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Mechanisms of Cancer Chemoprevention by Curcumin

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Curcumin is a major component of the Curcuma species, which is commonly used as a yellow coloring and flavoring agent in foods. Curcumin has shown anti-carcinogenic activity in animals as indicated by its ability to block colon tumor initiation by azoxymethane and skin tumor promotion induced by phorbol ester TPA. Recently, curcumin has been considered by oncologists as a potential third generation cancer chemopreventive agent, and clinical trials using it have been carried out in several laboratories. Curcumin possesses anti-inflammatory activity and is a potent inhibitor of reactive oxygen-generating enzymes, such as lipoxygenase/cyclooxygenase, xanthine dehydrogenase/oxidase and induc- ible nitric oxide synthase. Curcumin is also a potent inhibitor of protein kinase C, EGF-receptor tyrosine kinase and I?B kinase. In addition, curcumin inhibits the activation of NF?B and the expression of c-jun, c-fos, c-myc and iNOS. It is proposed that curcumin may suppress tumor promotion by blocking signal transduction pathways in the target cells. Curcumin was first biotransformed to dihydrocurcumin and tetrahydrocurcumin, and these compounds were subsequently converted into monoglucuronide conjugates. The experimental results suggest that curcumin-glucuronide, dihydrocurcumin- glucuronide, tetrahydrocurcumin-glucuronide and tetrahydrocurcumin are major metabolites of curcumin in mice.
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Proc. Natl. Sci. Counc. ROC(B)
Cancer Chemoprevention by Curcumin
Vol. 25, No. 2, 2001. pp. 59-66
(Invited Review Paper)
Mechanisms of Cancer Chemoprevention by Curcumin
JEN-KUN LIN* AND SHOEI-YN LIN-SHIAU**
*Institute of Biochemistry
College of Medicine
National Taiwan University
Taipei, Taiwan, R.O.C.
**Institute of Toxicology
College of Medicine
National Taiwan University
Taipei, Taiwan, R.O.C.
(Received January 17, 2000; Accepted March 14, 2000)
ABSTRACT
Curcumin is a major component of the Curcuma species, which is commonly used as a yellow coloring and
flavoring agent in foods. Curcumin has shown anti-carcinogenic activity in animals as indicated by its ability to block
colon tumor initiation by azoxymethane and skin tumor promotion induced by phorbol ester TPA. Recently, curcumin has
been considered by oncologists as a potential third generation cancer chemopreventive agent, and clinical trials using it
have been carried out in several laboratories. Curcumin possesses anti-inflammatory activity and is a potent inhibitor of
reactive oxygen-generating enzymes, such as lipoxygenase/cyclooxygenase, xanthine dehydrogenase/oxidase and induc-
ible nitric oxide synthase. Curcumin is also a potent inhibitor of protein kinase C, EGF-receptor tyrosine kinase and I?B
kinase. In addition, curcumin inhibits the activation of NF?B and the expression of c-jun, c-fos, c-myc and iNOS. It is
proposed that curcumin may suppress tumor promotion by blocking signal transduction pathways in the target cells.
Curcumin was first biotransformed to dihydrocurcumin and tetrahydrocurcumin, and these compounds were subsequently
converted into monoglucuronide conjugates. The experimental results suggest that curcumin-glucuronide, dihydrocurcumin-
glucuronide, tetrahydrocurcumin-glucuronide and tetrahydrocurcumin are major metabolites of curcumin in mice.
Key Words: curcumin, curcuma species, curcumin-glucuronide, biotransformation, ROS, NF?B, iNOS, signal
transduction, antioxidant, chemoprevention
I. Introduction
used for centuries in tradition Chinese medicine to treat a va-
riety of inflammatory conditions, such as hepatitis and bile
Curcumin (diferuloylmethane) is a major yellow pig-
duct disorders.
ment that has been isolated from the ground rhizome of the
Curcumin has been demonstrated to have potent anti-
Curcuma species, Zingiberaceae (Table 1). Seven major spe-
oxidant (Kunchandy and Rao, 1990; Subramanian et al., 1994;
cies of Curcuma including Curcuma longa Linn., C. xanthor-
Sreejayan, 1994) and anti-inflammatory activity (Huang et
rhiza Roxb., C. wenyujin (Y.H. Chen et C, Ling); C. sichuane-
al., 1988, 1991, 1997; Shih and Lin, 1993), and to inhibit the
nsis; C. kwangsiensis; C. aeruginosa Roxb.; and C. elata Roxb.
carcinogen-DNA adduct (Conney et al., 1991) and tumori-
have been cultivated in China and their composition of curcu-
genesis in several animal models (Huang et al., 1992, 1994,
minoids were analyzed (Chen and Fang, 1997). Three major
1995; Rao et al., 1995) as shown by the findings summarized
curcuminoids namely curcumin, demethoxycurcumin and
in Table 2.
bisdemethoxycurcumin occur naturally in these Curcuma
species. The contents of curcuminoids of these plants vary
II. Biological Activities of Curcumin In
with the site and cultivation period as illustrated in Table 1. It
Vitro and In Vivo
seems that C. longa L. (turmeric) has the highest concentra-
tion of curcumin as compared to the other species.
1. Scavenging of Reactive Oxygen Species (ROS)
Turmeric is widely used as a spice and coloring agent
in several foods, such as curry, mustard, bean cake, cassava
Curcumin is a potent scavenger of a variety of ROS, in-
paste and potato chips, as well as in cosmetics and drugs.
cluding superoxide anion (Kunchandy and Rao, 1990), hy-
Another species C. wenyujin (Y.H. Chen et C. Ling) has been
droxyl radical, singlet oxygen (Subramanian et al., 1994), ni-
– 59 –

J.K. Lin and S.Y. Lin-Shiau
Table 1. Curcuminoid Contents in the Rhizome of Curcuma Species
Curcuma species
Origin (year)a
Curcuminoid (%)b
Total
Cur
Dcur
Bdcur
Curcuma longa Linn.
Nan-ning (1981)
3.97
1.84
1.09
1.01
Curcuma longa Linn.
Cheng-du (1979)
3.83
2.03
1.12
0.82
Curcuma longa Linn.
Beijing (1980)
3.82
1.79
1.11
0.75
Curcuma longa Linn.
Nan-Chang (1965)
1.41
0.70
0.35
0.25
Curcuma longa Linn.
Kwang-Chou (1979)
1.28
0.63
0.40
0.52
Curcuma xanthorrhiza Roxb.
Kwang-Chou (1980)
2.10
1.43
0.86
0.12
Curcuma wenyujin (Y.H. Chen et C. Ling)
Che-Chiang (1979)
0.20
0.13
0.07
0.02
Curcuma sichuanensis
Si-Chuan (1980)
0.04
0.01
0.01
<0.01
Curcuma Kwangsinensis
Yun-nan (1980)
1.54
0.89
0.57
0.23
Curcuma aeruginosa Roxb.
Si-Chuan (1980)
0.04
0.01
0.01
<0.01
Curcuma elata Roxb.
Kwang-see (1980)
0.01
<0.01
<0.01
<0.01
Source: Chen and Fang (1997).
a Origin, the site of cultivation or collection; year, the time of sample collection.
b Total, total curcuminoid; Cur, curcumin; Dcur, demethoxycurcumin; Bdcur, bisdemethoxycurcumin.
Table 2. Biochemical Actions of Curcumin
application of curcumin strongly inhibited tumor promotion
in the skin of DMBA-initiated mice (Huang et al., 1988, 1992,
Biochemical action
Reference
1995). Including 0.5% – 2.0% curcumin in the diet decreased
Scavenges superoxide anion and hydroxyl
Kunchandy and Rao (1990)
BaP-induced forestomach tumors per mouse by 51% – 53%
radical
Scavenges singlet oxygen
Subramanian et al. (1994)
when it was administered during the initiation period and by
Inhibits lipid peroxidation
Sreejayan (1994)
47% – 67% when it was administered during the postinitiation
Inhibits TPA-induced ornithine
Huang et al. (1988)
period (Huang et al., 1994). Including curcumin in the diet
decarboxylase (ODC) mRNA and activity
decreased the number of N-ethyl-N’-nitro-N-nitrosoguanidine
Inhibits TPA-induced cellular
Shih and Lin (1993)
(ENNG)-induced duodenal tumors per mouse (Huang et al.,
8-hydroxydeoxyguanosine
Inhibits TPA-induced skin inflammation
Huang et al. (1997)
1994). Administration of curcumin in the diet decreased the
Inhibits lipoxygenase and cyclooxygenase
Huang et al. (1991)
number of azoxymethane (AOM)-induced colon tumors in
activities
mice (Huang et al., 1994) and in rats (Rao et al., 1995).
Inhibits arachidonic acid metabolism
Conney et al. (1991)
Inhibits the formation of carcinogen-DNA
Conney et al. (1991)
3. Induction of Apoptosis
adducts
Inhibits skin tumor initiation and promotion
Huang et al. (1992)
Inhibits BaP induced forestomach and lung
Huang et al. (1994)
We have demonstrated that curcumin (30 µM) induces
tumorigenesis
apoptosis in several tumor cell lines (Jiang et al., 1996). The
Inhibits ENNG-induced duodenal
Huang et al. (1994)
curcumin-induced apoptosis is highly dependent on the ori-
tumorigenesis
gin and malignancy of cell lines. It appears that the typical
Inhibits azoxymethane-induced colon
Rao et al. (1995)
tumorigenesis in mice and rats
apoptosis can only be induced in immortalized mouse em-
bryo fibroblast NIH 3T3, erbB2 oncogene-transformed NIH
3T3, mouse Sarcoma 180, human colon cancer cell HT29,
tric oxide and peroxynitrite. Curcumin has the ability to pro-
human kidney cancer cell 293, and human hepatocellular car-
tect lipids, hemoglobin, and DNA against oxidative degrada-
cinoma HepG2 cells but not in primary cultures of mouse
tion. Pure curcumin has more potent superoxide anion scav-
embryonic fibroblast C3H 10T1/2, rat embryonic fibroblast
enging activity than demethoxycurcumin or bisdemetho-
or human foreskin fibroblast cells (Jiang et al., 1996). Treat-
xycurcumin (Kunchandy and Rao, 1990). Curcumin is also a
ment of NIH 3T3 cells with the PKC inhibitor staurosporine,
potent inhibitor of ROS-generating enzyme cyclooxygenase
the tyrosine kinase inhibitor herbimycin A or arachidonic acid
and lipoxygenase in mouse epidermis (Huang et al., 1991).
metabolism inhibitor quinacrine induces typical apoptosis.
These findings suggest that blocking the cellular signal trans-
2. Inhibition of Chemical Carcinogenesis
duction in immortalized or transformed cells might trigger
the induction of apoptosis.
Curcumin inhibited chemical carcinogenesis in differ-
We have also demonstrated that curcumin (3.5 µg/ml)
ent tissue sites in several experimental animal models as in-
induces human promyelocytic HL-60 cells. The apoptosis-
dicated by Table 2. Curcumin inhibited tumor initiation by
inducing activity of curcumin occurred in a dose- and time-
benzo[a]pyrene (BaP) and 7,12-dimethylbenz[a]anthracene
dependent manner. Flow cytometric analysis showed that the
(DMBA) in mouse epidermis (Conney et al., 1991). Topical
hypodiploid DNA peak of propidium iodide-stained nuclei
– 60 –

Cancer Chemoprevention by Curcumin
appeared 4 h after treatment with 7 µg/ml curcumin. The
Table 3. Modulation of Tumor Biomarkers by Curcumin
apoptotic effect of curcumin was not affected by cyclohex-
Tumor biomarker
Reference
imide, actinomycin D, EGTA, W7 (calmodulin inhibitor),
Inhibition of TPA-induced c-jun and
Huang et al. (1991) and
sodium orthovanadate, or genistein whereas an endonuclease
c-fos expression
Lu et al. (1994)
inhibitor, ZnSO4 , and a proteinase inhibitor, N-tosyl-L-lysine
Inhibition of TPA-induced protein
Liu et al. (1993)
chloro-methyl-ketone (TLCK), could markedly abrogate cur-
kinase C (PKC)
cumin-induced apoptosis. The antioxidants N-acetyl-L-cys-
Inhibition of TPA-induced
Korutla et al. (1994)
EGF-receptor tyrosine kinase (RTK)
teine (NAC), L-ascorbic acid, alpha-tocopherol, catalase and
Inhibition of inducible nitric oxide
Chan et al. (1998)
superoxide dismutase all effectively prevented curcumin-in-
synthase (iNOS)
duced apoptosis. Furthermore, overexpression of bcl-2 in HL-
Inhibition of NF?B and I?B kinase
(unpublished, from Pan and Lin)
60 cells delayed the entry of curcumin-treated cells into
(IKK) activation
apoptosis, suggesting that bcl-2 plays an important role in the
Inhibition of TPA-induced xanthine
Lin and Shih (1994)
oxidase
early stage of curcumin-triggered apoptotic cell death (Kuo et
Inhibition of p53 gene expression
Chen et al. (1996)
al., 1996).
Induction of HSP70 gene expression
Chen et al. (1996)
Reduction of ER(+)PgR(+)
Inano et al. (1999)
III. Mechanisms of Cancer Chemopre-
mammary tumor
vention by Curcumin
Inhibition of TPA-induced
Lee and Lin (1997)
transformation in mouse fibroblast cells
Inhibition of the invasion of
Lin et al. (1998)
1. Suppression of c-jun and c-fos Expression
hepatocellular carcinoma cells by
suppressing matrix metalloproteinase-9
In 1991, we have made an interesting finding that the
Induction of apoptosis in NIH 3T3
Jiang et al. (1996)
phorbol ester TPA induced transcriptional factor c-jun/AP-1
fibroblast cells
Induction of apoptosis in human
Kuo et al. (1996)
in mouse fibroblast cells was suppressed by curcumin (Huang
leukemia HL-60 cells
et al., 1991). Elevated expression of genes transcriptionally
induced by TPA is among the events required for tumor pro-
motion. Functional activation of the transcriptional factor c-
Curcumin (10 µM) inhibits EGF receptor kinase activ-
jun/AP-1 is believed to play an important role in signal trans-
ity by up to 90% in a dose- and time-dependent manner and
duction of TPA-induced tumor promotion. Suppression of c-
also inhibits EGF-induced tyrosine phosphorylation of EGF-
jun/AP-1 activation by curcumin (10 µM) was observed in
receptors in A431 cells (Korutla and Kumar, 1994). Treat-
mouse fibroblast cells. The results of in vitro experiments
ment of NIH 3T3 cells with a saturating concentration of EGF
indicate that inhibition of c-jun/AP-1 binding to its cognate
for 5 – 15 min induced increased EGF-R tyrosine phosphory-
motif, 5'-TGACTCAG-3', by curcumin may be responsible
lation by 4 to 11-folds and this effects was inhibited by curcu-
to the inhibition of c-jun/AP-1-mediated gene expression
min, which also inhibited the growth of EGF-stimulated cells
(Huang et al., 1991). These findings show for the first time
(Korutla et al., 1995).
that the effect of curcumin on TPA-induced inflammation/
Recent studies in our laboratory have demonstrated that
tumor promotion can be studied at the molecular level as il-
curcumin blocks NF?B activation by down-regulating I?B
lustrated in Table 3.
kinase activity in macrophages (unpublished results). Cur-
Curcumin also inhibits the TPA- and UVB light-induced
cumin has been shown to suppress the expression of induc-
expression of c-jun and c-fos in JB6 cells and in mouse epi-
ible nitric oxide synthase (iNOS) in vivo (Chan et al., 1998).
dermis (Lu et al., 1994).
3. Suppression of Colonic Aberrant Crypt Foci
2. Inhibition of Protein Kinase C (PKC) and EGFR
through Inhibiting iNOS
Tyrosine Kinase
It has been demonstrated that iNOS is overexpressed in
When mouse fibroblast cells (NIH 3T3) were treated
colonic tumors of humans and also in rats treated with a colon
with TPA alone, PKC translocated from the cytosolic fraction
carcinogen. INOS appears to regulate cyclooxygenase-2
to the particulate (membrane) fraction. Treatment with 15 or
(COX-2) expression and the production of pro-inflammatory
20 µM curcumin for 15 min inhibited TPA-induced PKC ac-
prostaglandins, which are known to play a key role in colon
tivity in particulate fractions by 26 or 60% and did not affect
tumor development. Experiments were designed to study the
the level of PKC protein. Curcumin also inhibited the PKC
inhibitory effects of curcumin on the formation of azoxyme-
activity in both cytosolic and particulate fractions in vitro by
thane (AOM)-induced colonic aberrant crypt foci (ACF)
competing with phosphatidylserine. However, the inhibitory
in male F344 rats. Both iNOS activity and colonic ACF for-
effect of curcumin was reduced following preincubation with
mation were significantly inhibited by curcumin (Rao et al.,
thiol compounds (Liu et al., 1993).
1999).
– 61 –

J.K. Lin and S.Y. Lin-Shiau
4. Inhibition of COX-2 by Curcumin in Bile Acid and
through the initial depletion of intracellular Ca+2, followed by
PMA-Treated Cells
the suppression of the p53 gene function in the target cells
(Chen et al., 1996).
The inhibition of PMA- or chenodeoxycholate (CD)-
induced COX-2 by curcumin in several human gastrointesti-
7. Reduction of ER(+)PgR(+) Mammary Tumor
nal cell lines (SK-GT-4, SCC450, IEC-18 and HCA-7) was
studied (Zhang et al., 1999). Treatment with curcumin sup-
The chemopreventive effects of curcumin on diethylstil-
pressed CD- and PMA-mediated induction of COX-2 m-RNA
bestrol (DES)-induced tumor promotion in rat mammary
as well as protein level and synthesis of prostaglandin E2 in
glands initiated with radiation have been evaluated (Inano et
these cell lines. Nuclear run-offs revealed increased rates of
al., 1999). The administration of dietary curcumin significantly
COX-2 transcription after treatment with CD or PMA , and
reduced the incidence (28%) of mammary tumors. Multiplicity
these effects were inhibited by curcumin. Treatment with CD
and Iball’s index of mammary tumors were also decreased by
or PMA increased the binding of AP-1 to DNA. This effect
curcumin. Rats fed a curcumin diet showed a reduced inci-
was also inhibited by curcumin (Huang et al., 1991; Zhang et
dence of the development of both mammary adenocarcinoma
al., 1999). Furthermore, the activity of COX-2 was found to
and ER(+)PgR(+) tumors in comparison with a control group.
be directly inhibited by curcumin in vitro (Zhang et al., 1999).
These findings suggest that curcumin has a potent preventive
These findings may provide new insightes into the cancer
activity during the DES-dependent promotion stage of radia-
chemoprevention properties of curcumin.
tion-induced mammary tumorigenesis (Inano et al., 1999).
Curcumin has also been found to suppress TPA-induced trans-
5. Inhibition of Xanthine Oxidase
formation in mouse fibroblast cells (Lee and Lin, 1997).
Treatment of NIH 3T3 cells with the tumor promoter
8. Curcumin acts as Inducer of Phase-2 Detoxifica-
TPA results within 30 min in a 1.8 fold elevation of xanthine
tion Enzymes
oxidase activity, an enzyme capable of generating ROS, such
as superoxide and hydrogen peroxide. Simultaneous admin-
Several possible mechanisms of the observed anti-tu-
istration of 2 and 10 µM curcumin with 100 ng/ml TPA was
mor effects of curcumin have been suggested. Among these,
found to inhibit TPA-induced increases in xanthine oxidase ac-
its antioxidant and anti-inflammatory properties have received
tivity measured 30 min later by 22.7% and 36.5% respectively
much attention as noted above. On the other hand, curcumin
(Lin and Shih, 1994). The TPA-induced conversion of xanthine
may be a natural chemoprotective agent, since it also elevates
dehydrogenase into xanthine oxidase is reduced by curcumin
the activities of Phase-2 detoxification enzymes of xenobiotic
to the basal level found in untreated cells. Activity of xanthine
metabolism, such as glutathione transferase, epoxide hydro-
oxidase is remarkably inhibited by curcumin in vitro, but not
lase and NADPH: quinone reductase, while inhibiting procar-
by its structurally related compounds caffeic acid, chlorogenic
cinogen activating Phase-1 enzymes, such as cytochrome p450
acid and ferulic acid. Based on these findings, the induction of
1A1 (Ciolino et al., 1998).
xanthine oxidase activity is seemed to be one of the major caus-
Based on compelling evidence that coordinate induction
ative elements in TPA-mediated tumor promotion, and the
of Phase-2 enzymes is a critical and sufficient condition for pro-
major inhibitiory mechanism by which curcumin inhibits TPA-
tection against toxicity and carcinogenicity (Talalay et al.,
induced increases in xanthine dehydrogenase/oxidase enzyme
1995), a series of naturally-occurring as well as synthetic struc-
activities is considered to occur through direct inactivation in
tural analogs of the dietary constituent curcumin were exam-
the protein level (Lin and Shih, 1994).
ined to elucidate which portions of the molecule are critical for
its ability to induce Phase-2 detoxification enzymes in murine
6. Modulation of Ca+2 and Cellular p53 Protein
hepatoma cells, and to assess the chemoprotective potential of
these compounds (Dinkova-Kostova and Talalay, 1999). Two
When COLO205 colorectal carcinoma cells were treat-
groups of compounds were studied: (1) classical Michael re-
ed with curcumin (60 µM), the appearance of apoptotic DNA
action receptors such as curcumin and (2) related ?-diketones
ladders was delayed about 5 h and G1 arrest was detected
such as dibenzoylmethane which lack direct Michael reactivity.
(Chen et al., 1996). Further analysis of the endonuclease ac-
Two structural elements was found to be required for high
tivities in these cells revealed that the activity of Ca+2-depen-
inducer potency: (1) hydroxy groups at the ortho-position on
dent endonuclease in COLO205 cells was profoundly inhib-
the aromatic rings and (2) the ?-diketone functionality.
ited, and that the extent of inhibition depended on the degree
of calcium depletion. The reduction of p53 gene expression
9. Suppression of Hepatocellualr Carcinoma Inva-
was accompanied by the induction of HSP70 gene expres-
sion by Inhibiting MMP-9
sion in the curcumin-treated cells. These findings suggest
that curcumin may induce the expression of the HSP70 gene
Recently, curcumin was further demonstrated to have
– 62 –

Cancer Chemoprevention by Curcumin
an anti-metastatic effect in mice. We attempted to investigate
HO
OH
the possible mechanism of this effect. A highly invasive SK-
H
OCH
3O
3
O
O
Hep-1 cell line of human hepatocellular carcinoma was se-
H
lected for this study. An in vitro assay, without or with the
Curcumin
Matrigel matrix, was used to quantify cellular migration and
invasion. Gelatin-based zymography was adopted to assay
the secretion of matrix metalloproteinase-9 (MMP-9). We
HO
O
found that curcumin at 10 µM , inhibited by 17.4 and 70.6%
CHO
C
CH=CHCOOH
CH=CHCOCH3
H3O
H
cellular migration and invasion of SK-Hep-1 cells, respec-
O
O
H
OCH3
OCH
tively. Compared with a less invasive human hepatocellular
3
OCH3
OH
OH
OH
carcinoma cell line, Huh 7, SK-Hep-1 showed a much higher
Trans-6-(4’-Hydroxy-3’-
Vanillin
Ferulic acid
Feruloyl methane
level of MMP-9 secretion. Furthermore, parallel with its anti-
methoxyphenyl)-2,4-dioxo-
5-hexenal
invasion activity, curcumin inhibited MMP-9 secretion in SK-
Hep-1 in a dose-dependent fashion. We conclude that cur-
Fig. 1. Degradation of curcumin in aqueous solution. The major degradation
product of curcumin in 0.1 M phosphate buffer at pH 7.2 was
cumin has a significant anti-invasion activity in SK-Hep-1
tentatively identified as trans-6-(4’-hydroxy-3’-methoxyphenyl)-2,
cells, and that this effect is associated with its inhibitory effect
4-dioxo-5-hexenal while the minor products were identified as
on MMP-9 secretion (Lin et al., 1998).
vanillin, ferulic acid and feruloylmethane. [Data from Wang et al.
(1997)].
IV. Biotransformations of Curcumin
2. Biotransformations of Curcumin in Mice
1. Chemical Degradation of Curcumin
We have investigated the pharmacokinetic properties
Curcumin is a yellow antioxidant substance. It seems
of curcumin in mice (Pan et al., 1999). After intraperitoneal
that curcumin is sensitive to oxygen in aqueous solution, and
adminstration of curcumin (0.1 g/kg) to mice, about 2.25 µg/
that it is affected by UV under solar light exposure. The deg-
ml of the curcumin appeared in the plasma during the first 15
radation kinetics of curcumin under various pH conditions
min. One hour after administration, the levels of curcumin in
and the stability of curcumin in physiological matrices were
the intestine, spleen, liver and kidneys were 177, 26, 27, and
investigated in our laboratory (Wang et al., 1997). When
7.5 µg/g, respectively. Only traces (0.41 µg/g ) were observed
curcumin was incubated in 0.1 M phosphate buffer and se-
in the brain at 1 h. To clarify the nature of the metabolites of
rum-free medium, pH 7.2 at 37°C, about 90% of the com-
curcumin, the plasma was analyzed using reversed-phase
pound decomposed within 30 min. A series of pH conditions
HPLC, and two putative conjugates were observed. Further
ranging from 3 to 10 were tested, and the results showed that
treatment of the plasma with ?-glucuronidase resulted in a
decomposition was pH-dependent and occurred faster under
decrease in the levels of these two putative conjugates and in
neutral-basic conditions. Curcumin is more stable in cell cul-
the concomitant appearance of tetrahydrocurcumin and cur-
ture medium containing 10% fetal calf cerum and in human
cumin, respectively. To investigate the nature of these glu-
blood; less than 20% of the curcumin decomposed within 1 h,
curinide conjugates in vivo, the plasma was analyzed by means
and after incubation for 8 h, about 50% of the curcumin still
of electrospray. The chemical structures of these metabolites
remained (Wang et al., 1997). Based on mass and spectro-
were determined by means of MS/MS analysis. The experi-
photometrical analysis, trans-6-(4’-hydroxy-3’-methoxy-
mental results suggested that curcumin was first biotrans-
phenyl)-2,4-dioxo-5-hexenal was tentatively identified as a
formed into dihydrocurcumin and tetrahydrocurcumin and
major degradation product while vanillin, ferulic acid and
these compounds subsequently were converted to monoglu-
feruloylmethane were identified as minor degradation prod-
curonide conjugates as illustrated in Fig. 2. These results sug-
ucts (Fig. 1) (Wang et al., 1997).
gest that curcumin-glucuronide, dihydrocurcumin-glucuro-
Since curcumin decomposes rapidly in serum-free
nide, tetrahydrocurcumin-glucuronide and tetrahydro-cur-
medium, precautions must be taken during cell culture expe-
cumin are major metabolites of curcumin in vivo.
riments. In addition, the biological effects caused by the deg-
radation products of curcumin, especially vanillin, must be
V. A Proposal for the Action Mechanisms
taken into consideration. Vanillin, a naturally occurring fla-
of Curcumin
voring agent, has been reported to inhibit mutagenesis in bac-
terial and mammalian cells. It may act as an antimutagen by
Recent intensive studies on the action mechanisms of
modifying DNA replication and DNA repair systems after
curcumin in various biological systems have indicated that
cellular DNA damage caused by mutagens occurs. Vanillin
this compound employs multiple anti-tumor promoting path-
is also a powerful scavenger of superoxide and hydroxyl rad-
ways (Lin et al., 1994). It has been demonstrated that TPA-
icals.
induced tumor promotion is significantly inhibited by curcu-
– 63 –

J.K. Lin and S.Y. Lin-Shiau
HO
OH
first inhibited (Liu et al., 1993). At the same time, the activity
H3CO
OCH3
of EGF receptor tyrosine kinase is also inhibited (Korutla and
OH
O
UDP-glucuronate
Curcumin
Kumar, 1994). Some PKC-mediated nuclear protein factors,
UDP-glucuronosyl transferase
H
?-glucuronidase
such as I?B kinase and NF?B, are then inhibited through vari-
UDP
H
OH
H OH
ous signal transduction pathways. The TRE binding activity
NADPH
reductase

HO
OO
H
COO–
of c-jun/AP-1 is then repressed (Huang et al., 1991), and fi-
H3CO
OCH3
nally the transcriptions of genes essential for cell prolifera-
OH
O
HO
OH
Curcumin-glucuronoside
tion are suppressed as indicated by the inhibition of related
H
OCH
3CO
3
OH
O
UDP-glucuronate
enzymes, such as ornithine decarboxylase, PKC, cyclooxyge-
H
Dihydrocurcumin
UDP-glucuronosyl transferase
NADPH
nase and lipoxygenase (Table 2).
H
OH
reductase
UDP
?-glucuronidase
H OH
It appears that activation of calcium-dependent protein
O O
HO
H
COO–
NADPH
kinases (such as PKC) or inhibition of protein phosphatases
reductase
H3CO
OCH3
OH
O
results in tumor promotion (Haystead et al., 1989). In the
HO
OH
Dihydrocurcumin-glucuronoside
case of tumor promoters, it appears that a common final ef-
H
OCH
3CO
3
OH
O
fect is an increase in phosphorylation of the protein substrate
UDP-glucuronate
H
Tetrahydrocurcumin
UDP-glucuronosyl transferase
NADPH
on serine or threonine residues. The nature of these substrates
H
OH
reductase
UDP
?-glucuronidase
H OH
HO
OO
H
COO–
NADPH
Growth factors
H3CO
OCH3
reductase
Cytokines
TPA
OH
O
Cur
Cur
HO
OH
Tetrahydrocurcumin-glucuronoside
NADPH/NADH
RTK
(TNFR)
Oxidase
H
OCH
(EGFR)
3CO
3
PKC
UDP-glucuronate
OH
O
Xanthine
UDP-glucuronosyl transferase
H
Cur
Oxidase
Hexahydrocurcumin
NADPH
H
OH
reductase
NIK
UDP
Grb2
?-glucuronidase
H OH
Ras
Cur
ROS
HO
OO
H
COO–
MEKK1
H
JNK
3CO
OCH3
OH
O
Hexahydrocurcumin-glucuronoside
IKK
NF?B
Fig. 2. Biotransformations of curcumin in mice. Two main transformation
?B
AP-1
c-myc
c-jun
c-fos
iNOS
Cru
pathways, namely, reduction and glucuronidation of Curcumin, are
Nucleus
depicted. Our preliminary results indicate that NADPH is required
C-Jun C-Fos
iNOS
for reduction reaction but the nature of the reductase is unknown.
Cytosol
Myc
Furthermore, most of the conjugated derivatives are hydrolyzed by ?-
PKC
glucosidase and has been identified as glucuronides in mouse plasma.
[Data from Pan et al. (1999)].
Cur
Proliferation, Carcinogenesis, Inflammation
TPA
Apoptosis, Differentiation
Fig. 3. A proposal model illustrating the proposed action mechanism of
min (Huang et al., 1988, 1997; Rao et al., 1995). TPA is a
curcumin for the inhibition of carcinogenesis and inflammation.
versatile biological active agent which induces several mo-
Extracellular growth factors, cytokines, or tumor promoter 12-O-
tetradeca-noylphorbol-13-acetate (TPA) binds to membrane receptors,
lecular biological processes, namely, enhanced expression of
such as epidermal growth factor receptor (EGFR), tumor necrosis
cellular oncogenes such as c-jun, c-fos and c-myc; induction
factor receptor (TNFR), or protein kinase C (PKC), resulting in the
of ornithine decarboxylase; elevation or translocation of PKC;
activation of a number of serine, threonine or tyrosine kinases, which
induction of cyclooxygenase and lipoxygenase; and other
include ras, NF?B inducing kinase (NIK), mitogen-activated protein
processes. It seems that all of these biochemical processes
kinase (MAPK), extracellular response kinase (ERK), MAPK/ERK
kinase kinase (MEKK
are required for anabolic pathways and cell proliferation that
1), I?B kinase (IKK) and c-jun N-terminal
kinase (JNK). JNK is activated by MAPK kinase (MKK4), causing
lead to tumor promotion. It is noteworthy that all of these
activation of the c-jun protein which forms a heterodimer with the c-
processes have been shown to be effectively inhibited by the
fos protein thus enhancing the activity of the transcription factor AP-
presence of curcumin (Tables 2 and 3).
1. Recent studies indicate that both IKK and PKC are important for
It is conceivable that the molecular mechanism of ac-
activation of NF?B which leads to enhancement of the expression of
c-myc, iNOS and other cellular proliferation genes. Reactive oxygen
tion of curcumin is quite complicated and dispersed. The lo-
species (ROS) are considered to be endogenous mitogenic factors (or
cations of targets of its action vary from genome (DNA) level,
apoptotic factors under certain conditions) that can activate NF?B
to the messenger (RNA) level, to the enzyme (protein) level
and other transcription factors in the nucleus. Ultimately, activation
(Lin et al., 1994). The action of curcumin may proceed si-
of the MAPK family members causes activation of specific transcrip-
multaneously or sequentially through these different levels.
tion factors, such as NF?B, AP-1, serum response factor (SRF) and
others which help determine the fate of cell such as proliferation,
Accordingly, we propose the following pathways for the ac-
carcinogenesis,inflammation or apoptosis. Curcumin (Cur) has been
tion of curcumin (Fig. 3). The primary target of curcumin
demonstrated to block several sites of these multiple signal transduc-
could be the plasma membrane where the activity of PKC is
tion pathways as indicated by the blockade sympbol (?).
– 64 –

Cancer Chemoprevention by Curcumin
has not been completely characterized, but the convergence
H. (1994) Inhibitory effects of dietary curcumin on forestomach, duadenal
of the actions of disparate tumor promoters on specific phos-
and colon carcinogenesis in mice. Cancer Res., 54:5841-5847.
Huang, M.T., Ma, W., Lu, Y.P., Chang, R.L., Fischer, C., Manchand, P.S.,
phorylation of protein substrate on serine and threonine resi-
Newmark, H.L. and Conney, A.H. (1995) effect of curcumin, demethoxy-
dues strongly implicates signal transduction in tumor pro-
curcumin, bisdemethoxy-curcumin and tetrahydrocurcumin on TPA-in-
motion. It appears that when any essential component of a
duced tumor promotion. Carcinogenesis, 16:2493-2497.
signal transduction pathway is rendered hyperactive or auto-
Huang, M.T., Ma, W., Yen, P., Xie, J.G., Han, J., Fenkel, K., Grunberger, D.
nomous, it may acquire the ability to drive the cell into un-
and Conney, A.H. (1997) Inhibitory effects of topical application of low
doses of curcumin on TPA-induced tumor promotion and oxidized DNA
checked proliferation leading to tumor promotion. Curcumin
bases in mouse epidermis. Carcinogenesis, 18:83-88.
may attenuate or suppress the hyperactivity of these compo-
Inano, H., Onoda, M., Inofuku, N., Kubota, M., Kamada, Y., Osawa, T.,
nents of signal transduction and maintain simultaneously the
Kobayashi, H. and Wakabayashi, K. (1999) Chemoprevention by cur-
normal cell function.
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in rats irradiated with ?-rays. Carcinogenesis, 20:1011-1018.
Acknowledgment
Jiang, M.C., Yang-Yen, H.F., Yen, J.J. and Lin, J.K. (1996) Curcumin in-
duces apoptosis in immortalized NIH 3T3 and malignant cancer cell
lines. Nutr. Cancer, 26:111-120.
This study was supported by the National Science Council,
Kuo, M.L., Huang, T.S. and Lin, J.K. (1996) Curcumin, an antioxidant and
R.O.C., under grants NSC 89-2316-B-002-016 and NSC 88-EPA-Z-002-
anti-tumor promoter, induced apoptosis in human leukemia cells. Bio-
021, and by the National Health Research Institutes, R.O.C., under grant
chim. Biophys. Acta, 1317:95-100.
DOH-88-403.
Korutla, L. and Kumar, R. (1994) Inhibitory effects of curcumin on epider-
mal growth factor receptor kinase activity in A431 cells. Biochim.
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