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bits10. It also shows adjuvant chemoprotection in experi- trypsin20. Curcumin protects isoproterenol-induced myocar-
mental forestomach and oral cancer models of Swiss mice dial infarction in rats21. Curcumin, FHM and BHM also
and Syrian golden hamsters11. Curcumin also increases have anticoagulant activity22,23. Curcumin and an ether-
mucin secretion in rabbits12. Curcumin, the ethanol extract extract of C. longa have hypolipemic action in rats24 and
of the rhizomes, sodium curcuminate, [feruloyl-(4-hydroxy- lower cholesterol, fatty acids and triglycerides in alcohol-
cinnamoyl)-methane] (FHM) and [bis-(4-hydroxycinna- induced toxicity25. Curcumin is also reported to have anti-
moyl)-methane] (BHM) and their derivatives, have high bacterial15, antiamoebic26 and antiHIV27 activities. Curcumin
antiinflammatory activity against carrageenin-induced rat also shows antioxidant activity2831. It also shows antitu-
paw oedema13,14. Curcumin is also effective in formalin- mour3234 and anticarcinogenic3538 activities. The volatile
induced arthritis13. Curcumin reduces intestinal gas for- oil of C. longa shows antiinflammatory39, antibacterial40,41
mation15 and carbon tetrachloride and D-galactosamine- and antifungal41 activities. The petroleum ether extract of
induced glutamate oxaloacetate transaminase and glutamate C. longa is reported to have antiinflammatory activity42.
pyruvate transaminase levels16,17. It also increases bile Petroleum ether and aqueous extracts have 100% antiferti-
secretion in anaesthetized dogs 18 and rats19, and elevates lity effects in rats43. Fifty per cent ethanolic extract of C.
the activity of pancreatic lipase, amylase, trypsin and chymo- longa shows hypolipemic action44 in rats. Ethanolic extract
also possesses antitumour activity45. Alcoholic extract and
sodium curcuminate can also offer antibacterial activity15,18.
The crude ether and chloroform extracts of C. longa stem
are also reported to have antifungal effects46. A C. longa
fraction containing ar-turmerone has potent antivenom
activity47.
tion in rats. The antiulcer effect is mediated by scaveng- trosamine and 2-acetylaminofluorine-induced altered
ing of reactive oxygen species by curcumin (unpublished hepatic foci development58. Increased bile production
observation). was reported in dogs by both curcumin and essential oil
of C. longa19,59.
Intestine: Curcumin has some good effects on the intes-
tine also. Antispasmodic activity of sodium curcuminate Pancreas: 1-phenyl-1-hydroxy-n-pentane, a synthetic deri-
was observed in isolated guinea pig ileum14. Antiflatulent vative of p-tolylmethylcarbinol (an ingredient of C. longa)
activity was also observed in both in vivo and in vitro increases plasma secretion and bicarbonate levels60. Cur-
experiments in rats15. Curcumin also enhances intestinal cumin also increases the activity of pancreatic lipase, amy-
lipase, sucrase and maltase activity56. lase, trypsin and chymotrypsin20.
to indomethacin and salicylate, has recently been reported73. oxylated phenols and an enol form of -diketone; the struc-
Curcumin offers antiinflammatory effect through inhibi- ture shows typical radical-trapping ability as a chain-break-
tion of NFB activation74. Curcumin has also been shown ing antioxidant (Figure 1)88,89. Generally, the nonenzymatic
to reduce the TNF--induced expression of the tissue factor antioxidant process of the phenolic material is thought to
gene in bovine aortic-endothelial cells by repressing acti- be mediated through the following two stages:
vation of both AP-1 and NFB75. The antiinflammatory
role of curcumin is also mediated through downregulation S-OO + AH SOOH + A ,
of cyclooxygenase-2 and inducible nitric oxide synthe- A + X Nonradical materials,
tase through suppression of NFB activation34. Curcumin
also enhances wound-healing in diabetic rats and mice76, where S is the substance oxidized, AH is the phenolic anti-
and in H2O2-induced damage in human keratinocytes and oxidant, A is the antioxidant radical and X is another
fibroblasts31. radical species or the same species90 as A . A and X
dimerize to form the non-radical product. Masuda et al.89
further studied the antioxidant mechanism of curcumin
Antioxidant effect using linoleate as an oxidizable polyunsaturated lipid and
The antioxidant activity of curcumin was reported77 as early proposed that the mechanism involves oxidative coupling
as 1975. It acts as a scavenger of oxygen free radicals6,78. reaction at the 3position of the curcumin with the lipid
It can protect haemoglobin from oxidation29. In vitro, cur- and a subsequent intramolecular DielsAlder reaction.
cumin can significantly inhibit the generation of reactive
oxygen species (ROS) like superoxide anions, H2O2 and Anticarcinogenic effect induction of apoptosis
nitrite radical generation by activated macrophages, which
play an important role in inflammation79. Curcumin also Curcumin acts as a potent anticarcinogenic compound.
lowers the production of ROS in vivo79. Its derivatives, Among various mechanisms, induction of apoptosis plays
demethoxycurcumin and bis-demethoxycurcumin also have an important role in its anticarcinogenic effect. It induces
antioxidant effect29,30. Curcumin exerts powerful inhibi- apoptosis and inhibits cell-cycle progression, both of which
tory effect against H2O2-induced damage in human kera- are instrumental in preventing cancerous cell growth in rat
tinocytes and fibroblasts31 and in NG 108-15 cells80. Cur- aortic smooth muscle cells91. The antiproliferative effect is
cumin reduces oxidized proteins in amyloid pathology in mediated partly through inhibition of protein tyrosine kinase
Alzheimer transgenic mice81. It also decreases lipid per- and c-myc mRNA expression and the apoptotic effect may
oxidation in rat liver microsomes, erythrocyte membranes partly be mediated through inhibition of protein tyrosine
and brain homogenates28. This is brought about by main- kinase, protein kinase C, c-myc mRNA expression and bcl-2
taining the activities of antioxidant enzymes like super- mRNA expression91. Curcumin induces apoptotic cell death
oxide dismutase, catalase and glutathione peroxidase82. by DNA-damage in human cancer cell lines, TK-10, MCF-7
Recently, we have observed that curcumin prevents oxida- and UACC-62 by acting as topoisomerase II poison92.
tive damage during indomethacin-induced gastric lesion Recently, curcumin has been shown to cause apoptosis in
not only by blocking inactivation of gastric peroxidase, mouse neuro 2a cells by impairing the ubiquitinprotea-
but also by direct scavenging of H2O2 and OH (unpub- some system through the mitochondrial pathway93. Cur-
lished observation). Since ROS have been implicated in cumin causes rapid decrease in mitochondrial membrane
the development of various pathological conditions8385, potential and release of cytochrome c to activate caspase
curcumin has the potential to control these diseases through 9 and caspase 3 for apoptotic cell death93. Recently, an
its potent antioxidant activity. interesting observation was made regarding curcumin-in-
Contradictory to the above-mentioned antioxidant effect, duced apoptosis in human colon cancer cell and role of
curcumin has pro-oxidant activity. Kelly et al.86 reported heat shock proteins (hsp) thereon94. In this study, SW480
that curcumin not only failed to prevent single-strand DNA cells were transfected with hsp 70 cDNA in either the sense
breaks by H2O2, but also caused DNA damage. As this or antisense orientation and stable clones were selected
damage was prevented by antioxidant -tocopherol, the and tested for their sensitivity to curcumin. Curcumin was
pro-oxidant role of curcumin has been proved. Curcumin found to be ineffective to cause apoptosis in cells having
also causes oxidative damage of rat hepatocytes by oxidi- hsp 70, while cells harbouring antisense hsp 70 were highly
zing glutathione and of human erythrocyte by oxidizing sensitive to apoptosis by curcumin as measured by nuclear
oxyhaemoglobin, thereby causing haemolysis87. The pro- condensation, mitochondrial transmembrane potential, re-
oxidant activity appears to be mediated through genera- lease of cytochrome c, activation of caspase 3 and caspase
tion of phenoxyl radical of curcumin by peroxidaseH2O2 9 and other parameters for apoptosis94. Expression of glu-
system, which cooxidizes cellular glutathione or NADH, tathione S-transferase P1-1 (GSTP1-1) is correlated to car-
accompanied by O2 uptake to form ROS87. cinogenesis and curcumin has been shown to induce apop-
The antioxidant mechanism of curcumin is attributed to tosis in K562 leukaemia cells by inhibiting the expression
its unique conjugated structure, which includes two meth- of GSTP1-1 at transcription level95. The mechanism of cur-
CURRENT SCIENCE, VOL. 87, NO. 1, 10 JULY 2004 47
REVIEW ARTICLES
cumin-induced apoptosis has also been studied in Caki activation and oligonucleosomal DNA fragmentation106.
cells, where curcumin causes apoptosis through down- Curcumin also inhibits proliferation of rat thymocytes104.
regulation of Bcl-XL and IAP, release of cytochrome c These strongly imply that cell growth and cell death share a
and inhibition of Akt, which are markedly blocked by N- common pathway at some point and that curcumin affects
acetylcysteine, indicating a role of ROS in curcumin- a common step, presumably involving modulation of AP-1
induced cell death96. In LNCaP prostrate cancer cells, cur- transcription factor104,106.
cumin induces apoptosis by enhancing tumour necrosis
factor-related apoptosis-inducing ligand (TRAIL)97. The
combined treatment of the cell with curcumin and TRAIL
Pro/antimutagenic activity
induces DNA fragmentation, cleavage of procaspase 3, 8
Curcumin exerts both pro- and antimutagenic effects. At
and 9, truncation of Bid and release of cytochrome c from
100 and 200 mg/kg body wt doses, curcumin has been
mitochondria, indicating involvement of both external re-
shown to reduce the number of aberrant cells in cyclo-
ceptor-mediated and internal chemical-induced apoptosis
phosphamide-induced chromosomal aberration in Wistar
in these cells97. In colorectal carcinoma cell line, curcu-
rats107. Turmeric also prevents mutation in urethane (a
min delays apoptosis along with the arrest of cell cycle at
powerful mutagen) models108. Contradictory reports also
G1 phase98. Curcumin also reduces P53 gene expression,
exist. Curcumin and turmeric enhance -radiation-induced
which is accompanied with the induction of HSP-70 gene
chromosome aberration in Chinese hamster ovary109. Cur-
through initial depletion98 of intracellular Ca2+. Curcumin
cumin has also been shown to be non-protective against
also produces nonselective inhibition of proliferation in
hexavalent chromium-induced DNA strand break. In fact,
several leukaemia, nontransformed haematopoietic pro-
the total effect of chromium and curcumin is additive in
genitor cells and fibroblast cell lines99. That curcumin indu-
causing DNA breaks in human lymphocytes and gastric
ces apoptosis and large-scale DNA fragmentation has also
mucosal cells110.
been observed in V9V2+ T cells through inhibition of
isopentenyl pyrophosphate-induced NFB activation, proli-
feration and chemokine production100. Curcumin induces Anticoagulant activity
apoptosis in human leukaemia HL-60 cells, which is bloc-
ked by some antioxidants35. Colon carcinoma is also pre- Curcumin shows anticoagulant activity by inhibiting col-
vented by curcumin through arrest of cell-cycle progression lagen and adrenaline-induced platelet aggregation in vitro
independent of inhibition of prostaglandin synthesis101. as well as in vivo in rat thoracic aorta23.
Curcumin suppresses human breast carcinoma through
multiple pathways. Its antiproliferative effect is estrogen-
dependent in ER (estrogen receptor)-positive MCF-7 cells Antifertility activity
and estrogen-independent in ER-negative MDA-MB-231
cells37. Curcumin also downregulates matrix metallopro- Petroleum ether and aqueous extracts of turmeric rhizo-
teinase (MMP)-2 and upregulates tissue inhibitor of met- mes show 100% antifertility effect in rats when fed orally43.
alloproteinase (TIMP)-1, two common effector molecules Implantation is completely inhibited by these extracts111.
involved in cell invasion37. It also induces apoptosis through Curcumin inhibits 5-reductase, which converts testoste-
P53-dependent Bax induction in human breast cancer cells38. rone to 5-dihydrotestosterone, thereby inhibiting the growth
However, curcumin affects different cell lines differently. of flank organs in hamster112. Curcumin also inhibits human
Whereas leukaemia, breast, colon, hepatocellular and ova- sperm motility and has the potential for the development
rian carcinoma cells undergo apoptosis in the presence of of a novel intravaginal contraceptive113.
curcumin, lung, prostate, kidney, cervix and CNS malig-
nancies and melanoma cells show resistance to cytotoxic Antidiabetic effect
effect of curcumin102.
Curcumin also suppresses tumour growth through vari- Curcumin prevents galactose-induced cataract formation
ous pathways. Nitric oxide (NO) and its derivatives play at very low doses114. Both turmeric and curcumin decrease
a major role in tumour promotion. Curcumin inhibits iNOS blood sugar level in alloxan-induced diabetes in rat115. Cur-
and COX-2 production69 by suppression of NFB activa- cumin also decreases advanced glycation end products-
tion34. Curcumin also increases NO production in NK cells induced complications in diabetes mellitus116.
after prolonged treatment, culminating in a stronger tumou-
ricidal effect33. Curcumin also induces apoptosis in AK-5
tumour cells through upregulation103 of caspase-3. Reports Antibacterial activity
also exist indicating that curcumin blocks dexamethasone-
induced apoptosis of rat thymocytes104,105. Recently, in Both curcumin and the oil fraction suppress growth of
Jurkat cells, curcumin has been shown to prevent gluta- several bacteria like Streptococcus, Staphylococcus, Lac-
thione depletion, thus protecting cells from caspase-3 tobacillus, etc.15. The aqueous extract of turmeric rhizomes
48 CURRENT SCIENCE, VOL. 87, NO. 1, 10 JULY 2004
REVIEW ARTICLES
has antibacterial effects117. Curcumin also prevents growth Pharmacokinetic studies on curcumin
of Helicobacter pylori CagA+ strains in vitro118.
Curcumin, when given orally or intraperitoneally to rats,
is mostly egested in the faeces and only a little in the
Antifungal effect urine129,130. Only traces of curcumin are found in the blood
from the heart, liver and kidney. Curcumin, when added
Ether and chloroform extracts and oil of C. longa have
to isolated hepatocytes, is quickly metabolized and the
antifungal effects41,46,119. Crude ethanol extract also pos-
major biliary metabolites are glucuronides of tetrahydro-
sesses antifungal activity120. Turmeric oil is also active
curcumin and hexahydrocurcumin131,132. Curcumin, after
against Aspergillus flavus, A. parasiticus, Fusarium moni-
metabolism in the liver, is mainly excreted through bile.
liforme and Penicillium digitatum121.
The ethanol extract of the rhizomes has anti-Entamoeba Although various studies have been carried out with tur-
histolytica activity. Curcumin has anti-Leishmania activ- meric extracts and some of its ingredients in several animal
ity in vitro122. Several synthetic derivatives of curcumin models1,4,133, only a few clinical studies are reported so far.
have anti-L. amazonensis effect123. Anti-Plasmodium falci-
parum and anti-L. major effects of curcumin have also been Turmeric
reported124.
Powdered rhizome is used to treat wounds, bruises, infla-
med joints and sprains134 in Nepal. In current traditional
Antiviral effect Indian medicine, it is used for the treatment of biliary dis-
orders, anorexia, cough, diabetic wounds, hepatic disorders,
Curcumin has been shown to have antiviral activity4. It acts rheumatism and sinusitis48. Data are also available show-
as an efficient inhibitor of Epstein-Barr virus (EBV) key ing that the powder, when applied as capsules to patients
activator Bam H fragment z left frame 1 (BZLF1) protein with respiratory disease, gives relief from symptoms like
transcription in Raji DR-LUC cells125. EBV inducers such dyspnoea, cough and sputum135. A short clinical trial in
as 12-0-tetradecanoylphorbol-13-acetate, sodium butyrate 18 patients with definite rheumatoid arthritis showed signi-
and transforming growth factor-beta increase the level of ficant improvement in morning stiffness and joint swelling
BZLF1 m-RNA at 1248 h after treatment in these cells, after two weeks of therapy with oral doses of 120 mg/
which is effectively blocked by curcumin125. Most impor- day53. Application of the powder in combination with
tantly, curcumin also shows anti-HIV (human immunodefi- other plant products is also reported for purification of
ciency virus) activity by inhibiting the HIV-1 integrase blood and for menstrual and abdominal problems136.
needed for viral replication27,126. It also inhibits UV light-
induced HIV gene expression127. Thus curcumin and its ana-
logues may have the potential for novel drug development Curcumin
against HIV. In patients undergoing surgery, oral application of curcu-
min reduces post-operative inflammation137. Recently, cur-
Antifibrotic effect cumin has been formulated as slow-release biodegradable
microspheres for the treatment of inflammation in arth-
Curcumin suppresses bleomycin-induced pulmonary fibro- ritic rats138. It is evident from the study that curcumin-
sis in rats128. Oral administration of curcumin at 300 mg/kg biodegradable microspheres could be successfully emplo-
dose inhibits bleomycin-induced increase in total cell counts yed for therapeutic management of inflammation138.
and biomarkers of inflammatory responses. It also sup-
presses bleomycin-induced alveolar macrophage-produc- Safety evaluation with turmeric and curcumin
tion of TNF-, superoxide and nitric oxide. Thus curcumin
acts as a potent antiinflammatory and antifibrotic agent. Detailed studies have been reported on the safety evalua-
tion of the rhizomes of C. longa and its alcohol extract,
curcumin132,139. The major findings are presented below.
Antivenom effect
Male and female Wistar rats, guinea pigs and monkeys were 7. Vopel, G., Gaisbaver, M. and Winkler, W., Phytotherapie in der
fed with turmeric at much higher doses (2.5 g/kg body wt) Praxis. Deutscher Arzteverlag, Kolu, 1990, 74.
8. Vogel and Pelletier, J. Pharm., 1815, 2, 50.
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observed in the appearance and weight of kidney, liver and of curcumin. J. Chem. Soc., 1973, 20, 23792388.
heart132. Also, no pathological or behavioural abnormali- 10. Gujral, M. L., Chowdhury, N. K. and Saxena, P. N., The effect of
ties were noticed and no mortality was observed. certain indigenous remedies on the healing of wounds and ulcers.
J. Indian State Med. Assoc., 1953, 22, 273276.
11. Azuine, M. A. and Bhide, S. V., Adjuvant chemoprevention of ex-
Curcumin perimental cancer: catechin and dietary turmeric in forestomach
and oral cancer models. J. Ethnopharmacol., 1994, 44, 211217.
Curcumin was given to Wistar rats, guinea pigs and mon- 12. Lee, C. J., Lee, J. H., Seok, J. H., Hur, G. M., Park, Y. C., Seol, I. C.
keys of both sexes at a dose of 300 mg/kg body wt. No and Kim, Y. H., Effects of baicalein, berberine, curcumin and hes-
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13. Ghatak, N. and Basu, N., Sodium curcuminate as an effective
growth and the level of erythrocytes, leucocytes, blood antiinflammatory agent. Indian J. Exp. Biol., 1972, 10, 235236.
constituents such as haemoglobin, total serum protein, alka- 14. Srihari Rao, T., Basu, N. and Siddqui, H. H., Anti inflammatory
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15. Bhavani Shankar, T. N. and Sreenivasa Murthy, V., Effect of tur-
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