dichloromethane. Chem Pharm Bull (Tokyo) 51, 1345–1347 (2003).
250. M. Iqbal, Y. Okazaki and S. Okada, In vitro curcumin modulates ferric nitrilotriac-
etate (Fe-NTA) and hydrogen peroxide (H2O2)-induced peroxidation of microsomal
membrane lipids and DNA damage. Teratog Carcinog Mutagen 1(Suppl), 151–160
251. B. D. Johnston and E. G. DeMaster, Suppression of nitric oxide oxidation to nitrite
by curcumin is due to the sequestration of the reaction intermediate nitrogen dioxide,
not nitric oxide. Nitric Oxide 8, 231–234 (2003).
252. R. Rukkumani, M. Sri Balasubashini, and V. P. Menon, Protective effects of curcumin
and photo-irradiated curcumin on circulatory lipids and lipid peroxidation products in
alcohol and polyunsaturated fatty acid-induced toxicity. Phytother Res 17, 925–929
oxidative damage and trace elements level in the liver of rats and mice. Toxicol Lett
151, 79–85 (2004).
Res 24, 563–569 (2004).
255. M. O. Iwunze and D. McEwan, Peroxynitrite interaction with curcumin solubilized
in ethanolic solution. Cell Mol Biol (Noisy-le-grand) 50, 749–752 (2004).
256. C. Kalpana and V. P. Menon, Modulatory effects of curcumin on lipid peroxidation
and antioxidant status during nicotine-induced toxicity. Pol J Pharmacol 56, 581–586
December 22, 2006 16:34
30 AGGARWAL ET AL.
on the antioxidant status of red blood cells and the liver in high-fat-fed rats. Ann Nutr
Metab 48, 314–320 (2004).
258. B. Mishra, K. I. Priyadarsini, M. K. Bhide, R. M. Kadam, and H. Mohan, Reactions
of superoxide radicals with curcumin: Probable mechanisms by optical spectroscopy
and EPR. Free Radical Res 38, 355–362 (2004).
259. R. Barreto, S. Kawakita, J. Tsuchiya, E. Minelli, K. Pavasuthipaisit, A. Helmy, and F.
Marotta, Metal-induced oxidative damage in cultured hepatocytes and hepatic lyso-
somal fraction: beneficial effect of a curcumin/absinthium compound. Chin J Dig Dis
260. J. Chen, D. Wanming, D. Zhang, Q. Liu, and J. Kang, Water-soluble antioxidants
improve the antioxidant and anticancer activity of low concentrations of curcumin in
human leukemia cells. Pharmazie 60, 57–61 (2005).
261. S. Durgaprasad, C. G. Pai, Vasanthkumar, J. F. Alvres, and S. Namitha, A pilot study
of the antioxidant effect of curcumin in tropical pancreatitis. Indian J Med Res 122,
262. V. Eybl, D. Kotyzova, L. Leseticky, M. Bludovska, and J. Koutensky, The influence
of curcumin and manganese complex of curcumin on cadmium-induced oxidative
damage and trace elements status in tissues of mice. J Appl Toxicol 26(3), 207–212
263. W. M. Weber, L. A. Hunsaker, S. F. Abcouwer, L. M. Deck, and D. L. Vander Jagt,
Anti-oxidant activities of curcumin and related enones. Bioorg Med Chem 13, 3811–
264. M. Sreepriya and G. Bali, Effects of administration of Embelin and Curcumin on
lipid peroxidation, hepatic glutathione antioxidant defense and hematopoietic system
during N-nitrosodiethylamine/Phenobarbital-induced hepatocarcinogenesis in Wistar
rats. Mol Cell Biochem, 1–7 (2006).
Biophys Acta 1760, 70–77 (2006).
266. A. R. Shahed, E. Jones, and D. Shoskes, Quercetin and curcumin up-regulate antiox-
idant gene expression in rat kidney after ureteral obstruction or ischemia/reperfusion
injury. Transplant Proc 33, 2988 (2001).
267. F. Bonte, M. S. Noel-Hudson, J. Wepierre and A. Meybeck, Protective effect of cur-
cuminoids on epidermal skin cells under free oxygen radical stress. Planta Med 63,
268. S. Watanabe and T. Fukui, Suppressive effect of curcumin on trichloroethylene-
induced oxidative stress. J Nutr Sci Vitaminol (Tokyo) 46, 230–234 (2000).
269. J. L. Quiles, M. D. Mesa, C. L. Ramirez-Tortosa, C. M. Aguilera, M. Battino, A. Gil
stress and attenuates aortic fatty streak development in rabbits. Arterioscler Thromb
Vasc Biol 22, 1225–1231 (2002).
270. W. H. Chan, C. C. Wu, and J. S. Yu, Curcumin inhibits UV irradiation-induced oxida-
tive stress and apoptotic biochemical changes in human epidermoid carcinoma A431
cells. J Cell Biochem 90, 327–338 (2003).
271. P. Mahakunakorn, M. Tohda, Y. Murakami, K. Matsumoto, H. Watanabe, and O.
Vajaragupta, Cytoprotective and cytotoxic effects of curcumin: dual action on H2O2-
induced oxidative cell damage in NG108-15 cells. Biol Pharm Bull 26, 725–728
December 22, 200616:34
CURCUMIN: THE INDIAN SOLID GOLD 31
272. R. Rukkumani, K. Aruna, P. S. Varma, K. N. Rajasekaran, and V. P. Menon, Compar-
ative effects of curcumin and an analog of curcumin on alcohol and PUFA induced
oxidative stress. J Pharm Pharm Sci 7, 274–283 (2004).
273. R. Banjerdpongchai and P. Wilairat, Effects of water-soluble antioxidants and
MAPKK/MEK inhibitor on curcumin-induced apoptosis in HL-60 human leukemic
cells. Asian Pac J Cancer Prev 6, 282–285 (2005).
J Cell Physiol 205, 379–386 (2005).
treatment against oxidative stress in streptozotocin-induced diabetic rats. J Med Food
8, 251–255 (2005).
276. K. U. Schallreuter and H. Rokos, Turmeric (curcumin): A widely used curry ingredi-
ent, can contribute to oxidative stress in Asian patients with acute vitiligo. Indian J
Dermatol Venereol Leprol 72, 57–59 (2006).
277. I. Chattopadhyay, U. Bandyopadhyay, K. Biswas, P. Maity, and R. K. Banerjee, In-
domethacin inactivates gastric peroxidase to induce reactive-oxygen-mediated gastric
mucosal injury and curcumin protects it by preventing peroxidase inactivation and
scavenging reactive oxygen. Free Radical Biol Med 40, 1397–1408 (2006).
278. K. Cleary and R. F. McFeeters, Effects of oxygen and turmeric on the formation of
oxidative aldehydes in fresh-pack dill pickles. J Agric Food Chem 54, 3421–3427
279. G. Scapagnini, C. Colombrita, M. Amadio, V. D’Agata, E. Arcelli, M. Sapienza, A.
against oxidative stress. Antioxid Redox Signal 8, 395–403 (2006).
280. M. Yoshino, M. Haneda, M. Naruse, H. H. Htay, R. Tsubouchi, S. L. Qiao, W. H. Li,
K. Murakami, and T. Yokochi, Prooxidant activity of curcumin: Copper-dependent
formation of 8-hydroxy-2’-deoxyguanosine in DNA and induction of apoptotic cell
death. Toxicol In Vitro 18, 783–789 (2004).
duction and membrane mobility in curcumin- and tetrahydrocurcumin-treated human
gingival fibroblasts and human submandibular gland carcinoma cells. Oral Dis 11,
282. S. Fujisawa and Y. Kadoma, Anti- and pro-oxidant effects of oxidized quercetin,
curcumin or curcumin-related compounds with thiols or ascorbate as measured by the
induction period method. In Vivo 20, 39–44 (2006).
283. S. Bhaumik, R. Anjum, N. Rangaraj, B. V. Pardhasaradhi, and A. Khar, Curcumin
mediated apoptosis in AK-5 tumor cells involves the production of reactive oxygen
intermediates. FEBS Lett 456, 311–314 (1999).
284. J. Fang, J. Lu, and A. Holmgren, Thioredoxin reductase is irreversibly modified by
curcumin: A novel molecular mechanism for its anticancer activity. J Biol Chem 280,
hepatoma. J Biol Chem 248, 1219–1223 (1973).
286. E. C. Moore, A thioredoxin–thioredoxin reductase system from rat tumor. Biochem
Biophys Res Commun 29, 264–8, (1967).
287. K. U. Schallreuter and J. M. Wood, The activity and purification of membrane–
associated thioredoxin reductase from human metastatic melanotic melanoma.
Biochim Biophys Acta 967, 103–109 (1988).
December 22, 2006 16:34
32 AGGARWAL ET AL.
288. J. L. Quiles, C. Aguilera, M. D. Mesa, M. C. Ramirez-Tortosa, L. Baro, and A.
Gil, An ethanolic-aqueous extract of Curcuma longa decreases the susceptibility of
liver microsomes and mitochondria to lipid peroxidation in atherosclerotic rabbits.
Biofactors 8, 51–57 (1998).
289. L. M. Antunes, J. D. Darin, and L. Bianchi Nde, Effects of the antioxidants cur-
cumin or selenium on cisplatin-induced nephrotoxicity and lipid peroxidation in rats.
Pharmacol Res 43, 145–150 (2001).
290. A. Singh, S. P. Singh, and R. Bamezai, Postnatal modulation of hepatic biotransfor-
mation system enzymes via translactational exposure of F1 mouse pups to turmeric
and curcumin. Cancer Lett 96, 87–93 (1995).
of curcumin on cytochrome P450 and glutathione S–transferase activities in rat liver.
Biochem Pharmacol 51, 39–45 (1996).
hepatic biotransformation system enzymes in lactating mice and translactationally
exposed F1 pups. Nutr Cancer 25, 101–110 (1996).
293. M. L. van Iersel, J. P. Ploemen, M. Lo Bello, G. Federici, and P. J. van Bladeren,
S-transferase P1-1. Chem Biol Interact 108, 67–78 (1997).
294. M. Iqbal, S. D. Sharma, Y. Okazaki, M. Fujisawa, and S. Okada, Dietary supplemen-
tation of curcumin enhances antioxidant and phase II metabolizing enzymes in ddY
male mice: possible role in protection against chemical carcinogenesis and toxicity.
Pharmacol Toxicol 92, 33–38 (2003).
295. Y. Jiao, J. t. Wilkinson, E. Christine Pietsch, J. L. Buss, W. Wang, R. Planalp, F.
M. Torti, and S. V. Torti, Iron chelation in the biological activity of curcumin. Free
Radical Biol Med 40, 1152–1160 (2006).
296. A. C. Bharti, N. Donato, and B. B. Aggarwal, Curcumin (diferuloylmethane) inhibits
constitutive and IL-6-inducible STAT3 phosphorylation in human multiple myeloma
cells. J Immunol 171, 3863–3871 (2003).
297. R. K. Giri, V. Rajagopal, and V. K. Kalra, Curcumin, the active constituent of
turmeric, inhibits amyloid peptide-induced cytochemokine gene expression and
CCR5-mediated chemotaxis of THP-1 monocytes by modulating early growth
response-1 transcription factor. J Neurochem 91, 1199–1210 (2004).
298. D. Ranjan, C. Chen, T. D. Johnston, H. Jeon, and M. Nagabhushan, Curcumin in-
hibits mitogen stimulated lymphocyte proliferation, NFkappaB activation, and IL-2
signaling. J Surg Res 121, 171–177 (2004).
299. J. L. Arbiser, N. Klauber, R. Rohan, R. van Leeuwen, M. T. Huang, C. Fisher, E.
Flynn, and H. R. Byers, Curcumin is an in vivo inhibitor of angiogenesis. Mol Med 4,
300. D. Thaloor, A. K. Singh, G. S. Sidhu, P. V. Prasad, H. K. Kleinman, and R. K.
Maheshwari, Inhibition of angiogenic differentiation of human umbilical vein en-
dothelial cells by curcumin. Cell Growth Differ 9, 305–312 (1998).
301. J. S. Shim, J. H. Kim, H. Y. Cho, Y. N. Yum, S. H. Kim, H. J. Park, B. S. Shim, S.
H. Choi, and H. J. Kwon, Irreversible inhibition of CD13/aminopeptidase N by the
antiangiogenic agent curcumin. Chem Biol 10, 695–704 (2003).
giogenic activity of curcumin in hepatocellular carcinoma cells implanted nude mice.
Clin Hemorheol Microcirc 33, 127–135 (2005).
December 22, 2006 16:34
CURCUMIN: THE INDIAN SOLID GOLD 33
303. P. Yoysungnoen, P. Wirachwong, P. Bhattarakosol, H. Niimi, and S. Patumraj, Effects
of curcumin on tumor angiogenesis and biomarkers, COX-2 and VEGF, in hepato-
cellular carcinoma cell-implanted nude mice. Clin Hemorheol Microcirc 34, 109–115
304. A. Barik, K. I. Priyadarsini, and H. Mohan, Photophysical studies on binding of
curcumin to bovine serum albumins. Photochem Photobiol 77, 597–603 (2003).
305. F. Zsila, Z. Bikadi, and M. Simonyi, Unique, pH-dependent biphasic band shape of
the visible circular dichroism of curcumin-serum albumin complex. Biochem Biophys
Res Commun 301, 776–782 (2003).
306. A. Barik, B. Mishra, L. Shen, H. Mohan, R. M. Kadam, S. Dutta, H. Y. Zhang, and
K. I. Priyadarsini, Evaluation of a new copper(II)-curcumin complex as superoxide
dismutase mimic and its free radical reactions. Free Radical Biol Med 39, 811–822
of curcumin in complex with lipoxygenase and its significance in cancer. Int J Mol
Med 12, 17–24 (2003).
308. R. S. Ramsewak, D. L. DeWitt, and M. G. Nair, Cytotoxicity, antioxidant and anti-
inflammatory activities of curcumins I-III from Curcuma longa. Phytomedicine 7,
kinase in human multiple myeloma cells, leading to suppression of proliferation and
induction of apoptosis. Blood 101, 1053–1062 (2003).
310. N. Romiti, R. Tongiani, F. Cervelli, and E. Chieli, Effects of curcumin on P-
glycoprotein in primary cultures of rat hepatocytes. Life Sci 62, 2349–2358 (1998).
Modulation of P-glycoprotein expression and function by curcumin in multidrug-
resistant human KB cells. Biochem Pharmacol 64, 573–582 (2002).
312. R. D. Snyder and M. R. Arnone, Putative identification of functional interactions
between DNA intercalating agents and topoisomerase II using the V79 in vitro mi-
cronucleus assay. Mutat Res 503, 21–35 (2002).
313. J. L. Dyer, S. Z. Khan, J. G. Bilmen, S. R. Hawtin, M. Wheatley, M. U. Javed,
and F. Michelangeli, Curcumin: a new cell-permeant inhibitor of the inositol 1,4,5-
trisphosphate receptor. Cell Calcium 31, 45–52 (2002).
of curcumin (diferuloyl methane) in patients with postoperative inflammation. Int J
Clin Pharmacol Ther Toxicol 24, 651–654 (1986).
315. G. J. Kelloff, C. W. Boone, J. A. Crowell, V. E. Steele, R. Lubet, and C. C. Sigman,
Chemopreventive drug development: perspectives and progress. Cancer Epidemiol
Biomarkers Prev 3, 85–98 (1994).
316. J. S. James, Curcumin: Clinical trial finds no antiviral effect. AIDS Treat News
(no. 242), 1–2 (1996).
317. G. Shoba, D. Joy, T. Joseph, M. Majeed, R. Rajendran, and P. S. Srinivas, Influence
of piperine on the pharmacokinetics of curcumin in animals and human volunteers.
Planta Med 64, 353–356,(1998).
318. B. Lal, A. K. Kapoor, O. P. Asthana, P. K. Agrawal, R. Prasad, P. Kumar, and R. C.
Res 13, 318–322 (1999).
December 22, 200616:34
34 AGGARWAL ET AL.
319. A. Rasyid and A. Lelo, The effect of curcumin and placebo on human gall-bladder
function: an ultrasound study. Aliment Pharmacol Ther 13, 245–249,(1999).
320. M. C. Heng, M. K. Song, J. Harker, and M. K. Heng, Drug-induced suppression
of phosphorylase kinase activity correlates with resolution of psoriasis as assessed
by clinical, histological and immunohistochemical parameters. Br J Dermatol 143,
321. R. Lodha and A. Bagga, Traditional Indian systems of medicine. Ann Acad Med
Singapore 29, 37–41 (2000).
322. A. L. Cheng, C. H. Hsu, J. K. Lin, M. M. Hsu, Y. F. Ho, T. S. Shen, J. Y. Ko, J. T.
Lin, B. R. Lin, W. Ming-Shiang, H. S. Yu, S. H. Jee, G. S. Chen, T. M. Chen, C.
A. Chen, M. K. Lai, Y. S. Pu, M. H. Pan, Y. J. Wang, C. C. Tsai, and C. Y. Hsieh,
Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk
or pre-malignant lesions. Anticancer Res 21, 2895–2900 (2001).
323. S. M. Plummer, K. A. Hill, M. F. Festing, W. P. Steward, A. J. Gescher, and R. A.
Sharma, Clinical development of leukocyte cyclooxygenase 2 activity as a systemic
biomarker for cancer chemopreventive agents. Cancer Epidemiol Biomarkers Prev
10, 1295–1299 (2001).
324. R. A. Sharma, H. R. McLelland, K. A. Hill, C. R. Ireson, S. A. Euden, M. M. Manson,
M. Pirmohamed, L. J. Marnett, A. J. Gescher, and W. P. Steward, Pharmacodynamic
and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer.
Clin Cancer Res 7, 1894–1900 (2001).
on human gall bladder. Asia Pacific J Clin Nutr 11, 314–318 (2002).
326. M. Bayes, X. Rabasseda, and J. R. Prous, Gateways to clinical trials. Methods Find
Exp Clin Pharmacol 26, 723–753 (2004).
327. G. M. Cole, T. Morihara, G. P. Lim, F. Yang, A. Begum, and S. A. Frautschy, NSAID
and antioxidant prevention of Alzheimer’s disease: Lessons from in vitro and animal
models. Ann N Y Acad Sci 1035, 68–84 (2004).
328. G. Garcea, D. J. Jones, R. Singh, A. R. Dennison, P. B. Farmer, R. A. Sharma, W. P.
Steward, A. J. Gescher, and D. P. Berry, Detection of curcumin and its metabolites in
hepatic tissue and portal blood of patients following oral administration. Br J Cancer
90, 1011–1015 (2004).
329. R. A. Sharma, S. A. Euden, S. L. Platton, D. N. Cooke, A. Shafayat, H. R. Hewitt,
T. H. Marczylo, B. Morgan, D. Hemingway, S. M. Plummer, M. Pirmohamed, A. J.
Gescher, and W. P. Steward, Phase I clinical trial of oral curcumin: biomarkers of
systemic activity and compliance. Clin Cancer Res 10, 6847–6854 (2004).
330. M. Bayes, X. Rabasseda, and J. R. Prous, Gateways to clinical trials. Methods Find
Exp Clin Pharmacol 27, 711–738 (2005).
331. G. Garcea, D. P. Berry, D. J. Jones, R. Singh, A. R. Dennison, P. B. Farmer, R.
A. Sharma, W. P. Steward, and A. J. Gescher, Consumption of the putative chemo-
preventive agent curcumin by cancer patients: assessment of curcumin levels in the
Prev 14, 120–125 (2005).
A pilot study. Dig Dis Sci 50, 2191–2193 (2005).
333. D. Shoskes, C. Lapierre, M. Cruz-Corerra, N. Muruve, R. Rosario, B. Fromkin, M.
Braun, and J. Copley, Beneficial effects of the bioflavonoids curcumin and quercetin
on early function in cadaveric renal transplantation: A randomized placebo controlled
trial. Transplantation 80, 1556–1559 (2005).
December 22, 200616:34
CURCUMIN: THE INDIAN SOLID GOLD 35
334. C. D. Lao, M. T. t. Ruffin, D. Normolle, D. D. Heath, S. I. Murray, J. M. Bailey, M. E.
Boggs, J. Crowell, C. L. Rock, and D. E. Brenner, Dose escalation of a curcuminoid
formulation. BMC Complement Altern Med 6, 10 (2006).
F. M. Giardiello, Combination treatment with curcumin and quercetin of adenomas in
familial adenomatous polyposis. Clin Gastroenterol Hepatol 4, 1035–1038 (2006).
336. I. Gukovsky, C. N. Reyes, E. C. Vaquero, A. S. Gukovskaya, and S. J. Pandol, Cur-
cumin ameliorates ethanol and nonethanol experimental pancreatitis. Am J Physiol
Gastrointest Liver Physiol 284, G85–G9, (2003).
337. A. Gulcubuk, K. Sonmez, A. Gurel, K. Altunatmaz, N. Gurler, S. Aydin, L. Oksuz,
H. Uzun, and O. Guzel, Pathologic alterations detected in acute pancreatitis induced
by sodium taurocholate in rats and therapeutic effects of curcumin, ciprofloxacin and
metronidazole combination. Pancreatology 5, 345–353 (2005).
339. A. Liacini, J. Sylvester, W. Q. Li, and M. Zafarullah, Inhibition of interleukin-1-
stimulated MAP kinases, activating protein-1 (AP-1) and nuclear factor kappa B
(NF-kappa B) transcription factors down-regulates matrix metalloproteinase gene ex-
pression in articular chondrocytes. Matrix Biol 21, 251–262 (2002).
Induction of matrix metalloproteinase-13 gene expression by TNF-alpha is mediated
Exp Cell Res 288, 208–217 (2003).
pathways implicated in inducing matrix metalloproteinase-3, -13 and aggrecanase-1
genes in articular chondrocytes. Cell Signal 16, 469–476 (2004).
342. K. Sugimoto, H. Hanai, K. Tozawa, T. Aoshi, M. Uchijima, T. Nagata, and Y. Koide,
Curcumin prevents and ameliorates trinitrobenzene sulfonic acid-induced colitis in
mice. Gastroenterology 123, 1912–1922 (2002).
343. B. Salh, K. Assi, V. Templeman, K. Parhar, D. Owen, A. Gomez-Munoz, and
K. Jacobson, Curcumin attenuates DNB-induced murine colitis. Am J Physiol Gas-
trointest Liver Physiol 285, G235–G243 (2003).
344. Y. Jiang, Z. S. Li, F. S. Jiang, X. Deng, C. S. Yao, and G. Nie, Effects of different
ingredients of zedoary on gene expression of HSC-T6 cells. World J Gastroenterol
11, 6780–6786 (2005).
345. D. C. Kim, S. H. Kim, B. H. Choi, N. I. Baek, D. Kim, M. J. Kim, and K. T. Kim, Cur-
Biol Pharm Bull 28, 2220–2224 (2005).
346. S. Swarnakar, K. Ganguly, P. Kundu, A. Banerjee, P. Maity, and A. V. Sharma, Cur-
cumin regulates expression and activity of matrix metalloproteinases 9 and 2 during
347. O. S. Baek, O. H. Kang, Y. A. Choi, S. C. Choi, T. H. Kim, Y. H. Nah, D. Y. Kwon,
Y. K. Kim, Y. H. Kim, K. H. Bae, J. P. Lim, and Y. M. Lee, Curcumin inhibits
protease-activated receptor-2 and -4-mediated mast cell activation. Clin Chim Acta
338, 135–141 (2003).
348. A. Ram, M. Das, and B. Ghosh, Curcumin attenuates allergen-induced airway hyper-
responsiveness in sensitized guinea pigs. Biol Pharm Bull 26, 1021–1024 (2003).
December 22, 2006 16:34
36 AGGARWAL ET AL.
349. J. J. Lee, W. T. Huang, D. Z. Shao, J. F. Liao, and M. T. Lin, Blocking NF-kappaB
activation may be an effective strategy in the fever therapy. Jpn J Physiol 53, 367–375
Curcumin-induced apoptosis in scleroderma lung fibroblasts: role of protein kinase
cepsilon. Am J Respir Cell Mol Biol 31, 28–35 (2004).
immunomodulating properties and some reference antipsoriatic drugs in the modified
mouse tail test, an animal model of psoriasis. Skin Pharmacol 7, 324–334 (1994).
353. R. Verbeek, E. A. van Tol, and J. M. van Noort, Oral flavonoids delay recovery from
experimental autoimmune encephalomyelitis in SJL mice. Biochem Pharmacol 70,
354. P. S. Babu and K. Srinivasan, Influence of dietary curcumin and cholesterol on the
progression of experimentally induced diabetes in albino rat. Mol Cell Biochem 152,
turmeric (Curcuma longa) in streptozotocin induced diabetic rats. Mol Cell Biochem
166, 169–175 (1997).
356. G. B. Sajithlal, P. Chithra, and G. Chandrakasan, Effect of curcumin on the advanced
357. N. Arun and N. Nalini, Efficacy of turmeric on blood sugar and polyol pathway in
diabetic albino rats. Plant Foods Hum Nutr 57, 41–52 (2002).
358. R. K. Kempaiah and K. Srinivasan, Antioxidant status of red blood cells and liver in
359. T. Mahesh, M. M. Sri Balasubashini, and V. P. Menon, Photo-irradiated curcumin
supplementation in streptozotocin-induced diabetic rats: effect on lipid peroxidation.
Therapie 59, 639–644 (2004).
360. M. Kuroda, Y. Mimaki, T. Nishiyama, T. Mae, H. Kishida, M. Tsukagawa, K. Taka-
hashi, T. Kawada, K. Nakagawa, and M. Kitahara, Hypoglycemic effects of turmeric
(Curcuma longa L. rhizomes) on genetically diabetic KK-Ay mice. Biol Pharm Bull
28, 937–939 (2005).
361. J. B. Majithiya and R. Balaraman, Time-dependent changes in antioxidant enzymes
and vascular reactivity of aorta in streptozotocin-induced diabetic rats treated with
curcumin. J Cardiovasc Pharmacol 46, 697–705 (2005).
362. T. Osawa and Y. Kato, Protective role of antioxidative food factors in oxidative stress
caused by hyperglycemia. Ann NY Acad Sci 1043, 440–451 (2005).
apy: Common targets and common goals. Expert Opin Invest Drugs 13, 1327–1338
364. J. L. Abbruzzese and S. M. Lippman, The convergence of cancer prevention and
therapy in early-phase clinical drug development. Cancer Cell 6, 321–326 (2004).
K. Wakabayashi, Potent preventive action of curcumin on radiation-induced initiation
of mammary tumorigenesis in rats. Carcinogenesis 21, 1835–1841 (2000).
December 22, 2006 16:34
CURCUMIN: THE INDIAN SOLID GOLD 37
A. L. Cheng, Curcumin-containing diet inhibits diethylnitrosamine-induced murine
hepatocarcinogenesis. Carcinogenesis 21, 331–335 (2000).
367. S. E. Chuang, A. L. Cheng, J. K. Lin, and M. L. Kuo, Inhibition by curcumin of
and cell-cycle-related proteins in rats. Food Chem Toxicol 38, 991–995 (2000).
368. C. C. Chua, R. C. Hamdy, and B. H. Chua, Mechanism of transforming growth factor-
beta1-induced expression of vascular endothelial growth factor in murine osteoblastic
MC3T3-E1 cells. Biochim Biophys Acta 1497, 69–76 (2000).
in wistar rats. Nutr Cancer 45, 53–59 (2003).
nitrosodiethylamine/phenobarbital-induced hepatocarcinogenesis in Wistar rats. Fi-
toterapia 76, 549–555 (2005).
371. M. C. Jiang, H. F. Yang-Yen, J. K. Lin, and J. J. Yen, Differential regulation of p53, c-
Myc, Bcl-2 and Bax protein expression during apoptosis induced by widely divergent
stimuli in human hepatoblastoma cells. Oncogene 13, 609–616 (1996).
372. K. Imaida, S. Tamano, K. Kato, Y. Ikeda, M. Asamoto, S. Takahashi, Z. Nir, M.
Murakoshi, H. Nishino, and T. Shirai, Lack of chemopreventive effects of lycopene
and curcumin on experimental rat prostate carcinogenesis. Carcinogenesis 22, 467–
373. M. L. Kuo, T. S. Huang, and J. K. Lin, Curcumin, an antioxidant and anti-tumor
promoter, induces apoptosis in human leukemia cells. Biochim Biophys Acta 1317,
374. Y. Wu, Y. Chen, and W. Chen, Effects of concurrent use of rh-IFN-gamma and cur-
375. A. Bielak-Zmijewska, M. Koronkiewicz, J. Skierski, K. Piwocka, E. Radziszewska,
and E. Sikora, Effect of curcumin on the apoptosis of rodent and human nonprolifer-
ating and proliferating lymphoid cells. Nutr Cancer 38, 131–138 (2000).
376. Y. Chen, Y. Wu, J. He, and W. Chen, The experimental and clinical study on the
effect of curcumin on cell cycle proteins and regulating proteins of apoptosis in acute
myelogenous leukemia. J Huazhong Univ Sci Technol Med Sci 22, 295–298 (2002).
377. A. Duvoix, F. Morceau, M. Schnekenburger, S. Delhalle, M. M. Galteau, M. Dicato,
and M. Diederich, Curcumin-induced cell death in two leukemia cell lines: K562 and
Jurkat. Ann NY Acad Sci 1010, 389–392 (2003).
378. L. X. Wu, J. H. Xu, G. H. Wu, and Y. Z. Chen, Inhibitory effect of curcumin on
proliferation of K562 cells involves down-regulation of p210(bcr/abl) initiated Ras
signal transduction pathway. Acta Pharmacol Sin 24, 1155–1160 (2003).
379. A. Bielak-Mijewska, K. Piwocka, A. Magalska, and E. Sikora, P-glycoprotein ex-
pression does not change the apoptotic pathway induced by curcumin in HL-60 cells.
Cancer Chemother Pharmacol 53, 179–185 (2004).
380. E. Sikora, A. Bielak-Zmijewska, K. Piwocka, J. Skierski, and E. Radziszewska, Inhi-
bition of proliferation and apoptosis of human and rat T lymphocytes by curcumin, a
curry pigment. Biochem Pharmacol 54, 899–907 (1997).
and caspases, induced by curcumin in human lymphoblastoid T (Jurkat) cells. Exp
Cell Res 249, 299–307 (1999).
December 22, 200616:34
38 AGGARWAL ET AL.
382. E. Jaruga, S. Salvioli, J. Dobrucki, S. Chrul, J. Bandorowicz-Pikula, E. Sikora, C.
Franceschi, A. Cossarizza, and G. Bartosz, Apoptosis-like, reversible changes in
plasma membrane asymmetry and permeability, and transient modifications in mi-
tochondrial membrane potential induced by curcumin in rat thymocytes. FEBS Lett
433, 287–293 (1998).
383. D. Ranjan, T. D. Johnston, K. S. Reddy, G. Wu, S. Bondada, and C. Chen, Enhanced
apoptosis mediates inhibition of EBV-transformed lymphoblastoid cell line prolifer-
ation by curcumin. J Surg Res 87, 1–5 (1999).
384. H. L. Liu, Y. Chen, G. H. Cui, and J. F. Zhou, Curcumin, a potent anti-tumor reagent,
is a novel histone deacetylase inhibitor regulating B-NHL cell line Raji proliferation.
Acta Pharmacol Sin 26, 603–609 (2005).
385. S. Shishodia, G. Sethi, and B. B. Aggarwal, Curcumin: Getting back to the roots. Ann
NY Acad Sci 1056, 206–217 (2005).
386. C. Sun, X. Liu, Y. Chen, and F. Liu, Anticancer effect of curcumin on human B cell
non-Hodgkin’s lymphoma. J Huazhong Univ Sci Technolog Med Sci 25, 404–407
lymphoma. Zhonghua Zhong Liu Za Zhi 24, 348–352 (2002).
388. A. C. Bharti, S. Shishodia, J. M. Reuben, D. Weber, R. Alexanian, S. Raj-Vadhan,
Z. Estrov, M. Talpaz, and B. B. Aggarwal, Nuclear factor-kappaB and STAT3 are
constitutively active in CD138+ cells derived from multiple myeloma patients, and
suppression of these transcription factors leads to apoptosis. Blood 103, 3175–3184
389. S. Uddin, A. R. Hussain, P. S. Manogaran, K. Al-Hussein, L. C. Platanias, M. I.
Gutierrez, and K. G. Bhatia, Curcumin suppresses growth and induces apoptosis in
primary effusion lymphoma. Oncogene 24, 7022–7030 (2005).
by curcumin induces apoptosis through mitochondrial pathway. J Biol Chem 279,
391. A. Liontas and H. Yeger, Curcumin and resveratrol induce apoptosis and nuclear
translocation and activation of p53 in human neuroblastoma. Anticancer Res 24, 987–
by garcinol and curcumin through cytochrome c release and activation of caspases in
human leukemia HL-60 cells. J Agric Food Chem 49, 1464–1474 (2001).
393. S. Nagai, M. Kurimoto, K. Washiyama, Y. Hirashima, T. Kumanishi, and S. Endo,
Inhibition of cellular proliferation and induction of apoptosis by curcumin in human
malignant astrocytoma cell lines. J Neurooncol 74, 105–111 (2005).
394. K. Mehta, P. Pantazis, T. McQueen, and B. B. Aggarwal, Antiproliferative effect
of curcumin (diferuloylmethane) against human breast tumor cell lines. Anticancer
Drugs 8, 470–481 (1997).
395. C. Ramachandran and W. You, Differential sensitivity of human mammary epithelial
and breast carcinoma cell lines to curcumin. Breast Cancer Res Treat 54, 269–278
in human breast cancer cells through p53-dependent Bax induction. FEBS Lett 512,
397. J. M. Holy, Curcumin disrupts mitotic spindle structure and induces micronucleation
in MCF-7 breast cancer cells. Mutat Res 518, 71–84 (2002).
December 22, 2006 16:34
CURCUMIN: THE INDIAN SOLID GOLD 39
398. Z. M. Shao, Z. Z. Shen, C. H. Liu, M. R. Sartippour, V. L. Go, D. Heber, and M.
Nguyen, Curcumin exerts multiple suppressive effects on human breast carcinoma
cells. Int J Cancer 98, 234–240 (2002).
399. C. Ramachandran, S. Rodriguez, R. Ramachandran, P. K. Raveendran Nair, H. Fon-
seca, Z. Khatib, E. Escalon, and S. J. Melnick, Expression profiles of apoptotic genes
induced by curcumin in human breast cancer and mammary epithelial cell lines. An-
ticancer Res 25, 3293–3302 (2005).
400. L. Moragoda, R. Jaszewski, and A. P. Majumdar, Curcumin induced modulation of
cell cycle and apoptosis in gastric and colon cancer cells. Anticancer Res 21, 873–878
401. S. Aggarwal, Y. Takada, S. Singh, J. N. Myers, and B. B. Aggarwal, Inhibition of
growth and survival of human head and neck squamous cell carcinoma cells by cur-
cumin via modulation of nuclear factor-kappaB signaling. Int J Cancer 111, 679–692
402. G. Radhakrishna Pillai, A. S. Srivastava, T. I. Hassanein, D. P. Chauhan, and E.
Carrier, Induction of apoptosis in human lung cancer cells by curcumin. Cancer Lett
208, 163–170 (2004).
403. L. Li, B. B. Aggarwal, S. Shishodia, J. Abbruzzese, and R. Kurzrock, Nuclear factor-
kappaB and IkappaB kinase are constitutively active in human pancreatic cells, and
sion of proliferation and the induction of apoptosis. Cancer 101, 2351–2362 (2004).
404. M. Shi, Q. Cai, L. Yao, Y. Mao, Y. Ming, and G. Ouyang, Antiproliferation and
apoptosis induced by curcumin in human ovarian cancer cells. Cell Biol Int 30, 221–
405. R. Kuttan, P. C. Sudheeran, and C. D. Josph, Turmeric and curcumin as topical agents
in cancer therapy. Tumori 73, 29–31 (1987).
406. M. A. Azuine and S. V. Bhide, Chemopreventive effect of turmeric against stomach
and skin tumors induced by chemical carcinogens in Swiss mice. Nutr Cancer 17,
407. M. T. Huang, E. E. Deschner, H. L. Newmark, Z. Y. Wang, T. A. Ferraro, and A.
H. Conney, Effect of dietary curcumin and ascorbyl palmitate on azoxymethanol-
induced colonic epithelial cell proliferation and focal areas of dysplasia. Cancer Lett
64, 117–121 (1992).
408. M. T. Huang, Z. Y. Wang, C. A. Georgiadis, J. D. Laskin, and A. H. Conney,
Inhibitory effects of curcumin on tumor initiation by benzo[a]pyrene and 7,12-
dimethylbenz[a]anthracene. Carcinogenesis 13, 2183–2186 (1992).
409. M. T. Huang, W. Ma, P. Yen, J. G. Xie, J. Han, K. Frenkel, D. Grunberger, and A. H.
Conney, Inhibitory effects of topical application of low doses of curcumin on 12-O-
tetradecanoylphorbol-13-acetate-induced tumor promotion and oxidized DNA bases
in mouse epidermis. Carcinogenesis 18, 83–88 (1997).
410. P. Limtrakul, S. Lipigorngoson, O. Namwong, A. Apisariyakul, and F. W. Dunn,
411. M. C. Jiang, H. F. Yang-Yen, J. J. Yen, and J. K. Lin, Curcumin induces apoptosis
in immortalized NIH 3T3 and malignant cancer cell lines. Nutr Cancer 26, 111–120
412. J. A. Bush, K. J. Cheung, Jr., and G. Li, Curcumin induces apoptosis in human
melanoma cells through a Fas receptor/caspase-8 pathway independent of p53. Exp
Cell Res 271, 305–314 (2001).
December 22, 2006 16:34
40AGGARWAL ET AL.
413. M. Zheng, S. Ekmekcioglu, E. T. Walch, C. H. Tang, and E. A. Grimm, Inhibition of
nuclear factor-kappaB and nitric oxide by curcumin induces G2/M cell cycle arrest
and apoptosis in human melanoma cells. Melanoma Res 14, 165–171 (2004).
414. D. R. Siwak, S. Shishodia, B. B. Aggarwal, and R. Kurzrock, Curcumin-induced
antiproliferative and proapoptotic effects in melanoma cells are associated with sup-
pression of IkappaB kinase and nuclear factor kappaB activity and are independent
of the B-Raf/mitogen-activated/extracellular signal-regulated protein kinase pathway
and the Akt pathway. Cancer 104, 879–890 (2005).
415. W. H. Chan and H. J. Wu, Anti-apoptotic effects of curcumin on photosensitized
human epidermal carcinoma A431 cells. J Cell Biochem 92, 200–212 (2004).
416. M. A. Azuine and S. V. Bhide, Adjuvant chemoprevention of experimental cancer:
Catechin and dietary turmeric in forestomach and oral cancer models. J Ethnophar-
macol 44, 211–217 (1994).
by dietary curcumin and hesperidin: comparison with the protective effect of beta-
carotene. Cancer Res 54, 4653–4659 (1994).
418. K. Krishnaswamy, V. K. Goud, B. Sesikeran, M. A. Mukundan, and T. P. Krishna,
and curcumin. Nutr Cancer 30, 163–166 (1998).
419. N. Li, X. Chen, J. Liao, G. Yang, S. Wang, Y. Josephson, C. Han, J. Chen, M.
T. Huang, and C. S. Yang, Inhibition of 7,12-dimethylbenz[a]anthracene (DMBA)-
induced oral carcinogenesis in hamsters by tea and curcumin. Carcinogenesis 23,
420. N. Li, X. Chen, C. Han, and J. Chen, [Chemopreventive effect of tea and curcumin
on DMBA-induced oral carcinogenesis in hamsters]. Wei Sheng Yan Jiu 31, 354–357
and H. Mori, Chemopreventive effect of curcumin on N-nitrosomethylbenzylamine-
induced esophageal carcinogenesis in rats. Jpn J Cancer Res 91, 893–898
422. M. T. Huang, Y. R. Lou, W. Ma, H. L. Newmark, K. R. Reuhl, and A. H. Conney,
Inhibitory effects of dietary curcumin on forestomach, duodenal, and colon carcino-
genesis in mice. Cancer Res 54, 5841–5847 (1994).
423. S. V. Singh, X. Hu, S. K. Srivastava, M. Singh, H. Xia, J. L. Orchard, and H. A. Zaren,
Mechanism of inhibition of benzo[a]pyrene-induced forestomach cancer in mice by
dietary curcumin. Carcinogenesis 19, 1357–1360 (1998).
424. S. Ikezaki, A. Nishikawa, F. Furukawa, K. Kudo, H. Nakamura, K. Tamura, and
H. Mori, Chemopreventive effects of curcumin on glandular stomach carcinogene-
sis induced by N-methyl-N’-nitro-N-nitrosoguanidine and sodium chloride in rats.
Anticancer Res 21, 3407–3411 (2001).
425. S. Perkins, R. D. Verschoyle, K. Hill, I. Parveen, M. D. Threadgill, R. A. Sharma,
M. L. Williams, W. P. Steward, and A. J. Gescher, Chemopreventive efficacy and
pharmacokinetics of curcumin in the min/+ mouse, a model of familial adenomatous
polyposis. Cancer Epidemiol Biomarkers Prev 11, 535–540 (2002).
426. S. Perkins, A. R. Clarke, W. Steward, and A. Gescher, Age-related difference in
susceptibility of Apc(Min/+) mice towards the chemopreventive efficacy of dietary
aspirin and curcumin. Br J Cancer 88, 1480–1483 (2003).
427. M. A. Pereira, C. J. Grubbs, L. H. Barnes, H. Li, G. R. Olson, I. Eto, M. Juliana,
L. M. Whitaker, G. J. Kelloff, V. E. Steele, and R. A. Lubet, Effects of the phyto-
December 22, 2006 16:34
CURCUMIN: THE INDIAN SOLID GOLD 41
chemicals, curcumin and quercetin, upon azoxymethane-induced colon cancer and
7,12-dimethylbenz[a]anthracene-induced mammary cancer in rats. Carcinogenesis
17, 1305–1311 (1996).
428. M. J. Wargovich, C. D. Chen, A. Jimenez, V. E. Steele, M. Velasco, L. C. Stephens, R.
uation of potential chemopreventive agents in the rat. Cancer Epidemiol Biomarkers
Prev 5, 355–360 (1996).
429. H. S. Samaha, G. J. Kelloff, V. Steele, C. V. Rao, and B. S. Reddy, Modulation of
apoptosis by sulindac, curcumin, phenylethyl-3-methylcaffeate, and 6-phenylhexyl
isothiocyanate: apoptotic index as a biomarker in colon cancer chemoprevention and
promotion. Cancer Res 57, 1301–1305 (1997).
430. T. Kawamori, R. Lubet, V. E. Steele, G. J. Kelloff, R. B. Kaskey, C. V. Rao, and B. S.
Reddy, Chemopreventive effect of curcumin, a naturally occurring anti-inflammatory
agent, during the promotion/progression stages of colon cancer. Cancer Res 59, 597–
431. C. V. Rao, T. Kawamori, R. Hamid, and B. S. Reddy, Chemoprevention of colonic
aberrant crypt foci by an inducible nitric oxide synthase-selective inhibitor. Carcino-
genesis 20, 641–644 (1999).
432. Y. Kwon, M. Malik, and B. A. Magnuson, Inhibition of colonic aberrant crypt foci by
curcumin in rats is affected by age. Nutr Cancer 48, 37–43 (2004).
433. S. R. Volate, D. M. Davenport, S. J. Muga, and M. J. Wargovich, Modulation of
aberrant crypt foci and apoptosis by dietary herbal supplements (quercetin, curcumin,
silymarin, ginseng and rutin). Carcinogenesis 26, 1450–1456 (2005).
434. J. M. Kim, S. Araki, D. J. Kim, C. B. Park, N. Takasuka, H. Baba-Toriyama, T. Ota,
Z. Nir, F. Khachik, N. Shimidzu, Y. Tanaka, T. Osawa, T. Uraji, M. Murakoshi, H.
Nishino, and H. Tsuda, Chemopreventive effects of carotenoids and curcumins on
mouse colon carcinogenesis after 1,2-dimethylhydrazine initiation. Carcinogenesis
19, 81–85 (1998).
435. R. Hanif, L. Qiao, S. J. Shiff, and B. Rigas, Curcumin, a natural plant phenolic food
additive, inhibits cell proliferation and induces cell cycle changes in colon adeno-
carcinoma cell lines by a prostaglandin-independent pathway. J Lab Clin Med 130,
by interfering with the cell cycle and inducing apoptosis in colon carcinoma cells.
Anticancer Res 19, 3675–3680 (1999).
437. R. Rashmi, T. R. Santhosh Kumar, and D. Karunagaran, Human colon cancer cells
differ in their sensitivity to curcumin-induced apoptosis and heat shock protects them
by inhibiting the release of apoptosis-inducing factor and caspases. FEBS Lett 538,
apoptosis in HCT116 human colon cancer cells. Carcinogenesis 25, 2183–2189
439. S. C. Wei, Y. S. Lin, P. N. Tsao, J. J. Wu-Tsai, C. H. Wu, and J. M. Wong, Compari-
son of the anti-proliferation and apoptosis-induction activities of sulindac, celecoxib,
curcumin, and nifedipine in mismatch repair-deficient cell lines. J Formos Med Assoc
103, 599–606 (2004).
440. G. Song, Y. B. Mao, Q. F. Cai, L. M. Yao, G. L. Ouyang, and S. D. Bao, Curcumin
induces human HT-29 colon adenocarcinoma cell apoptosis by activating p53 and
regulating apoptosis-related protein expression. Braz J Med Biol Res 38, 1791–1798
December 22, 200616:34
42AGGARWAL ET AL.
441. K. Singletary, C. MacDonald, M. Wallig, and C. Fisher, Inhibition of 7,12-
dimethylbenz[a]anthracene (DMBA)-induced mammary tumorigenesis and DMBA-
DNA adduct formation by curcumin. Cancer Lett 103, 137–141 (1996).
free aqueous turmeric extract in 7,12-dimethylbenz[a]anthracene-induced rat mam-
mary tumorigenesis. Cancer Lett 123, 35–40 (1998).
adducts and tumors induced by 7,12-dimethylbenz[a]anthracene. Carcinogenesis 19,
444. H. Inano, M. Onoda, N. Inafuku, M. Kubota, Y. Kamada, T. Osawa, H. Kobayashi,
and K. Wakabayashi, Chemoprevention by curcumin during the promotion stage of
tumorigenesis of mammary gland in rats irradiated with gamma-rays. Carcinogenesis
20, 1011–1018 (1999).
of turmeric (Curcuma longa). Cancer Lett 29, 197–202, (1985).
446. M. Nagabhushan and S. V. Bhide, Curcumin as an inhibitor of cancer. J Am Coll Nutr
11, 192–128 (1992).
447. S. S. Hecht, P. M. Kenney, M. Wang, N. Trushin, S. Agarwal, A. V. Rao,
and P. Upadhyaya, Evaluation of butylated hydroxyanisole, myo-inositol, cur-
cumin, esculetin, resveratrol and lycopene as inhibitors of benzo[a]pyrene plus
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in A/J
mice. Cancer Lett 137, 123–130 (1999).
448. A. Khar, A. M. Ali, B. V. Pardhasaradhi, Z. Begum, and R. Anjum, Antitumor activity
Lett 445, 165–168 (1999).
449. M. Churchill, A. Chadburn, R. T. Bilinski, and M. M. Bertagnolli, Inhibition of in-
testinal tumors by curcumin is associated with changes in the intestinal immune cell
profile. J Surg Res 89, 169–175 (2000).
450. B. Lal, A. K. Kapoor, P. K. Agrawal, O. P. Asthana, and R. C. Srimal, Role of cur-
cumin in idiopathic inflammatory orbital pseudotumours. Phytother Res 14, 443–447
451. S. Busquets, N. Carbo, V. Almendro, M. T. Quiles, F. J. Lopez-Soriano, and J. M.
Argiles, Curcumin, a natural product present in turmeric, decreases tumor growth but
does not behave as an anticachectic compound in a rat model. Cancer Lett 167, 33–38
452. G. P. Collett, C. N. Robson, J. C. Mathers, and F. C. Campbell, Curcumin modifies
Apc(min) apoptosis resistance and inhibits 2-amino 1-methyl-6-phenylimidazo[4,5-
b]pyridine (PhIP) induced tumour formation in Apc(min) mice. Carcinogenesis 22,
453. P. Sindhwani, J. A. Hampton, M. M. Baig, R. Keck, and S. H. Selman, Curcumin
prevents intravesical tumor implantation of the MBT-2 tumor cell line in C3H mice.
J Urol 166, 1498–1501 (2001).
454. H. Inano and M. Onoda, Radioprotective action of curcumin extracted from Curcuma
Biol Phys 53, 735–743 (2002).
455. H. Inano and M. Onoda, Prevention of radiation-induced mammary tumors. Int J
Radiat Oncol Biol Phys 52, 212–223 (2002).
December 22, 200616:34
CURCUMIN: THE INDIAN SOLID GOLD 43
456. N. Ozen, E. Uslu, M. Ozen, S. Aydin, T. Altug, A. Belce, and E. Kokoglu, Curcumin’s
effects on sialic acid level and sialidase activity in Ehrlich ascites tumor bearing mice.
Tohoku J Exp Med 197, 221–227 (2002).
457. N. Frank, J. Knauft, F. Amelung, J. Nair, H. Wesch, and H. Bartsch, No prevention
of liver and kidney tumors in Long-Evans Cinnamon rats by dietary curcumin, but
inhibition at other sites and of metastases. Mutat Res 523–524, 127–135 (2003).
458. J. Gertsch, M. Guttinger, J. Heilmann, and O. Sticher, Curcumin differentially mod-
ulates mRNA profiles in Jurkat T and human peripheral blood mononuclear cells.
Bioorg Med Chem 11, 1057–1063 (2003).
anti-tumoral effect of curcumin against melanoma cells. Int J Cancer 111, 381–387
460. M. Belakavadi and B. P. Salimath, Mechanism of inhibition of ascites tumor growth
in mice by curcumin is mediated by NF-kB and caspase activated DNase. Mol Cell
Biochem 273, 57–67 (2005).
461. A. Pal and A. K. Pal, Radioprotection of turmeric extracts in bacterial system. Acta
Biol Hung 56, 333–343 (2005).
462. M. Notarbartolo, P. Poma, D. Perri, L. Dusonchet, M. Cervello, and N. D’Alessandro,
Antitumor effects of curcumin, alone or in combination with cisplatin or doxorubicin,
on human hepatic cancer cells. Analysis of their possible relationship to changes in
NF-kB activation levels and in IAP gene expression. Cancer Lett 224, 53–65 (2005).
463. A. K. Singh, G. S. Sidhu, T. Deepa, and R. K. Maheshwari, Curcumin inhibits the
proliferation and cell cycle progression of human umbilical vein endothelial cell.
Cancer Lett 107, 109–115 (1996).
464. R. G. Mehta and R. C. Moon, Characterization of effective chemopreventive agents in
mammary gland in vitro using an initiation-promotion protocol. Anticancer Res 11,
465. J. A. Sokoloski, K. Shyam, and A. C. Sartorelli, Induction of the differentiation of
HL-60 promyelocytic leukemia cells by curcumin in combination with low levels of
vitamin D3. Oncol Res 9, 31–39 (1997).
466. S. C. Gautam, Y. X. Xu, K. R. Pindolia, N. Janakiraman, and R. A. Chapman, Non-
selective inhibition of proliferation of transformed and nontransformed cells by the
anticancer agent curcumin (diferuloylmethane). Biochem Pharmacol 55, 1333–1337
467. E. Jaruga, A. Sokal, S. Chrul, and G. Bartosz, Apoptosis-independent alterations in
membrane dynamics induced by curcumin. Exp Cell Res 245, 303–312 (1998).
468. E. Jaruga, A. Bielak-Zmijewska, E. Sikora, J. Skierski, E. Radziszewska, K. Piwocka,
and G. Bartosz, Glutathione-independent mechanism of apoptosis inhibition by cur-
cumin in rat thymocytes. Biochem Pharmacol 56, 961–965 (1998).
469. S. H. Jee, S. C. Shen, C. R. Tseng, H. C. Chiu, and M. L. Kuo, Curcumin induces a
p53-dependent apoptosis in human basal cell carcinoma cells. J Invest Dermatol 111,
470. S. M. D’Ambrosio, R. Gibson-D’Ambrosio, G. E. Milo, B. Casto, G. J. Kelloff, and
V. E. Steele, Differential response of normal, premalignant and malignant human oral
epithelial cells to growth inhibition by chemopreventive agents. Anticancer Res 20,
cancer-I. curcumin induces apoptosis in both androgen-dependent and androgen-
independent prostate cancer cells. Prostate Cancer Prostatic Dis 3, 84–93 (2000).
December 22, 2006 16:34
44 AGGARWAL ET AL.
472. T. M. Elattar and A. S. Virji, The inhibitory effect of curcumin, genistein, quercetin
473. Y. Wu, Y. Chen, and M. He, The influence of curcumin on the cell cycle of HL-60
cells and contrast study. J Tongji Med Univ 20, 123–125 (2000).
474. B. K. Batth, R. Tripathi, and U. K. Srinivas, Curcumin-induced differentiation of
mouse embryonal carcinoma PCC4 cells. Differentiation 68, 133–140 (2001).
475. B. Cipriani, G. Borsellino, H. Knowles, D. Tramonti, F. Cavaliere, G. Bernardi, L.
Battistini, and C. F. Brosnan, Curcumin inhibits activation of Vgamma9Vdelta2 T
cells by phosphoantigens and induces apoptosis involving apoptosis-inducing factor
and large scale DNA fragmentation. J Immunol 167, 3454–3462 (2001).
476. T. Dorai, Y. C. Cao, B. Dorai, R. Buttyan, and A. E. Katz, Therapeutic potential
of curcumin in human prostate cancer. III. Curcumin inhibits proliferation, induces
apoptosis, and inhibits angiogenesis of LNCaP prostate cancer cells in vivo. Prostate
47, 293–303 (2001).
in cancer prevention; effects of preventive agents on estrogen-related endometrial
carcinogenesis model and on an in vitro model in human colorectal cells. Mutat Res
480–481, 201–207 (2001).
478. D. Morin, S. Barthelemy, R. Zini, S. Labidalle, and J. P. Tillement, Curcumin induces
the mitochondrial permeability transition pore mediated by membrane protein thiol
oxidation. FEBS Lett 495, 131–136 (2001).
479. A. Mukhopadhyay, C. Bueso-Ramos, D. Chatterjee, P. Pantazis, and B. B. Aggarwal,
Oncogene 20, 7597–7609 (2001).
480. S. Pal, T. Choudhuri, S. Chattopadhyay, A. Bhattacharya, G. K. Datta, T. Das, and G.
Sa, Mechanisms of curcumin-induced apoptosis of Ehrlich’s ascites carcinoma cells.
Biochem Biophys Res Commun 288, 658–665 (2001).
481. K. Piwocka, E. Jaruga, J. Skierski, I. Gradzka, and E. Sikora, Effect of glutathione
cells. Free Radical Biol Med 31, 670–678 (2001).
482. R. J. Anto, A. Mukhopadhyay, K. Denning, and B. B. Aggarwal, Curcumin (difer-
uloylmethane) induces apoptosis through activation of caspase-8, BID cleavage and
cytochrome c release: its suppression by ectopic expression of Bcl-2 and Bcl-xl. Car-
cinogenesis 23, 143–150 (2002).
483. M. J. Park, E. H. Kim, I. C. Park, H. C. Lee, S. H. Woo, J. Y. Lee, Y. J. Hong, C. H.
Rhee, S. H. Choi, B. S. Shim, S. H. Lee, and S. I. Hong, Curcumin inhibits cell cycle
progression of immortalized human umbilical vein endothelial (ECV304) cells by
up-regulating cyclin-dependent kinase inhibitor, p21WAF1/CIP1, p27KIP1 and p53.
Int J Oncol 21, 379–383 (2002).
484. K. Piwocka, A. Bielak-Mijewska and E. Sikora, Curcumin induces caspase-3-
independent apoptosis in human multidrug-resistant cells. Ann NY Acad Sci 973,
485. J. H. Bae, J. W. Park, and T. K. Kwon, Ruthenium red, inhibitor of mitochondrial
Ca2+depletion and cytochrome c release. Biochem Biophys Res Commun 303, 1073–
486. D. Deeb, Y. X. Xu, H. Jiang, X. Gao, N. Janakiraman, R. A. Chapman, and S.
C. Gautam, Curcumin (diferuloyl-methane) enhances tumor necrosis factor-related
December 22, 200616:34
CURCUMIN: THE INDIAN SOLID GOLD 45
apoptosis-inducing ligand-induced apoptosis in LNCaP prostate cancer cells. Mol
Cancer Ther 2, 95–103 (2003).
487. A. Pol, M. Bergers, and J. Schalkwijk, Comparison of antiproliferative effects of
experimental and established antipsoriatic drugs on human keratinocytes, using a
simple 96-well-plate assay. In Vitro Cell Dev Biol Anim 39, 36–42 (2003).
488. T. Dorai, J. P. Dutcher, D. W. Dempster, and P. H. Wiernik, Therapeutic potential
of curcumin in prostate cancer–V: Interference with the osteomimetic properties of
hormone refractory C4-2B prostate cancer cells. Prostate 60, 1–17 (2004).
489. J. Holy, Curcumin inhibits cell motility and alters microfilament organization and
function in prostate cancer cells. Cell Motil Cytoskeleton 58, 253–268 (2004).
490. R. Rashmi, S. Kumar, and D. Karunagaran, Ectopic expression of Hsp70 confers re-
sistance and silencing its expression sensitizes human colon cancer cells to curcumin-
induced apoptosis. Carcinogenesis 25, 179–187 (2004).
491. D. W. Scott and G. Loo, Curcumin-induced GADD153 gene up-regulation in human
colon cancer cells. Carcinogenesis 25, 2155–2164 (2004).
role of glutathione and bcl-2. Mol Cancer Ther 3, 1101–1108 (2004).
493. M. Fullbeck, X. Huang, R. Dumdey, C. Frommel, W. Dubiel, and R. Preissner, Novel
curcumin- and emodin-related compounds identified by in silico 2D/3D conformer
screening induce apoptosis in tumor cells. BMC Cancer 5, 97 (2005).
494. X. Gao, D. Deeb, H. Jiang, Y. B. Liu, S. A. Dulchavsky, and S. C. Gautam, Curcumin
differentially sensitizes malignant glioma cells to TRAIL/Apo2L-mediated apoptosis
through activation of procaspases and release of cytochrome c from mitochondria. J
Exp Ther Oncol 5, 39–48 (2005).
495. E. M. Jung, J. H. Lim, T. J. Lee, J. W. Park, K. S. Choi, and T. K. Kwon, Curcumin
sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced
apoptosis through reactive oxygen species-mediated upregulation of death receptor 5
(DR5). Carcinogenesis 26, 1905–1913 (2005).
496. S. Mishra, N. Kapoor, A. Mubarak Ali, B. V. Pardhasaradhi, A. L. Kumari, A. Khar,
and K. Misra, Differential apoptotic and redox regulatory activities of curcumin and
its derivatives. Free Radica Biol Med 38, 1353–1360 (2005).
497. S. D. Park, J. H. Jung, H. W. Lee, Y. M. Kwon, K. H. Chung, M. G. Kim, and C. H.
proliferation of human hepatic myofibroblasts. Int Immunopharmacol 5, 555–569
498. R. Rashmi, S. Kumar, and D. Karunagaran, Human colon cancer cells lacking Bax
resist curcumin-induced apoptosis and Bax requirement is dispensable with ectopic
499. Q. Wang, A. Y. Sun, A. Simonyi, M. D. Jensen, P. B. Shelat, G. E. Rottinghaus, R. S.
tive mechanisms of curcumin against cerebral ischemia-induced neuronal apoptosis
and behavioral deficits. J Neurosci Res 82, 138–148 (2005).
500. C. W. Lee, W. N. Lin, C. C. Lin, S. F. Luo, J. S. Wang, J. Pouyssegur, and C. M. Yang,
Transcriptional regulation of VCAM-1 expression by tumor necrosis factor-alpha in
human tracheal smooth muscle cells: involvement of MAPKs, NF-kappaB, p300, and
histone acetylation. J Cell Physiol 207, 174–186 (2006).
carcinoma cell invasion in vitro and suppresses matrix metalloproteinase-9 secretion.
Oncology 55, 349–353 (1998).
December 22, 2006 16:34
46AGGARWAL ET AL.
502. J. I. Fenton, M. S. Wolff, M. W. Orth, and N. G. Hord, Membrane-type matrix met-
alloproteinases mediate curcumin-induced cell migration in non-tumorigenic colon
epithelial cells differing in Apc genotype. Carcinogenesis 23, 1065–1070 (2002).
503. A. Banerji, J. Chakrabarti, A. Mitra, and A. Chatterjee, Effect of curcumin on gelati-
nase A (MMP-2) activity in B16F10 melanoma cells. Cancer Lett 211, 235–242
504. R. Rukkumani, K. Aruna, P. S. Varma, and V. P. Menon, Curcumin influences hepatic
expression patterns of matrix metalloproteinases in liver toxicity. Ital J Biochem 53,
505. Q. H. Yao, D. Q. Wang, C. C. Cui, Z. Y. Yuan, S. B. Chen, X. W. Yao, J. K. Wang,
and J. F. Lian, Curcumin ameliorates left ventricular function in rabbits with pres-
sure overload: inhibition of the remodeling of the left ventricular collagen network
associated with suppression of myocardial tumor necrosis factor-alpha and matrix
metalloproteinase-2 expression. Biol Pharm Bull 27, 198–202 (2004).
506. S. Y. Kim, S. H. Jung, and H. S. Kim, Curcumin is a potent broad spectrum inhibitor
of matrix metalloproteinase gene expression in human astroglioma cells. Biochem
Biophys Res Commun 337, 510–516 (2005).
507. M. S. Woo, S. H. Jung, S. Y. Kim, J. W. Hyun, K. H. Ko, W. K. Kim, and H. S. Kim,
Biophys Res Commun 335, 1017–1025 (2005).
508. E. Y. Shin, S. Y. Kim, and E. G. Kim, c-Jun N-terminal kinase is involved in motility
of endothelial cell. Exp Mol Med 33, 276–283 (2001).
509. P. V. Leyon and G. Kuttan, Studies on the role of some synthetic curcuminoid deriva-
tives in the inhibition of tumour specific angiogenesis. J Exp Clin Cancer Res 22,
510. E. V. Bobrovnikova-Marjon, P. L. Marjon, O. Barbash, D. L. Vander Jagt, and S. F.
Abcouwer, Expression of angiogenic factors vascular endothelial growth factor and
interleukin-8/CXCL8 is highly responsive to ambient glutamine availability: role of
nuclear factor-kappaB and activating protein-1. Cancer Res 64, 4858–4869 (2004).
511. W. G. Cao, M. Morin, V. Sengers, C. Metz, T. Roger, R. Maheux, and A. Akoum,
Tumour necrosis factor-alpha up-regulates macrophage migration inhibitory factor
Hum Reprod 21, 421–428 (2006).
512. M. L. Cho, Y. O. Jung, Y. M. Moon, S. Y. Min, C. H. Yoon, S. H. Lee, S. H. Park, C.
S. Cho, D. M. Jue, and H. Y. Kim, Interleukin-18 induces the production of vascular
endothelial growth factor (VEGF) in rheumatoid arthritis synovial fibroblasts via AP-
1-dependent pathways. Immunol Lett 103, 159–166 (2006).
513. B. H. Babu, B. S. Shylesh, and J. Padikkala, Antioxidant and hepatoprotective effect
of Acanthus ilicifolius. Fitoterapia 72, 272–277 (2001).
514. S. Nishizono, T. Hayami, I. Ikeda, and K. Imaizumi, Protection against the diabeto-
genic effect of feeding tert–butylhydroquinone to rats prior to the administration of
streptozotocin. Biosci Biotechnol Biochem 64, 1153–1158 (2000).
515. P. Suryanarayana, M. Saraswat, T. Mrudula, T. P. Krishna, K. Krishnaswamy, and G.
B. Reddy, Curcumin and turmeric delay streptozotocin-induced diabetic cataract in
rats. Invest Ophthalmol Vis Sci 46, 2092–2099 (2005).
516. M. Dikshit, L. Rastogi, R. Shukla, and R. C. Srimal, Prevention of ischaemia-induced
biochemical changes by curcumin & quinidine in the cat heart. Indian J Med Res 101,
December 22, 200616:34
CURCUMIN: THE INDIAN SOLID GOLD47
517. C. Nirmala and R. Puvanakrishnan, Protective role of curcumin against isoproterenol
induced myocardial infarction in rats. Mol Cell Biochem 159, 85–93 (1996).
519. H. W. Chen and H. C. Huang, Effect of curcumin on cell cycle progression
and apoptosis in vascular smooth muscle cells. Br J Pharmacol 124, 1029–1040
proliferation of cultured bovine smooth muscle cells and on expression of low density
lipoprotein receptor in cells. Chin Med J (Engl) 112, 308–311 (1999).
521. M. Sato, G. A. Cordis, N. Maulik, and D. K. Das, SAPKs regulation of ischemic
preconditioning. Am J Physiol Heart Circ Physiol 279, H901–H907 (2000).
522. P. Manikandan, M. Sumitra, S. Aishwarya, B. M. Manohar, B. Lokanadam, and R.
in rats. Int J Biochem Cell Biol 36, 1967–1980 (2004).
523. G. Ramaswami, H. Chai, Q. Yao, P. H. Lin, A. B. Lumsden, and C. Chen, Curcumin
blocks homocysteine-induced endothelial dysfunction in porcine coronary arteries. J
Vasc Surg 40, 1216–1222 (2004).
524. K. T. Nguyen, N. Shaikh, K. P. Shukla, S. H. Su, R. C. Eberhart, and L. Tang, Molec-
ular responses of vascular smooth muscle cells and phagocytes to curcumin-eluting
bioresorbable stent materials. Biomaterials 25, 5333–5346 (2004).
525. R. Srivastava, V. Puri, R. C. Srimal, and B. N. Dhawan, Effect of curcumin on platelet
aggregation and vascular prostacyclin synthesis. Arzneimittelforschung 36, 715–717
526. K. C. Srivastava, A. Bordia, and S. K. Verma, Curcumin, a major component of food
in human blood platelets. Prostaglandins Leukot Essent Fatty Acids 52, 223–227
527. B. H. Shah, Z. Nawaz, S. A. Pertani, A. Roomi, H. Mahmood, S. A. Saeed, and
A. H. Gilani, Inhibitory effect of curcumin, a food spice from turmeric, on platelet-
activating factor- and arachidonic acid-mediated platelet aggregation through inhibi-
tion of thromboxane formation and Ca2+signaling. Biochem Pharmacol 58, 1167–
528. C. Sumbilla, D. Lewis, T. Hammerschmidt, and G. Inesi, The slippage of the Ca2+
pump and its control by anions and curcumin in skeletal and cardiac sarcoplasmic
reticulum. J Biol Chem 277, 13,900–13,906 (2002).
529. Y. Sasaki, H. Goto, C. Tohda, F. Hatanaka, N. Shibahara, Y. Shimada, K. Terasawa,
and K. Komatsu, Effects of curcuma drugs on vasomotion in isolated rat aorta. Biol
Pharm Bull 26, 1135–1143 (2003).
530. C. M. Terry, J. A. Clikeman, J. R. Hoidal, and K. S. Callahan, Effect of tumor necro-
sis factor-alpha and interleukin-1 alpha on heme oxygenase-1 expression in human
endothelial cells. Am J Physiol 274, H883–H891 (1998).
531. M. C. Ramirez-Tortosa, M. D. Mesa, M. C. Aguilera, J. L. Quiles, L. Baro, C. L.
Ramirez-Tortosa, E. Martinez-Victoria, and A. Gil, Oral administration of a turmeric
extract inhibits LDL oxidation and has hypocholesterolemic effects in rabbits with
experimental atherosclerosis. Atherosclerosis 147, 371–378 (1999).
532. K. H. Thompson, K. Bohmerle, E. Polishchuk, C. Martins, P. Toleikis, J. Tse, V.
December 22, 200616:34
48 AGGARWAL ET AL.
muscle cell or mouse lymphoma cell proliferation by a vanadyl curcumin complex
compared to curcumin alone. J Inorg Biochem 98, 2063–2070 (2004).
533. K. Keshavarz, The influence of turmeric and curcumin on cholesterol concentration
of eggs and tissues. Poult Sci 55, 1077–1083 (1976).
activity and on serum and hepatic cholesterol levels in the rat. Int J Vitam Nutr Res
61, 364–369 (1991).
535. K. B. Soni and R. Kuttan, Effect of oral curcumin administration on serum peroxides
and cholesterol levels in human volunteers. Indian J Physiol Pharmacol 36, 273–275
Monit 11, BR228–234, (2005).
538. C. Fan, X. Wo, Y. Qian, J. Yin, and L. Gao, Effect of curcumin on the expression of
LDL receptor in mouse macrophages. J Ethnopharmacol 105, 251–254 (2006).
J. Diaz-Alperi, A. Bernd, E. Quintanilla Almagro, and J. Miquel, An hydroalcoholic
extract of Curcuma longa lowers the abnormally high values of human-plasma fib-
rinogen. Mech Ageing Dev 114, 207–210 (2000).
540. K. A. Naidu and N. B. Thippeswamy, Inhibition of human low density lipopro-
tein oxidation by active principles from spices. Mol Cell Biochem 229, 19–23
541. R. Olszanecki, J. Jawien, M. Gajda, L. Mateuszuk, A. Gebska, M. Korabiowska, S.
knockout mice. J Physiol Pharmacol 56, 627–635 (2005).
542. W. F. Chen, S. L. Deng, B. Zhou, L. Yang, and Z. L. Liu, Curcumin and its analogues
as potent inhibitors of low density lipoprotein oxidation: H-atom abstraction from the
Free Radical Biol Med 40, 526–535 (2006).
543. S. A. Frautschy, W. Hu, P. Kim, S. A. Miller, T. Chu, M. E. Harris-White, and G.
M. Cole, Phenolic anti-inflammatory antioxidant reversal of Abeta-induced cognitive
deficits and neuropathology. Neurobiol Aging 22, 993–1005 (2001).
544. D. S. Kim, S. Y. Park, and J. K. Kim, Curcuminoids from Curcuma longa L. (Zingib-
eraceae) that protect PC12 rat pheochromocytoma and normal human umbilical vein
endothelial cells from betaA(1-42) insult. Neurosci Lett 303, 57–61 (2001).
545. G. P. Lim, T. Chu, F. Yang, W. Beech, S. A. Frautschy, and G. M. Cole, The curry
spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer
transgenic mouse. J Neurosci 21, 8370–8377 (2001).
546. M. Grundman and P. Delaney, Antioxidant strategies for Alzheimer’s disease. Proc
Nutr Soc 61, 191–202 (2002).
547. S. Y. Park and D. S. Kim, Discovery of natural products from Curcuma longa that
protect cells from beta-amyloid insult: a drug discovery effort against Alzheimer’s
disease. J Nat Prod 65, 1227–1231 (2002).
548. L. Adlerz, M. Beckman, S. Holback, R. Tehranian, V. Cortes Toro, and K. Iverfeldt,
Accumulation of the amyloid precursor-like protein APLP2 and reduction of APLP1
in retinoic acid-differentiated human neuroblastoma cells upon curcumin-induced
neurite retraction. Brain Res Mol Brain Res 119, 62–72 (2003).
December 22, 2006 16:34
CURCUMIN: THE INDIAN SOLID GOLD49
549. L. Baum and A. Ng, Curcumin interaction with copper and iron suggests one possible
mechanism of action in Alzheimer’3s disease animal models. J Alzheimers Dis 6,
367–77; discussion 443–449 (2004).
550. K. Ono, K. Hasegawa, H. Naiki, and M. Yamada, Curcumin has potent anti–
amyloidogenic effects for Alzheimer’s beta-amyloid fibrils in vitro. J Neurosci Res
75, 742–750 (2004).
551. G. M. Cole, G. P. Lim, F. Yang, B. Teter, A. Begum, Q. Ma, M. E. Harris-
White and S. A. Frautschy, Prevention of Alzheimer’s disease: Omega-3 fatty acid
and phenolic anti-oxidant interventions. Neurobiol Aging 26(Suppl 1), 133–136
552. H. Kim, B. S. Park, K. G. Lee, C. Y. Choi, S. S. Jang, Y. H. Kim, and S. E. Lee,
Effects of naturally occurring compounds on fibril formation and oxidative stress of
beta-amyloid. J Agric Food Chem 53, 8537–8541 (2005).
553. J. M. Ringman, S. A. Frautschy, G. M. Cole, D. L. Masterman, and J. L. Cummings,
A potential role of the curry spice curcumin in Alzheimer’s disease. Curr Alzheimer
Res 2, 131–136 (2005).
554. F. Yang, G. P. Lim, A. N. Begum, O. J. Ubeda, M. R. Simmons, S. S. Ambegaokar, P.
P. Chen, R. Kayed, C. G. Glabe, S. A. Frautschy, and G. M. Cole, Curcumin inhibits
formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid
in vivo. J Biol Chem 280, 5892–5901 (2005).
oil extracted from Curcuma longa (Zingiberaceae). J Ethnopharmacol 49, 163–169
activity of turmeric oil: A byproduct from curcumin manufacture. J Agric Food Chem
47, 4297–4300 (1999).
557. M. Wuthi-udomlert, W. Grisanapan, O. Luanratana, and W. Caichompoo, Antifungal
activity of Curcuma longa grown in Thailand. Southeast Asian J Trop Med Public
Health 31(Suppl 1), 178–182 (2000).
558. J. Jankun, A. M. Aleem, S. Malgorzewicz, M. Szkudlarek, M. I. Zavodszky, D. L.
Dewitt, M. Feig, S. H. Selman, and E. Skrzypczak-Jankun, Synthetic curcuminoids
modulate the arachidonic acid metabolism of human platelet 12-lipoxygenase and
reduce sprout formation of human endothelial cells. Mol Cancer Ther 5, 1371–1382
lipoxygenase by binding to its central cavity: theoretical and X-ray evidence. Int J
Mol Med 6, 521–526 (2000).
560. M. E. Braga, P. F. Leal, J. E. Carvalho, and M. A. Meireles, Comparison of yield,
using various techniques. J Agric Food Chem 51, 6604–6611 (2003).
pigments from Curcuma longa [L] by steam distillation and extraction with volatile
solvents. J Agric Food Chem 51, 6802–6807 (2003).
for the enrichment of nonpolar compounds from aqueous extracts of plant materials.
J Nat Prod 68, 1386–1389 (2005).
P1: OTE/SPH Download full-text
December 22, 200616:34
50 AGGARWAL ET AL.
563. V. M. Dirsch, H. Stuppner, and A. M. Vollmar, The Griess assay: suitable for a bio-
guided fractionation of anti-inflammatory plant extracts? Planta Med 64, 423–426
for the determination of curcumin, demethoxycurcumin, and bisdemethoxycurcumin.
J Agric Food Chem 50, 3668–3672 (2002).
ometric detection of curcumin in Chinese herbal medicine pretreated by solid-phase
extraction. J Chromatogr A 962, 117–125 (2002).
J Agric Food Chem 50, 1355–1361 (2002).
567. Y. Pak, R. Patek, and M. Mayersohn, Sensitive and rapid isocratic liquid chromatog-
raphy method for the quantitation of curcumin in plasma. J Chromatogr B Analyt
Technol Biomed Life Sci 796, 339–346 (2003).
568. M. Bernabe-Pineda, M. T. Ramirez-Silva, M. Romero-Romo, E. Gonzalez-Vergara,
and A. Rojas-Hernandez, Determination of acidity constants of curcumin in aqueous
solution and apparent rate constant of its decomposition. Spectrochim Acta A Mol
Biomol Spectrosc 60, 1091–1097 (2004).
569. M. Lechtenberg, B. Quandt, and A. Nahrstedt, Quantitative determination of cur-
cuminoids in Curcuma rhizomes and rapid differentiation of Curcuma domestica Val.
and Curcuma xanthorrhiza Roxb. by capillary electrophoresis. Phytochem Anal 15,
570. M. J. Ansari, S. Ahmad, K. Kohli, J. Ali, and R. K. Khar, Stability-indicating HPTLC
determination of curcumin in bulk drug and pharmaceutical formulations. J Pharm
Biomed Anal 39, 132–138 (2005).
571. L. A. May, E. Tourkina, S. R. Hoffman, and T. A. Dix, Detection and quantitation of
curcumin in mouse lung cell cultures by matrix-assisted laser desorption ionization
time of flight mass spectrometry. Anal Biochem 337, 62–69 (2005).
572. F. Wang, X. Wu, S. Liu, Z. Jia, and J. Yang, The sensitive fluorimetric method for the
determination of curcumin using the enhancement of mixed micelle. J Fluoresc 16,
573. H. H. Tonnesen and J. Karlsen, Studies on curcumin and curcuminoids. VI. Kinetics
574. H. H. Tonnesen, J. Karlsen, and G. B. van Henegouwen, Studies on curcumin and
curcuminoids. VIII. Photochemical stability of curcumin. Z Lebensm Unters Forsch
183, 116–122 (1986).
ies on curcumin and curcuminoids. IX: Investigation of the photobiological activity
of curcumin using bacterial indicator systems. J Pharm Sci 76, 371–373 (1987).
576. T. A. Dahl, W. M. McGowan, M. A. Shand, and V. S. Srinivasan, Photokilling of
bacteria by the natural dye curcumin. Arch Microbiol 151, 183–185 (1989).
578. T. A. Dahl, P. Bilski, K. J. Reszka, and C. F. Chignell, Photocytotoxicity of curcumin.
Photochem Photobiol 59, 290–294 (1994).
579. Y. J. Wang, M. H. Pan, A. L. Cheng, L. I. Lin, Y. S. Ho, C. Y. Hsieh, and J. K.
Lin, Stability of curcumin in buffer solutions and characterization of its degradation
products. J Pharm Biomed Anal 15, 1867–1876 (1997).