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23
Curcumin Derived from
Turmeric (
Curcuma longa
):
a Spice for All Seasons
Bharat B. Aggarwal, Anushree Kumar, Manoj S. Aggarwal,
and Shishir Shishodia
CONTENTS
23.1 Introduction...........................................................................................................................350
23.2 Anticancer Properties of Curcumin .....................................................................................351
23.2.1
Curcumin Inhibits Tumorigenesis........................................................................351
23.2.2
Curcumin Exhibits Antiproliferative Effects against Cancer Cells.....................352
23.2.3
Curcumin Down-Regulates the Activity of Epidermal Growth
Factor Receptor (EGFR) and Expression of HER2/neu .....................................353
23.2.4
Curcumin Down-Regulates the Activation of Nuclear
Factor-
k
b (Nf-
k
b).................................................................................................354
23.2.5
Curcumin Down-Regulates the Activation of STAT3 Pathway ..........................354
23.2.6
Curcumin Activates Peroxisome Proliferator-Activated
Receptor-
) ............................................................................................355
23.2.7 Curcumin Down-Regulates the Activation of Activator
Protein-1 (AP-1) and C-Jun N-Terminal Kinase (JNK) .....................................355
23.2.8 Curcumin Suppresses the Induction of Adhesion Molecules .............................355
23.2.9 Curcumin Down-Regulates Cyclooxygenase-2 (COX-2) Expression ................355
23.2.10 Curcumin Inhibits Angiogenesis..........................................................................356
23.2.11 Curcumin Suppresses the Expression of MMP9 and Inducible
Nitric Oxide Synthase (INOS).............................................................................356
23.2.12 Curcumin Down-Regulates Cyclin D1 Expression .............................................356
23.2.13 Curcumin Is Chemopreventive ............................................................................356
23.2.14 Curcumin Inhibits Tumor Growth and Metastasis in Animals ...........................357
23.2.15 Curcumin Inhibits Androgen Receptors and AR-Related
Cofactors ..............................................................................................................358
23.3 Effect of Curcumin on Atherosclerosis and Myocardial Infarction ....................................359
23.3.1 Curcumin Inhibits the Proliferation of Vascular Smooth
Muscle Cells.........................................................................................................359
23.3.2 Curcumin Lowers Serum Cholesterol Levels......................................................360
23.3.3 Curcumin Inhibits LDL Oxidation ......................................................................361
23.3.4 Curcumin Inhibits Platelet Aggregation ..............................................................362
23.3.5 Curcumin Inhibits Myocardial Infarction ............................................................362
23.4 Other Effect of Curcumin ....................................................................................................363
23.4.1
g
(PPAR-
g
Curcumin Suppresses Diabetes............................................................................363
23.4.2
Curcumin Stimulates Muscle Regeneration ........................................................364
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© 2005 by CRC Press LLC
349
 
350
Phytopharmaceuticals in Cancer Chemoprevention
23.4.3 Curcumin Enhances Wound Healing ...................................................................365
23.4.4 Curcumin Suppresses Symptoms Associated with Arthritis ...............................365
23.4.5 Curcumin Reduces the Incidence of Cholesterol
Gallstone Formation.............................................................................................366
23.4.6 Curcumin Modulates Multiple Sclerosis .............................................................366
23.4.7 Curcumin Blocks the Replication of HIV ...........................................................367
23.4.8 Curcumin Affects Alzheimer’s Disease ...............................................................367
23.4.9 Curcumin Protects against Cataract Formation ...................................................368
23.4.10 Curcumin Protects from Drug-Induced Myocardial Toxicity .............................368
23.4.11 Curcumin Protects from Alcohol-Induced Liver Injury ......................................368
23.4.12 Curcumin Protects from Drug-Induced Lung Injury ..........................................369
23.4.13 Curcumin Prevents Adriamycin-Induced Nephrotoxicity ...................................371
23.4.14 Curcumin Protects from Scarring ........................................................................371
23.4.15 Curcumin Protects from Inflammatory Bowel Disease.......................................371
23.4.16 Curcumin Enhances the Immunosuppressive Activity
of Cyclosporine ....................................................................................................372
23.4.17 Curcumin Protects against Various Forms of Stress ...........................................372
23.4.18 Curcumin Protects against Endotoxin Shock ......................................................372
23.4.19 Curcumin Protects against Pancreatitis ...............................................................372
23.4.20 Curcumin Inhibits Multidrug Resistance (MDR)................................................372
23.5 Curcumin Metabolism ..........................................................................................................373
23.6 Clinical Experience with Curcumin.....................................................................................374
23.7 Curcumin Analogs ................................................................................................................376
23.8 Sources of Curcumin............................................................................................................377
23.9 Conclusion ............................................................................................................................378
Acknowledgment............................................................................................................................379
References ......................................................................................................................................379
23.1 INTRODUCTION
or turmeric is a tropical plant native to southern and southeastern tropical Asia.
A perennial herb belonging to the ginger family, turmeric measures up to 1 m high with a short
stem and tufted leaves (Figure 23.1A). The parts used are the rhizomes. Perhaps the most active
component in turmeric is curcumin, which may make up 2 to 5% of the total spice in turmeric
(Figure 23.1B). Curcumin is a diferuloylmethane present in extracts of the plant. Curcuminoids
are responsible for the yellow color of turmeric and curry powder. They are derived from turmeric
by ethanol extraction. The pure orange-yellow, crystalline powder is insoluble in water. The
structure of curcumin (C
) was first described in 1815 by Vogel and Pellatier and in 1910
was shown to be diferuloylmethane by Lampe et al. [1]. Chemical synthesis in 1913 confirmed
its identity [2].
Turmeric is widely consumed in the countries of its origin for a variety of uses, including as
a dietary spice, a dietary pigment, and an Indian folk medicine for the treatment of various illnesses.
It is used in the textile and pharmaceutical industries [3] and in Hindu religious ceremonies in one
form or another. Current traditional Indian medicine uses it for biliary disorders, anorexia, cough,
diabetic wounds, hepatic disorders, rheumatism, and sinusitis [4]. The old Hindu texts have
described it as an aromatic stimulant and carminative [5].
21
H
20
O
6
Powder of turmeric mixed with slaked
lime is a household remedy for the treatment of sprains and swelling caused by injury, applied
locally over the affected area. In some parts of India, the powder is taken orally for the treatment
of sore throat. This nonnutritive phytochemical is pharmacologically safe, considering that it has
been consumed as a dietary spice, at doses up to 100 mg/day, for centuries [6]. Recent phase I
Curcuma longa
Curcumin Derived from Turmeric (Curcuma longa): a Spice for All Seasons
351
OO
CH 3 O
OCH 3
Curcumin I
(77%)
HO
OH
OO
Curcumin II
OCH 3
HO
OH
Demethoxycurcumin
(17%)
t.s. of rhizome
OO
Curcumin III
plant
HO
OH
Bis-Demethoxycurcumin
(3%; less active)
rhizome
A
B
FIGURE 23.1
The plant
Curcuma longa
(panel A), from which curcumin is derived, and its structure
(panel B).
clinical trials indicate that people can tolerate a dose as high as 8 g/day [7]. In the U.S., curcumin
is used as a coloring agent in cheese, spices, mustard, cereals, pickles, potato flakes, soups, ice-
creams, and yogurts (www.kalsec.com).
Curcumin is not water-soluble, but it is soluble in ethanol or in dimethylsulfoxide. The
degradation kinetics of curcumin under various pH conditions and the stability of curcumin in
physiological matrices have been established [8]. When curcumin was incubated in 0.1
M
phosphate
C), about 90% decomposed within 30 min. A series
of pH conditions ranging from 3 to 10 were tested, and the results showed that decomposition
was pH-dependent and occurred faster at neutral-basic conditions. It is more stable in cell culture
medium containing 10% fetal calf serum and in human blood. Less than 20% of curcumin
decomposed within 1 h, and after incubation for 8 h, about 50% of curcumin still remained. Trans-
6-(4
∞
-methoxyphenyl)-2,4-dioxo-5-hexenal was predicted to be the major degradation
product, and vanillin, ferulic acid, and feruloyl methane were identified as minor degradation
products. The amount of vanillin increased with incubation time.
Numerous studies have indicated that curcumin has antioxidant and anti-inflammatory prop-
erties. A Medline search revealed over 1000 publications describing various activities of this
polyphenol. The following sections describe some of its major biological and clinical effects.
¢
-hydroxy-3
¢
23.2 ANTICANCER PROPERTIES OF CURCUMIN
23.2.1 C
URCUMIN
I
NHIBITS
T
UMORIGENESIS
Numerous reports suggest that curcumin has chemopreventive and chemotherapeutic effects (Figure
23.2). Its anticancer potential in various systems was recently reviewed by our laboratory [9].
Curcumin blocks tumor initiation induced by benzo[a]pyrene and 7,12dimethylbenz[a]anthracene
buffer and serum-free medium (pH 7.2 at 37
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352
Phytopharmaceuticals in Cancer Chemoprevention
Constitutive activation of
transcription factors
STAT3, AP-1& NF-kB
Overexpression:
Oncogenes
HER2
Growth factors
(e.g; EGF, PDGF, FGF)
Growth factor receptors
Survival factors
(e.g; Survivin, Bcl-2 and Bcl-x1)
Cyclin D1
Decoy receptor
Overexpression:
Matrix metalloproteases
Cyclooxygenase-2
Adhesion molecules
Chemokines
TNF
Tumor Suppressor genes
Transformation
Proliferation
Invasion
Normal
cells
Tumor
cells
Tumor
growth
Tumor
Metastasis
curcumin
FIGURE 23.2
Various steps involved in tumorigenesis and metastasis and their suppression by curcumin.
curcumin was
found to suppress carcinogenesis of the skin [12–15], the forestomach [16, 17], the colon [18–20],
and the liver [21] in mice. Curcumin also suppresses mammary carcinogenesis [22–24].
In vivo,
23.2.2 C
URCUMIN
XHIBITS
A
NTIPROLIFERATIVE
E
FFECTS
AGAINST
ANCER
C
H] thymidine incorporation, and clonogenic assay [31]. We also showed that curcumin can
overcome Adriamycin resistance in MCF-7 cells [31]. Recently, we have shown that curcumin can
activate caspase-8, which leads to cleavage of Bid, thus resulting in sequential release of mitochon-
drial cytochrome C and activation of caspase-9 and caspase-3 [34]. More recently, we have dem-
onstrated that curcumin can suppress the proliferation of multiple myeloma cells [35]. Woo et al.
[36] have demonstrated that curcumin can cause cell damage by inactivating the Akt-related cell
survival pathway and release of cytochrome c, providing a new mechanism for curcumin-induced
cytotoxicity.
Zheng et al. [37] explored the apoptosis-inducing effects of curcumin in human ovarian tumor
A2780 cells. They found that curcumin could significantly inhibit the growth of ovarian cancer
cells by inducing apoptosis through up-regulation of caspase-3 and down-regulation of expression
of NF-
B. Studies have also been performed to examine the synergy of curcumin with other
antiproliferative agents. Deeb et al. [38] investigated whether curcumin and TNF-related apoptosis-
inducing ligand (TRAIL) cooperatively interact to promote death of LNCaP cells. At concentra-
tions at which neither of the two agents alone produced significant cytotoxicity in LNCaP cells,
cell death was markedly enhanced (two- to three-fold) if tumor cells were treated with curcumin
and TRAIL together. The combined curcumin and TRAIL treatment increased the number of
hypodiploid cells and induced DNA fragmentation in LNCaP cells. The combined treatment
induced cleavage of procaspase-3, procaspase-8, and procaspase-9, truncation of BID, and release
k
[10], and it suppresses phorbol ester-induced tumor promotion [11, 12].
E
C
ELLS
Compounds that block or suppress the proliferation of tumor cells have potential as anticancer
agents. Curcumin has been shown to inhibit the proliferation of a wide variety of tumor cells,
including B-cell and T-cell leukemia [25–28], colon carcinoma [29], and epidermoid carcinoma
cells [30]. It has also been shown to suppress the proliferation of various breast carcinoma cell
lines in culture [31–33]. We showed that the growth of the breast tumor cell lines BT20, SKBR3,
MCF-7, T47D, and ZR75-1 is completely inhibited by curcumin, as indicated by MTT dye uptake,
[
3
256296359.003.png
Curcumin Derived from Turmeric (Curcuma longa): a Spice for All Seasons
353
Cyclin D1
↓
5 -LOX
↓
COX2
↓
i NOS
↓
M MP9
↓
I L-8 ↓
I L-6
↓
TNF
↓
I L-12
↓
Gene expression
IKK ↓
EGFR
↓
NF-
B
↓
AP-1
↓
H ER2
↓
Egr-1 ↓
AKT
↓
STAT1 ↓
Src ↓
STAT3 ↓
Protein
kinas es
Curcumin
Transcription
factors
JAK2 ↓
STAT5
TYK2 ↓
PPARg ↑
JNK ↓
EpRE ↓
PKA ↓
CBP
↓
PKC ↓
β -catenin ↑
Others
Enzymes
Nrf2
↑
VCAM-1
↓
B cl-2
↓
Bcl-x1
↓
I CAM-1
↓
FTPase
↓
GST
↑
GSH-px
TF
↓
AR/ARP
↓
P53
↑
MDR
↓
ELAM-1
↓
Hemeoxygenase
↑
Xanthine oxidase
↓
u PA
↓
FIGURE 23.3
Molecular targets shown to be regulated by curcumin.
of cytochrome c from the mitochondria, indicating that both the extrinsic (receptor mediated) and
intrinsic (chemical induced) pathways of apoptosis are triggered in prostate cancer cells treated
with a combination of curcumin and TRAIL. These results define a potential use of curcumin to
sensitize prostate cancer cells for TRAIL-mediated immunotherapy.
Chan et al. [39] demonstrated that curcumin increased the sensitivity of ovarian cancer cells
(CAOV3 and SKOV3) to cisplatin. The effect was obtained both when the compound was added
simultaneously with cisplatin and when it was added 24 h before. Curcumin inhibited the production
of interleukin 6 (IL-6) in these cell lines (Figure 23.3), suggesting that one of the mechanisms for
synergy between cisplatin and curcumin involved reducing the autologous production of IL-6.
However, the synergy was also observed in the low IL-6 producer, SKOV3, indicating that additional
targets were responsible. The down-regulation of IL-6 by curcumin was also noted in multiple
myeloma cells [35].
23.2.3 C
URCUMIN
D
OWN
-R
EGULATES
THE
A
CTIVITY
OF
E
PIDERMAL
G
ROWTH
F
ACTOR
R
ECEPTOR
(EGFR)
AND
E
XPRESSION
OF
HER2/
NEU
HER2/neu and epithelial growth factor receptor (EGFR) activity represent one possible mechanism
by which curcumin suppresses the growth of breast cancer cells. Almost 30% of the breast cancer
cases have been shown to overexpress the HER2/neu protooncogene [40], and both HER2 and EGF
receptors stimulate proliferation of breast cancer cells. Overexpression of these two proteins cor-
relates with progression of human breast cancer and poor patient prognosis [40]. Curcumin has
been shown to down-regulate the activity of EGFR and HER2/neu [30, 41] and to deplete the cells
of HER2/neu protein [42]. Additionally, we have recently found that curcumin can down-regulate
bcl-2 expression, which may contribute to its antiproliferative activity [43].
κ
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