See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/232764258

A Review of Therapeutic Effects of Curcumin

Article  in  Current Pharmaceutical Design · October 2012

DOI: 10.2174/1381612811319110006 · Source: PubMed

CITATIONS READS
145 8,519

2 authors:

Ali Noorafshan Soheil Ashkani Esfahani

Shiraz University of Medical Sciences Massachusetts General Hospital
162 PUBLICATIONS   1,481 CITATIONS    58 PUBLICATIONS   689 CITATIONS   

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Medical Ethics View project

Traditional medicine View project

All content following this page was uploaded by Soheil Ashkani Esfahani on 22 May 2014.

The user has requested enhancement of the downloaded file.

Send Orders of Reprints at reprints@benthamscience.net
2032 Current Pharmaceutical Design, 2013, 19, 2032-2046

A Review of Therapeutic Effects of Curcumin

Ali Noorafshan1 and Soheil Ashkani-Esfahani2,*

1
Histomorphometry & Stereology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; 2Student Research Commit-
tee, Shiraz University of Medical Sciences, Shiraz, Iran

Abstract: There is a growing interest in herbal medicine. Scientific studies have demonstrated the beneficial pharmacological effects of
curcumin. Curcumin is a bright yellow spice, derived from the rhizome of Curcuma longa Linn. It has been proven that curcumin is a
highly pleiotropic molecule which can be a modulator of intracellular signaling pathways that control cell growth, inflammation, and
apoptosis. Curcumin might be a potential candidate for the prevention and/or treatment of some diseases due to its anti-oxidant, anti-
inflammatory activities and an excellent safety profile. We present an updated concise review of currently available animal and clinical
studies demonstrating the therapeutic effect of curcumin.
Keywords: Curcumin, therapeutic effects, review.

INTRODUCTION
O O
Curcumin, a bright yellow spice, derived from the rhizome of
Curcuma longa Linn, was primarily isolated by Vogel (1842), and H3CO OCH3
was structurally characterized by Milobedeska and colleagues
(1910); it was synthesized and confirmed in 1913 by Lampe and
colleagues [1, 2]. Curcumin is the active ingredient in the herbal HO OH
Curcumin (I)
remedy and dietary spice turmeric [1, 2]. Curcumin has a long his-
tory of administration in traditional medicine of China, India and O O
Iran, and it has been used in different folks for the treatment of OCH3
many diseases such as diabetes, liver disease, rheumatoid diseases,
atherosclerosis, infectious diseases and cancers [3]. The powder of
turmeric rhizome is used in cookery, medicine, fabric dying and HO OH
also cosmetics for many centuries [3, 4]. This important spice was Demethoxycurcumin (II)
introduced to the Western world in the 14th century [5]and up to
O O
now it is still in use. In the ancient Indian medicine, Ayurveda, a
topical agent made of turmeric paste has been used to treat common
ocular infections and inflammations; it has also been used in wound
dressing in conditions such as bites, burns, and some other skin
diseases [6]; a curcumin poultice has been applied to the perineal HO OH
Bis-demethoxycurcumin (III)
area to improve the healing process of any birth canal lacerations
[7]. Powdered turmeric has been consumed with hot milk for cure O OH
of cough and related respiratory problems [6, 7]. Roasted turmeric
H3CO OCH3
has been also administered as an anti-dysenteric agent [6, 7]. This
ancient medicine has been also used for treatment of other digestive
disorders such as indigestion, dyspepsia, flatulence, gastric and HO OH
duodenal ulcers [7]. It has also been used for alleviating the hallu-
cination states induced by some opioids and psychotropic drugs [4].

Structural Description, Bioavailability, and Safety of Curcumin OH O

Curcumin, 1, 7-bis (4-hydroxy-3-methoxyphenyl)-1,6- H3CO OCH3

heptadien-3,5-dione, is a lipophilic molecule that rapidly permeates
cell membrane [8]. It affects the function and structure of the cell
membrane and mimics typical events happening during the apopto-
sis process; however, the cellular response to curcumin contrasts
with the typical apoptosis process as curcumin induces immediate
and partly reversible loss of membrane integrity, of which cells
could recover in a relatively short time [8]. It was also mentioned
that membranous alterations evoked by curcumin might underlie
some of its influences (ex. by changing access to phosphatidylser-
ine, curcumin may modulate the activity of protein kinase C) [8, 9].
*Address correspondence to this author at the Student research committee,
Shiraz University of medical sciences, Neshat st., Shiraz, Iran;
Tel:/Fax: +98-711-2304372; E-mail: soashkani@gmail.com
HO OH
Equilibrating Keto-Enol Tautomers
Fig. (1). Curcumin I, II, and III (curcumin, demethoxycurcumin, bisde-
methyoxy curcumin), and curcumin keto-enol tautomers.
The simple molecular structure along with the relative density
of functional groups in curcumin provides researchers with an out-
standing target for structure-activity relationship and lead optimiza-
tion studies. Many studies were published concerning the pharma-
cologic and metabolic features of curcumin [10, 11]. Typical extract
of Curcuma longa L. contains the structures I to III, (I)Diferu-
loylmethane/Curcumin (II) Demethoxycurcumin and (III) Bisde-

1873-4286/13 $58.00+.00 © 2013 Bentham Science Publishers

The Therapeutic Effects of Curcumin
methoxycurcumin, demonstrated in (Fig. 1), of which I is the most
common (Fig. 2) [12, 13]. There is a controversy as to whether I or
III is the most potent antioxidant, anti inflammatory, and anti-tumor
agent [12, 14]. Since curcumin was demonstrated to have poor
bioavailability and selectivity [15, 16], numerous analogues of this
material have been introduced and tested in order to evaluate their
activities against known biological targets, and also to improve
upon the pharmacological profile of the natural product (improve
their bioavailability, selectivity, and stability) [17-21]; moreover,
Saladini et al. reported improved solubility by modifying the struc-
ture by covalent linking of a sugar to curcumin, and studied its po-
tential as an agent for treating iron-overload disease [22]. Research-
ers introduced numerous approaches to improve the bioavailability
of curcumin, to provide longer circulation, and to increase cellular
permeability and resistance to metabolic processes. These ap-
proaches include the use of adjuvants such as Piperine that inter-
feres with glucuronidation in liver, and some adjuvants that can
block rapid metabolism of curcumin, the use of liposomal curcu-
min, making curcumin nanoparticles, the use of curcumin-
phospholipid complexes, and the use of structural analogues of
curcumin. The structural analogues of curcumin have been reported
to enhance the rate of absorption with a peak plasma half-life [23-
25]. Recent investigations have considered curcumin a lead com-
pound for the design of new chemotherapeutic agents for treatment
of cancers including colon cancers [26], prostate cancers [27], and
other conditions with indication of chemotherapy [28-30]. In a
study on curcumin, it was stated that by replacing the diketone
group by an a,b-unsaturated ketone and asymmetrical replacing the
phenolic groups by substituted phenyls and other aromatics, curcu-
min mimics various antiangiogenic activities [31]. Curcumin targets
many modulatory molecules which are summarized in table 1 and
some of them will be discussed further in this review.
O O
H3CO OCH3
C
A C
HO OH
B B
Fig. (2). Regions of Curcumin l. (A) b-diketone or keto-enol; (B) phenolic;
(C) alkene linker.
Curcumin is remarkably well tolerated, but its bioavailability is
poor. It does not appear to be toxic to animals [32] or humans [33],
even at high doses. Recent studies discussed on poor bioavailability
of curcumin because of poor absorption, rapid metabolism, and
rapid systemic elimination [34, 35]; however, comprehensive
pharmacokinetic data are still missing. In a phase I clinical trial by
Cheng et al (2001) on 25 cases with high-risk premalignant lesions,
curcumin was administered in a starting dose of 500 mg/day, and
after it caused no toxicity, the dose was then increased to 1000,
2000, 4000, 8000, and 12,000 mg/day, respectively. No toxicity
was observed up to 8 g/day; however, the serum concentration of
curcumin was not acceptable in lower doses. The serum level usu-
ally peaked at 1 to 2 hours after oral intake and gradually declined
within 12 hours. Moreover, urinary excretion of curcumin was un-
detectable [36]. In another investigation on 24 healthy subjects
curcumin was detected in the serum samples of only those who
received oral curcumin with doses of 10 and 12 g/day [37]. On the
other hand, Sharma and colleagues (2004) found that a daily oral
administration of 3.6 g curcumin leads to detectable levels in colo-
rectal tissue, which might be enough to exert pharmacological ac-
tivity on this part [38]. In a study done by Kuo-yi et al. (2007) they
Current Pharmaceutical Design, 2013, Vol. 19, No. 11 2033
reported 1% bioavailability for oral administration of curcumin in
rats [39]. On the elimination of curcumin, an investigation in rat
model demonstrated that after oral administration of 1 g/kg of cur-
cumin, more than 75% was excreted in feces and negligible amount
of curcumin was detected in urine [40]. FDA has declared curcumin
as “generally safe”. Although curcumin showed a wide variety of
pharmacological effects and has been found to be quite safe in both
animals and humans, there are some studies concerning its toxicity
[41]. The National Toxicology Program (NTP) evaluated the short
term toxicity as well as long-term toxicity of curcumin with differ-
ent concentrations (doses of 50, 250, 480, 1300 or 2600 mg/kg) for
periods of 13 weeks or 2 years in rats and mice. In 13-week study,
only increase in liver weight, discolored faces, and hyperplasia of
the mucosal epithelium in the cecum and colon of animals that re-
ceived 2600 mg/kg were noted as the only relative toxicity. No sign
of carcinogenesis was seen and no death was attributed to curcu-
min. Curcumin consumption did not have any effect on the food
intake when compared to control group and no mortality was ob-
served in the 2 year study. In 2600 mg/kg group, however, rats
developed chronic active inflammation, ulcers, hyperplasia of the
cecum, and stomach, intestinal carcinoma, hepatocellular adenoma,
and clitoral gland adenomas [42].
Curcumin as a Potent Anti-inflammatory Agent
For thousands of years curcumin has been known to possess
anti-inflammatory ability. Many of the activities associated with
curcumin are related to its ability to suppress acute and chronic
inflammations [43]. Nuclear factor kappa-B (NF-B) plays a criti-
cal role in signal transduction pathways that are involved in in-
flammatory diseases and various cancers [44]. The NF-B proteins
reside in the cellular cytoplasm inactively, but following their acti-
vation, which requires activation of various kinases and the phos-
phorylation and degradation of activation inhibitors such as I
B,
they are translocated to the nucleus; curcumin was shown to inhibit
TNF-dependent NF-B activation, as well as other activation path-
ways induced by various agents of which some were used to pro-
duce reactive oxygen intermediates that were also shown to be put
out by curcumin [45]. COX-2, the inducible form of cyclooxi-
genases, predominates at inflammatory sites, and a great number of
papers indicated a critical role of COX-2 in tumor promotion [45-
48]. Curcumin down-regulates the expression of COX-2 enzyme
and inhibits the expression of pro-inflammatory enzyme 5-LOX; It
also induces down-regulation of various inflammatory cytokines
such as TNF, IL-1, IL-6, IL-8, interferon
and some other
chemokines [49, 50]. In vivo studies on both human and animals
also revealed the anti-inflammatory effects of curcumin. A number
of clinical trials revealed the efficacy of curcumin in inflammatory
diseases such as inflammatory bowel disease (IBD) in human
through its modulatory impact on inflammatory factors [51]. In an
animal study on anti-inflammatory activity of curcumin, two oral
treatments of 92 ng/g of body weight showed anti-inflammatory
effect through reducing iNOS mRNA expression in the livers of
lipopolysaccharide-injected mice by 50-70% [52].
Antioxidative Activity of Curcumin
Oxidative stress plays a major role in the pathogenesis of vari-
ous diseases including cancer, diabetes, cardiovascular diseases,
neuronal cell injury, and hypoxia and many experimental models,
particularly in the field of injuries to nervous system, have been
introduced to investigate the therapeutic effects of different materi-
als as well as curcumin in this issue [53]. The most common ex-
perimental studies on curcumin, aside from providing new deriva-
tives, are those of its antioxidant potentials. The biological classifi-
cation of curcumin as both pro-oxidant and antioxidant, is well
supported by studies showing curcumin as a free radical scavenger,
a reducing agent, and a DNA damage inhibitor, especially in the
presence of Cu or Fe ions. Curcumin is able to bind to Fe, Mn and
Cu that was reported to modulate the antioxidant properties [54-56]
2034 Current Pharmaceutical Design, 2013, Vol. 19, No. 11
and radical scavenging effects [57, 58] of this agent. In vitro studies
have shown that curcumin inhibits nitric oxide and reactive oxygen
species (ROS) production in macrophages [59, 60]; it also inhibits
lipo-oxygenase as well as cyclooxigenase in fibroblast cells of rats
[61]. Oxidative stimulation of G-proteins in human brain mem-
branes by metabolic prooxidants, homocysteine, and hydrogen per-
oxide was shown to be significantly depressed by this material [62].
Cyclophosphamide-induced lung injury caused by antioxidative
defense mechanisms was increased by curcumin administration;
curcumin administration also inhibited lipid peroxidation in liver
microsomes as well as in brain homogenates of laboratory rats [45].
Anti-tumoral Properties of Curcumin Through Apoptosis In-
duction, Anti Angiogenesis and Anti Migratory Effects
Extensive researches have been done on anti-tumoral properties
of curcumin and several papers including many review articles were
published in this field; most authors suggested that the anti-
inflammatory, antioxidative, apoptosis inducing, and anti-
angiogenic abilities of curcumin are the main characteristics which
are involved in its anti tumoral activity [63-69]; for example, cur-
cumin has been found to inhibit growth of gastrointestinal and liver
cancers, and head and neck tumors; curcumin was able to target
breast stem/progenitor cells, as evidenced by suppressed mammos-
phere formation along serial passages and by a decrease in the per-
cent of ALDH-positive cells [70, 71].
Down-regulation of NF-B leads to suppression of Bcl-2 and
Bcl-XL which are the anti-apoptotic genes leading to apoptosis in-
duction [72]. Inhibition of COX-2 was reported as another mecha-
nism which is involved in anti-tumoral activity of curcumin which
was considered for being studied for treatment of colonic tumors by
this agent [45].Inhibition of Akt, a protein kinase that promotes cell
survival and inhibits apoptosis, is also enhanced by curcumin [73].
P53 gene, which mediates apoptosis under stressful situations, and
its downstream targets, were overexpressed in human basal cell
carcinoma [74], human hepatoblastoma [75], and human breast
cancer cells [76, 77] after curcumin administration.
In another study on colorectal carcinoma cell, however, p53, a
tumor suppressor gene, was decreased, while the heat-shock protein
70 had an increase concomitantly, after curcumin treatment [78].
Hence, the role of p53 in curcumin induced apoptosis was revealed
to be tissue-specific [79].
Tumors are dependent upon angiogenesis and providing the
blood supply to continue growth and to allow cancerous cells to
enter the circulation for metastasis; curcumin, other than apoptosis
inducing effect, was shown to interfere with many of the processes
involved in angiogenesis [80] including inhibition of fibroblast
growth factor (FGF)-induced neovascularization [80-82], ligands of
vascular endothelial growth factor (VEGF), and angiopoietin 1 and
2 [82]. Other than the factors which directly affect the angiogenesis
process, curcumin has the ability to regulate cell adhesion mole-
cules such as endothelial leukocyte adhesion molecule-1 (ELAM-
1), intracellular adhesion molecule-1 (ICAM-1), and vascular cell
adhesion molecule- 1 (VCAM-1), and cell surface proteins involved
in tumor metastasis [83].
Therapeutic Effects of Curcumin; Developments in the Last
Decades
Many researchers have worked on curcumin due to its various
therapeutic effects on different diseases. Shortly, curcumin has
received attention mostly due to its antioxidant, anti-inflammatory,
anti-tumoral, apoptosis-inducing, and anti-angiogenesis effects,
which were reported in many investigations. Curcumin acts on
multiple targets in cellular pathways making this agent able to per-
form multiple actions (Fig. 3) [84]. These therapeutic influences of
curcumin have been evaluated in many experiments for several
diseases. Some examples are briefly mentioned here with more
emphasizing on brain and neurological effects, cardiovascular ef-
Noorafshan and Ashkani-Esfahani
fects, and influences on the reproductive system which consist most
of our laboratory experiments and trials (Table 1).
Curcumin and the Nervous system
Curcumin has been extensively under investigations for its
therapeutic effects on nervous system, especially the brain and the
diseases related to this vital organ. We have recently attained some
good results on the protective activities of curcumin against neu-
rodegenerative diseases such as Alzheimer’s and Parkinson’s dis-
eases in animal models which are pending to be published. Review-
ing previous literature led to more expectation to receive positive
responses from curcumin administration in inflammatory brain
diseases as well as brain tumors. Purkayastha et al. (2009) showed
that curcumin effectively blocks brain tumor formation and also
removes brain tumor cells; They observed that the solubilized cur-
cumin causes activation of pro-apoptotic enzymes caspase 3/7 in
human oligodendroglioma, and mouse tumor cells N18 (neuroblas-
toma), GL261 (glioma), and B16F10 In vitro; A simultaneous de-
crease in cell viability was also revealed by MTT (3-(4, 5-
dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) assays;
curcumin effectively suppressed Cyclin D1, NF-B, Bcl-X L, Akt,
and VEGF, which explains its efficacy in blocking proliferation,
survival, and invasion of the B16F10 cells in the brain [85]. Cur-
cumin has been also used to treat medulloblastoma and glioblas-
toma cells [86]; the reduction in viable cell mass was associated
with a combination of G2/M phase changing arrest and apoptotic
induction. Curcumin also considerably decreased anchorage-
independent clonogenic growth and reduced the CD133-positive
stem-like populations. Downregulation of the insulin-like growth
factor pathways in DAOY medulloblastoma cells was observed,
levels of STAT3 were also attenuated; conclusively, curcumin
could inhibit malignant brain tumor growth via the modulation of
cell proliferation, survival and stem cell phenotype alterations[86].
Glioblastoma, the most aggressive form of brain and central nerv-
ous system tumors, is characterized by high rates of cell prolifera-
tion, migration and invasion. It has been demonstrated that curcu-
min-loaded glyceryl mono oleate (GMO) nanoparticles (NP) inhibit
cellular proliferation, migration and invasion along with a higher
percentage of cell cycle arrest and telomerase inhibition, thus result
in a greater percentage of apoptotic cell death in glioma cells com-
pared with native curcumin; the study of Kundu et al. also illus-
trated enhanced bioavailability of curcumin in blood serum and
brain tissue when delivered by curcumin-loaded GMO NPs com-
pared with native curcumin in a rat model[87].
Traumatic brain injury (TBI) is followed by an energy crisis of
the brain and often decrease in cognitive abilities[88]. The goal of a
study conducted by Sharma et al. was to determine the influence of
curcumin on molecular systems involved in the monitoring, bal-
ance, and transduction of cellular energy, in the hippocampus of
animals exposed to mild fluid percussion injury (FPI). The results
demonstrated that curcumin diet counteracted with the effects of
FPI and elevated the levels of AMP-activated protein kinase, ubiq-
uitous mitochondrial creatine kinase, cytochrome-c oxidase 2 in
curcumin treated group as compared to normal diet rats [89]. Alu-
minium, a well recognized neurotoxicant, is reported to be involved
in the etiology of Alzheimer’s disease due to its easy admittance
and collection in central nervous system, so Kakkar et al. (2011)
evaluated the therapeutic effects of curcumin loaded solid lipid
nanoparticles(C-SLNs) in aluminum induced behavioural, bio-
chemical and histopathological alterations in mice brain; treatment
with curcumin demonstrated recovery in membrane lipid oxidase
(LPO) and acetylcholine-esterase (AChE); histopathology of the
brain sections also pointed out significant improvements [90].
Cholesterol is critical to brain growth, but high levels of choles-
terol have been associated with neurodegenerative diseases. The
liver X receptor-/retinoid X receptor -
(LXR/RXR)-regulated
gene, ABCA1, effluxes cellular cholesterol to apolipoprotein A1
The Therapeutic Effects of Curcumin Current Pharmaceutical Design, 2013, Vol. 19, No. 11 2035

Fig. (3). Molecular targets of curcumin. Abbreviations: NF-B, nuclear factor-kappa B; AP-1, activating protein1; STAT, signal transducers and activators of
transcription; Nrf-2, nuclear factor 2-related factor; Egr-1, early growth response gene-1; PPAR-, peroxisome proliferator-activated receptor-gamma; CBP,
CREB-binding protein; EpRE; CTGF, connective tissue growth factor; EGF, epidermal growth factor; EGFRK, epidermal growth factor receptor-kinase; FGF,
fibroblast growth factor; HGF, hepatocyte growth factor; NGF, nerve growth factor; PDGF, platelet-derived growth factor; TGF-1, transforming growth
factor-1; VEGF, vascular endothelial growth factor; AR, androgen receptor; Arh-R, aryl hydrocarbon receptor; DR-5, death receptor-5; EGF-R, epidermal
growth factor-receptor; EPC-R, endothelial protein C-receptor; ER-
, estrogen receptor-alpha; 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, matrix metalloprote-
inase; TIMP, tissue inhibitor of metalloproteinase-3; iNOS, inducible nitric oxide oxidase; COX-2, cyclooxygenase-2; LOX, lipoxygenase; Gcl, glutamate-
cysteine ligase; NAT, arylamine N-acetyltransferases; IAP, inhibitory apoptosis protein; HSP-70, heat-shock protein 70; TNF-
, tumor necrosis factor alpha;
IL, interleukin; MCP, monocyte chemoattractant protein; MIF, migration inhibition protein; MIP, macrophage inflammatory protein; ERK, extracellular recep-
tor kinase; IARK, IL-1 receptor-associated kinase; cAK, autophosphorylation-activated protein kinase; CDPK, Ca2+-dependent protein kinase; cPK, protamine
kinase; JAK, janus kinase; JNK, c-jun N-terminal kinase; MAPK, mitogen-activated protein kinase; TK, protein tyrosine kinase; FAK, focal adhesion kinase;
PhK, phosphorylase kinase; pp60c-src, pp60c-src tyrosine kinase; PKA, protein kinase A; PKB, protein kinase B; PKC, protein kinase C; FPTase, farnesyl
protein transferase; GST, glutathione S-transferase; HO, hemeoxygenase; ICAM-1, intracellular adhesion molecule-1; VCAM-1, vascular cell adhesion mole-
cule-1; ELAM-1, endothelial leukocyte adhesion molecule-1; SHP-2, Src homology 2 domain-containing tyrosine phosphatase 2, uPA, urokinase-type plasmi-
nogen activator. (obtained from Aggarwal B.B. et al., 2008).

(apoA1), which plays an important role in reverse cholesterol trans-
port. In a study done by Tian et al. it was disclosed that curcumin
may act as a LXR agonist and then activate the ABCA1 promoter
and increase ABCA1 protein levels and apoA1 dependent cellular
cholesterol efflux from the brain [91], which in fact facilitates cho-
lesterol transportation and prevent its harmful effects on the brain.
The efficacy of curcumin on senile brain plaques and cerebral amy-
loid angiopathy (CAA) was determined in the aged brain of various
animal species and a patients with Alzheimer’s disease [92]. Find-
ings indicated that curcumin particularly binds to the aggregated A
molecules in various animals, and further to phosphorylated tau
protein, most likely according to its conformational nature[92];
thus, it helps amelioration of senile brain alterations and neurode-
generation.
Oxidative stress plays an important part in neuronal damages
and cognitive dysfunction made by chronic cerebral ischemia.
UCP2 (Uncoupling protein 2), which was shown to be increased as
a result of curcumin administration [93], have a central role in in-
hibiting oxidative stress [93]. Another study was conducted to ex-
amine the effect of curcumin on memory functions, brain insulin
receptors (IRs), AChE activity, and oxidative stress in intra-
cerebroventricular (ICV) area in Streptozotocin (STZ)-induced
dementia in rats. Results suggested that in addition to the anticho-
linesterase and antioxidant activity, effect on brain IR may also be
2036 Current Pharmaceutical Design, 2013, Vol. 19, No. 11 Noorafshan and Ashkani-Esfahani

Table 1. Diseases of Different Body Systems Taking Effects an important factor for protective effect of curcumin against STZ-
from Curcumin induced dementia [94].
Neuroprotective impacts of curcumin was also examined in
Nervous system • Alzheimer’s disease rat’s middle cerebral artery occlusion (MCAO) model [95]. Treat-
ment with curcumin could significantly improve neurobehavioral
• Parkinson’s disease
performance compared to untreated ischemic rats as judged by its
• Brain tumor effect on rota-rod performance and grid walking. An important
• Multiple sclerosis inhibition in lipid peroxidation and an increase in superoxide dis-
• Neurodegenerative diseases mutase (SOD) activity in corpus striatum and cerebral cortex were
observed following treatment with curcumin. Histologically, a de-
• Neuroinflammatory diseases
crease in the infarct area from 33% to 24% was observed in MCAO
• Traumatic brain injury rats treated with this agent [95].
• Ischemia A different study aimed to investigate the antidepressant-like
• Depression effect and the possible mechanisms of curcumin in a CORT-
• Encephalopathy (hepatic and/or uremic) induced depression model in rats [96]. The results suggest that cur-
cumin makes an antidepressant-like effect in CORT-treated rats,
Respiratory • Lung cancer which is probably mediated by increasing brain-derived neurotro-
system • Inflammatory lung diseases phic factors expression in the hippocampus and frontal cortex [96].
• Pneumonia (anti-bacterial effect) In our laboratory experiments we have been working on curcu-
min and its therapeutic effects on hepatic encephalopathy. We have
Cardiovascular • Cardiomyopathy (ex. Diabetic cardiomyo-
observed positive therapeutic influences of curcumin on behavioral
system pathy)
examinations as well as histopathological investigations in thio-
• Oxidative heart injury acetamide-induced hepatic encephalopathy in laboratory rats. To
• Cardiac hypertrophy sum up, curcumin, according to literature and our investigations, is
• Myocardial infarction a potent neuroprotective agent with uncertain adverse effects.

Urinary system • Renal tubular fibrosis Curcumin and the Respiratory system
• Inflammatory kidney diseases Pillai and his group investigated the cellular and molecular
• Oxidative kidney injury changes induced by curcumin leading to the reduction of apoptosis
in human lung cancer cell lines in a concentration dependent pat-
• Ischemic kidney damage
tern. A reduction in expression of p53, Bcl-2, and Bcl-XL was de-
• Cancers of urinary system (Kidney, prostate, tected after 12 h exposure of 40 μM curcumin. Bak and Caspase
bladder) genes remained unaffected up to 60 μM curcumin but displayed
Reproductive • Toxin induced oxidative damage (ex. Metro- diminution in expression levels at 80-160 μM [97]. It‘s also been
system nidazol, Aflatoxin, etc.) hypothesized that more bioavailable curcuminoid complex may
adjust lung carcinogenesis, mostly by inhibiting STAT3 activation
• Tumors of reproductive system
by Alexandrow et al. (2011) in vitro and in vivo. These reports
• Dysmenorrhea pointed out that the activity of the STAT3 pathway can be sup-
Digestive and • Tumors pressed by curcumin treatment, associated with a reduction in cell
hepato-biliary proliferation, supporting the hypothesis that inhibition of the
• GI ulcers
system STAT3 pathway characterizes at least one important means by
• Inflammatory bowel disease (Crohn’s, Ulcera- which curcumin brings out its effects on the broncho-epithelium
tive colitis) [98]. It is well known that matrix metalloproteinases (MMPs) play
• Pancreatitis an important role in the invasion, metastasis and angiogenesis of
• Hepatitis cancer cells [99], so substances suppressing the MMPs could pre-
vent the cancer cells migration and invasion. In one study the anti-
• Cirrhosis
tumor invasion and migration effects of lung cancer cells induced
• Jaundice by curcumin were examined. Their findings suggested that curcu-
• Hepatic injuries (ex. Drug induced) min has anti-metastatic ability by reducing invasiveness of cancer
• Oxidative damage cells through inhibition of MMP-2 and MMP-9 in human lung can-
cer[100]. Effect of dietary curcumin in radiation-induced lung dis-
Musculoskeletal • Inflammatory diseases (ex. Osteoarthritis) eases and lung tumor suppression was also examined in a murine
system and Skin • Oxidative stress model. In vitro, curcumin improved antioxidant defenses by in-
diseases creasing heme oxygenase 1 (HO-1) levels in primary lung endothe-
• Ischemic damage
lial and fibroblast cells and prevented radiation-induced production
• Insulin resistance
of ROS [101]. Curcumin, in clinically appropriate concentrations
• Tumors (ex. Osteosarcoma) for topical administration, demonstrated powerful antibacterial
• Osteoporosis effect against a facultative upper respiratory tract pathogen by
• Skin wound blocking bacterial growth, adherence, invasion, and pro-
inflammatory activation of upper respiratory tract epithelial cells
• Psoriasis
(by strongly suppressing IL-8 release) in vitro [102].
• Oxidative skin injury
Curcumin and the Cardiovascular System
Endocrine • Diabetes
system Many studies have pointed out that immune or inducible
• Hypothyroidism
(iNOS), and endothelial (eNOS) nitric oxide synthase play a crucial
• Endocrine tumors part in the pathogenesis of cardiovascular disorders, such as car-
diomyopathy, due to diabetes [103]. Since curcumin was shown to
The Therapeutic Effects of Curcumin
downregulate NOS and decrease NO oxidation, it may have inhibi-
tory effect on the development of cardiovascular disorders in hyper
oxidative diseases such as diabetes [104]. Farhangkhoee et al.
(2006) demonstrated that the myocardial tissue of rats with diabetes
revealed elevated levels of eNOS mRNA and iNOS mRNA versus
control rats, and curcumin treatment blocked eNOS mRNA and
iNOS mRNA upregulation showing a reduction in the oxidative
DNA impairment. Curcumin downregulates NOS by activation of
the NF-B and protein-1 (AP-1) [105]
A study in rats has revealed that adriamycin causes a rise in
heart rate, ST segment elevation, reduced myocardial glutathione
content and glutathione peroxidase activity, increased serum lipid
peroxide, and increased cardiac catalase activity[106]. In a study,
phenylbutyrate, a histone acetyl-transferase inhibitor, was demon-
strated to have a protective effect against adriamycin-induced car-
diac injury by increasing the level and the activity of cardiac man-
ganese superoxide dismutase enzyme[107].
Previous studies have revealed that p300 transcriptional activity
was increased during agonist-induced cardiac hypertrophy and after
blocking the p300-HAT activity, the agonist-mediated cardiac
growth was inhibited [108, 109]. Curcumin also revealed positive
effects in the prevention of cardiac hypertrophy and heart failure
[110, 111] since it has been reported to be an inhibitor of p300-
HAT[112]. Morimoto et al. (2008) have also evaluated these effects
in two various heart failure models: hypertensive heart disease in
salt-sensitive Dahl rats and surgically induced myocardial infarction
in rats. After the administration of curcumin for 7 weeks in salt-
sensitive hypertensive Dahl rats a considerable and valuable preser-
vation of the systolic function in the curcumin-treated group was
observed; In surgically-induced myocardial infarction rats, the sys-
tolic function was ameliorated in the curcumin-treated group, and
the hypertrophy of the non-infarcted myocardium was decreased
[111]. Li et al. demonstrated that rodents treated with oral curcumin
were noticeably resistant to cardiac hypertrophy caused by banding
of the aorta and the progression of heart failure was decreased
through reduction of the NF-B activation and inflammatory mark-
ers, including MCP-1, IL-6, IL-1, and TNF-
mRNA and protein
expression induced by aortic banding [110]. The parameters of
inflammatory process play an essential part in the pathogenesis of
many cardiovascular complications, like atherosclerotic process,
acute coronary syndrome[113], and atrial arrhythmias[114]. There-
fore, the anti-inflammatory effect of curcumin via down regulating
the NF-B, leading to a decrease in the expression of tumor ne-
crotic factor-
(TNF-
), IL-1 and IL- 6 [115], and blocking the
independent mitogen activated protein kinase (MAPK) pathways
[116], may prevent these complications. Curcumin also exhibited
anti-proliferative effect which is remarkably associated to its power
to induce HO-1[117]. It is well known that the HO-1 owns impor-
tant antioxidative and anti-inflammatory functions and effects in
concert with other fundamental enzymes in the preservation of cel-
lular homeostasis expression[118].
Curcumin and the Urinary System
Reviewing the literature about effects of curcumin on urinary
system revealed that curcumin prevents renal tubular fibrosis by
attenuation of TGF-b1-induced epithelial mesenchymal transition in
renal tubular cells through the downregulation of transcription
factor, snail-1, and also affecting different ILs and MMPs[119].
Epithelial mesenchymal transition not only is an essential phase of
kidney development during embryogenesis, but also is involved in
several adult pathologies, especially cancer and fibrosis. Epithelial
mesenchymal transition of tubular epithelial cells is known to play
an important part in renal fibrosis process. [119]. Paracetamol is an
agent which is introduced to impose a significant renal impairment,
characterized by the increase in blood urea nitrogen and creatinine,
in animal models. Moreover, paracetamol has been found to affect
renal function by decreasing renal blood supply, glomerular
Current Pharmaceutical Design, 2013, Vol. 19, No. 11 2037
filtration rate, and exerting acute and chronic nephrotoxicity which
is characterized by necrosis and damage to proximal tubule [120].
In a study by Yousef et al. (2010) it was concluded that curcumin,
according to its antioxidative and anti-inflammatory activities, has a
protective effect against paracetamol-induced oxidative kidney
damage [121]. Shahed et al. (2001) also reported the protective
influence of curcumin against ischemic kidney damage by
upregulation of antioxidant gene expression, particularly the
antioxidant enzyme Mn-superoxide dismutase, located on the
mitochondrial matrix [122].
Curcumin and male Reproductive System
The male reproductive system is consisted of the gonads and
the androgen hormones, the epididymides, the ductus or vasa defer-
ens, the seminal vesicles, the ejaculatory ducts, penis, and also cer-
tain accessory structures, such as prostate and the bulbourethral
glands. This system is of the main targets affected by curcumin.
Metronidazole, an anti-parasitic drug, acts as a testosterone
biosynthesis inhibitor which makes negative effects on the testis
[123]. Our laboratory investigations demonstrated that curcumin
can ameliorate the unfavorable effects of metronidazol such as de-
crease in tubule volume, length, diameter and height of germinal
epithelium, and also leydig cell hyperplasia in the testis. This ame-
liorative effect of curcumin on the above-mentioned parameters
could be due to its ability to scavenge the free radicals and acting as
an antioxidant agent, and also might be due to enhancement of se-
rum level of testosterone [124]. Another study was carried out to
evaluate the therapeutic effects of curcumin on the di-n-
butylphthalate (DBP)-induced testicular damage in rats [125]. Ben-
zenedicarboxylic acid dibutyl ester, also known as butylphthalate or
di-n-butylphthalate (DBP), is extensively used as a plasticizer in
cellulose plastics, as a solvent for dye, and for a variety of other
products[126]. Curcumin may stop peroxidative alteration in the
sperm and the testicular membrane which leads to enhancement of
sperm motility and decrease in spermatozoa defects[125]. Admini-
stration of curcumin could also relieve the inhibition of the antioxi-
dant enzymes, G6PD and -GT, and/or may have triggered their
synthesis that in turn attenuates the oxidative damage caused by
DBP or its metabolites [125]. Histopathologically, DBP-treated
testes demonstrated marked necrosis of testicular epidermal cells
and degeneration of seminiferous tubules[125]. Maintenance of the
structural and functional activity of seminiferous tubules by curcu-
min was somewhat similar to that of the control group, showing its
protective effect on the testes[125]. Mathuria et al. investigated the
influences of curcumin on aflatoxin -induced toxicity in mice sper-
matozoa. Aflatoxin noticeably reduced sperm count, viability, and
motility; different morphologic defects were encountered; thus,
treatment with curcumin improved aflatoxin-induced sperm de-
crease, immobilization, and viability, and enhanced the morpho-
logical characteristics of the sperm [127]. In a study conducted by
Giannessi et al., it was showed that curcumin protects Leydig cells
of mice from the damage caused by chronic alcohol consumption
[128]. It was seen that alcohol consumption inhibited testosterone
production and caused testicular atrophy and enhanced mitochon-
drial diameter by more than three folds. In curcumin-treated alco-
hol-fed mice the necrosis of Leydig cells was decreased in compari-
son to alcohol-fed mice; the diameters of the mitochondria were
considerably decreased even though testosterone plasma levels
were not considerably different from those of the controls[129].
Based on previously published reports, Cisplatin administration
caused irregularity of seminiferous tubules, reduction of seminifer-
ous epithelial layers, sperm maturation arrest, and perivascular
fibrosis; curcumin administration in cisplatin-treated rats consid-
erably prevented these histopathological changes. Curcumin af-
fected the rats by a major increase in plasma testosterone levels,
GSH levels and GSH-glutathione peroxidase activity, and a de-
2038 Current Pharmaceutical Design, 2013, Vol. 19, No. 11
crease in Malondialdehyde and nitric oxide levels in testicular tis-
sue[130]
Hong et al. evaluated the effects of curcumin on prostate cancer
cells invasion in both in vitro and in vivo. Curcumin was shown to
markedly reduce the tumor volume, MMP-2 activity, and MMP-9
activity in the tumor-bearing site. In the curcumin-treated group the
metastatic nodules were considerably fewer than the untreated
group, in vivo. Therefore, curcumin seemed to constitute a potential
agent for the prevention of cancer progression, or at least of the
initial phase of metastasis, in prostate cancer[131]. Chendil et al.
investigated the radiosensitizing outcomes of curcumin in p53 mu-
tant prostate cancer cell line PC-3 [132]. They strongly suggested
curcumin as a potent radiosensitizer; it acts by overcoming the im-
pacts of radiation-induced prosurvival gene expression in prostate
cancer. Another study showed direct anti-inflammatory activity of
MKP5 in prostate cells and suggested that upregulation of MKP5
by curcumin may contribute to their chemopreventive actions by
reducing prostatic inflammation [133]. Curcumin Analogues also
had been studied as novel androgen receptor antagonists with the
potential to act as an anti-prostate cancer agent. Results of an ex-
perimental study implied that the curcumin analogues may function
as a 17
-substituted dehydrotesterone, thus, some of these com-
pounds have been identified as a new class of anti-androgen agents
[134].
Curcumin and the Female Reproductive System
The female reproductive system consists of the paired ovaries
and oviducts, the uterus, the vagina, the external genitalia, and the
mammary glands. All of these structures have evolved structurally
and physiologically for the primary functions of ovulation, fertiliza-
tion of an ovum by a sperm, and process of pregnancy [135]. In this
field, Chlorpyrifos (CPF), an organophosphate pesticide, was
evaluated by Madhavi et al. for its potential to produce toxicity in
the reproductive system of mice following oral exposure. It was
concluded that CPF administration leads to increased levels of lipid
peroxidation and decreased levels of FSH hormone in mice which
caused inappropriate ovulation leading to infertility of mice, while
curcumin restored FSH levels and lactoperoxidase levels to greater
amount causing restored fertility in mice. CPF also brings about
histopathological alteration through degeneration of germinal epi-
thelium and graffian follicle, while curcumin treatment caused
normal architecture of graffian follicle and germinal epithelium in
mice [136].
A study was planned by El-Sayed to investigate the effects of
curcumin on the uterine contractility of non-pregnant rats in vitro.
Curcumin exhibited potential tocolytic effects in the rat uterus pos-
sibly through antagonizing receptor-dependent procedure (oxyto-
cin-induced contraction), an effect that could be beneficial in
women with dysmenorrhea or in premature labor[137]. The results
achieved from another study enclosed that curcumin produces a
smooth muscle relaxation effect on rat’s uterus by receptor-
dependent and independent mechanisms [138]. The growth-
inhibitory effect of curcumin on human ovary cancer was also in-
vestigated by Liduan and his colleagues [139]; after being treated
by various concentrations of curcumin, the growth of cancerous
masses was inhibited considerably in ovary. Some cancer cells
presented characteristic morphological changes of apoptosis. The
induction of apoptosis by down-regulating the expression of Bcl-2
and p53 was possibly one of its molecular mechanisms[139]. These
results were in agreement with those achieved by Xiaofen et al.
(2005) that reported the apoptosis-inducing effect of curcumin on
human ovary cancer [140]. Estradiol has been established as a risk
factor for cervical cancer and has been shown to play a synergistic
role with viral oncoproteins. One study conducted by Singh et al.
[141] showed that curcumin counteracts with the proliferative ef-
fects of estradiol and induces apoptosis in cervical cancer cells
Noorafshan and Ashkani-Esfahani
through inhibition of the pathways which were improved by estra-
diol [141].
Curcumin and Hepato-biliary and Digestive System
Paracetamol-induced hepatocellular necrosis is characterized by
increased liver enzymes and LDH activities. Paracetamol also
showed to cause decrease in plasma total protein, albumin and
globulin, while increased plasma bilirubin. The liver is the major
source of the serum proteins, in which the parenchymal cells are
responsible for synthesis of fibrinogen, albumin, many coagulation
factors and most of the globulins [142]. Researchers showed that
curcumin administration offered significant protection against he-
patic necrosis induced by paracetamol [121]. Another study also
exhibited curcumin’s hepatoprotective effect against arsenic-
induced liver damage [143]; Messner and colleagues also revealed
the antioxidant potential of curcumin in iron loading hepatotoxicity
and oxidative stress in rat’s liver without making any alteration in
iron uptake [144]. These papers highly suggested the responsibility
of antioxidative activity of curcumin for the demonstrated out-
comes.
Paraoxonase-1 is an enzyme which is mainly synthesised in the
liver and protects low density lipids (LDL) from oxidation, thereby
exhibiting antiatherogenic activities. In a experimental study cur-
cumin was introduced as a potent Paraoxonase-1 inducer in vitro,
but not in vivo, which could be due to its low bioavailability and
absorption in curcumin-fed mice [145]. Curcumin inhibits cell cycle
progression during normal liver regeneration in rats predominantly
at the level of the G2/M transition point in the cell cycle; this was
reported by Seehofer et al. (2009) who administered curcumin to
male Sprague-Dawley rats which underwent sham operation with
70% partial hepatectomy. They have seen that liver mass and func-
tion was not significantly changed. Nevertheless, they suggested
that application of curcumin should be performed with caution in
such conditions (high physiological cell proliferation)[146].
There are several studies on hepatoprotective properties of cur-
cumin suggesting different mechanisms of action for this agent to
impose its protection against oxidative, inflammatory and even
tumor producing states [147-150].
Reviewing articles on various therapeutic effects of curcumin
on gastro-intestinal (GI) system showed finite data of clinical trials.
It is expected to see positive effects from this medicine in GI dis-
eases related to inflammatory and oxidative states, particularly
chronic diseases of GI system which are among the common and
still under investigation diseases for diagnosis and treatment [151].
Many researches were done on palliative and healing effects of
curcumin on inflammatory bowel diseases, Crohn’s and ulcerative
colitis, which all reported positive therapeutic impacts of this agent
[152]. Clinical trials also indicated the fact that curcumin, according
to its safety for administration, can be used at least as an adjuvant
therapy for chronic diseases of GI system involving the inflamma-
tory response of the body; however, almost all of the published
studies suggested that larger-scale, double-blind trials are needed to
be conducted to establish a role for curcumin in the treatment of
inflammatory bowel diseases such as ulcerative colitis. In addition
to improving results when curcumin is used in conjunction with
conventional medications, it may pose a cost-beneficial alternative
[153]. Tumors of digestive system have also been investigated
whether they take positive effects from curcumin [154], and it was
obvious that curcumin, due to its multiple targets, and activities
against inflammation, angiogenesis, and metastasis of tumors (as
described above), possesses anti tumoral ability in GI tract as well
as liver (ex. Hepatocellular carcinoma) [155].
Curcumin and Musculoskeletal System
Considering the anti-inflammatory and antioxidant abilities of
curcumin, receiving positive response from its administration in
such problems in skeletal system was anticipated [156]. For in-
The Therapeutic Effects of Curcumin
stance, Lev-Ari et al. suggested COX-2 inhibition as the main
mechanism of curcumin action against the inflammatory and apop-
totic state in osteoarthritis. They have also recommended that com-
bination therapy of both Celecoxib and curcumin may bring about
positive results in treatment of osteoarthritis [157]. The effects of
curcumin on skeletal muscle were evaluated during ischemia-
reperfusion condition by Avci et al. (2012); Plasma TNF-
and IL-
1 levels were decreased significantly in curcumin-treated group of
ischemic reperfusion muscular injury. Levels of antioxidant en-
zymes (glutathione peroxidase, superoxide dismutase, and catalase)
activities, Malondialdehyde, and NO in muscle also revealed sig-
nificant reductions in the curcumin treated group compared with the
untreated group. They implied that curcumin had more potent anti-
oxidative activity than vitamin E in the skeletal muscle ischemic
damage [158].
Immobilization is characterized by activation of the ubiquitin-
proteasome-dependent proteolytic system and turning on the mito-
chondrial apoptotic pathway. Increased oxidative stress and in-
flammatory response are resulted from immobilized skeletal mus-
cles; In a study it was demonstrated that curcumin reduces the mus-
cular atrophy and improves muscle reloading by normalizing the
proteasome chymotrypsin-like activity, ubiquitin-conjugate levels
and caspase-3 activity [159]. Poylin et al. showed that curcumin
can prevent muscle atrophy induced by sepsis through its inhibitory
effect on NF-B [160]. Curcumin was also shown to improve mus-
cular insulin resistance by increasing oxidation of fatty acid and
glucose, through up-regulating the expression of phosphorylated
AMP-activated protein kinase, CD36, and carnitine palmitoyl trans-
ferase 1, and down-regulating the expression of pyruvate-
dehydrogenase-4 and phosphorylated-glycogen-synthase in vivo
and in vitro [161]. There are many published documents on thera-
peutic effects of curcumin on muscular tissue which mainly point to
the protective effects of this agent against muscular injuries of dif-
ferent origins through different pathways [162, 163].
Curcumin and Skin
Wound healing [164], and Psoriasis [165], were some examples
of the diseases which demonstrated to receive therapeutic effects
from curcumin. In psoriasis, the response rate was low, possibly
caused by a placebo effect or the natural history of psoriasis; hence,
large placebo-controlled studies are still needed before introducing
curcumin as a psoriasis treatment. Of the main mechanisms in-
volved in the wound healing activity of different agents are their
antioxidant and anti-inflammatory effects as well as induction of
collagen synthesis and vascularization [166, 167]. Curcumin was
also proved to have healing effects on skin wound caused by frac-
tionated irradiation [168], and carbon dioxide lasering[169].
Curcumin and Diabetes
Curcumin demonstrated anti-hyperglycemic and hypocholes-
terolemic effects in type 2 diabetes [170-172] as well as protective
effect against pancreatic injury (mostly on  cells which secrete
insulin) by its antioxidant and anti-inflammatory impact in a model
of STZ-induced pancreatic damage [173]. Some studies revealed
that curcumin not only attenuates the complications that are directly
made by diabetes, but also ameliorates the indirect complications
caused by this disease. For instance, diabetic neuropathy, a mi-
crovascular problem which occurs mostly due to oxidative damage
and inflammation, was shown to be improved after curcumin ad-
ministration [35]. Diabetic retinopathy [174], nephropathy [175],
and cardiomyopathy [176, 177], of the common complications of
long-lasting diabetes, were also ameliorated after curcumin con-
sumption.
Curcumin and Cancer
Curcumin has exhibited therapeutic effects against different
types of cancer.
Current Pharmaceutical Design, 2013, Vol. 19, No. 11 2039
- Breast Cancer: Many studies have described the anti-
carcinogenic effects of curcumin in various breast cancer cell lines
through several mechanisms. For example, curcumin revealed anti
breast cancer impact via inhibiting the cytochrome P450 [178],
inhibition of COX-1 and COX-2 enzymes, down-regulation of Bax
expression, inhibiting VEGF and b-FGF [179, 180], inhibiting te-
lomerase activity through human telomerase reverse transcriptase
[181], downregulating the expression of MMP-2, upregulating tis-
sue inhibitor of metalloproteinase-1 (TIMP-1) [182], blocking NF-
B [183], and downregulating the insulin-like growth factor-1
(IGF-1) [184]. In an animal study curcumin usage partially reversed
the tumor exosome-mediated inhibition of NK cell that may ac-
count for the anticancer properties of this substance [185].Curcumin
also exhibited anti-metastatic activity in breast cancer according to
previous in vivo investigations [178, 186].
- Gastrointestinal cancers: Curcumin was shown to inhibit the
cytokine-induced activation of iNOS, VCAM, and NF-B in human
esophageal microvascular endothelial cells from normal human
esophageal tissues [187]. Since these inflammatory molecules are
overexpressed in several cancerous tissues, curcumin was supposed
to indirectly affect the esophageal cancers. A study in rats revealed
the anti esophageal carcinogenesis effect of dietary curcumin (500
ppm) during initiation and post-initiation stages by 27% and 33%,
respectively [186]. Another study on rats also showed the efficacy
of curcumin as a chemopreventive agent by modulating the inci-
dence of neoplastic changes in the esophagus [188].
On the effects of curcumin in gastric tumors several in vivo
studies demonstrated the positive impacts of this agent against fore-
stomach cancers in animal models. In these investigations, dietary
curcumin inhibited the incidence and multiplicity of the tumor and
also played as a chemopreventive agent [178].
Curcumin also showed chemopreventive and anti metastatic
effects as well as apoptosis inducing impact on intestinal cancers in
animal models [178]. In a phase I clinical trial including six cases
with intestinal metaplasia of the stomach, one out of the six patients
showed histological improvement in pre-cancerous lesions after
receiving 0.5-12 g/day curcumin for 3 months [186].
Curcumin was shown to interrupt adhesion pathways, and in-
duce apoptosis through PARP cleavage, Caspase 3 and Bcl-X L
reduction, and increasing Caspase 8 activity, and also inhibiting the
tumoral cell proliferation in colorectal cancers [178, 189]. Moreo-
ver, curcumin administration leads to cell shrinkage, chromatin
condensation, and fragmentation of DNA in colonocytes [178, 190].
Curcumin-induced apoptosis regulated by Bax suggested that the
targeting of Bcl-XL can be taken into account to treat Bax-deficient,
chemotherapy-resistant cancers [178, 191]. Curcumin together with
celecoxib downregulate COX-2 expression by inhibition of prosta-
glandin formation [192], it can also induce apoptosis through a
parallel ceramide-associated pathway and ROS associated mecha-
nism [193]. In vivo studies demonstrated the chemopreventive and
anti-cancerous activities of curcumin in rodents [186, 194, 195] and
human [178, 186]. Curcumin induced apoptosis, inhibited the for-
mation of carcinogen-induced colorectal tumors, and induced apop-
tosis via mitochondrial pathways, in rats [194, 195]. In addition,
Liposomal curcumin exhibited noticeable anti-tumoral activity by
inhibiting angiogenesis as well as increasing the apoptosis and in-
hibiting the tumor growth in mice [196]. There were numerous
clinical studies on anti-tumoral effects of curcumin of which some
positive results were obtained such as anti-inflammatory impact in
advanced colorectal cancers as well as apoptosis induction; how-
ever, literatures revealed that according to extensive intestinal me-
tabolism of curcumin leading to low bioavailability, obtaining a
sufficient blood concentration in human is still a concern in clinical
studies [178, 186].
- Hepato-biliary and pancreatic cancers: Curcumin was re-
ported as a potent inhibitor of phenol sulfotransferase in human
2040 Current Pharmaceutical Design, 2013, Vol. 19, No. 11
liver and extrahepatic tissues [197]. Curcumin inhibited the IL-6
production, histone acetyl transferase activity, and AP-1activation
and also hypoxia-inducible factor-1 by degrading the aryl hydro-
carbon receptor nuclear translocator [198, 199]. In an in vitro study
using hepatic cancer cell lines, a combination of curcumin-cisplatin
as well as curcumin-doxorubicin had synergistic antitumor effects
[178]. A number of investigations have also described curcumin in
hepatocellular carcinoma in vivo. For instance, curcumin reduced
the number of gammaglutamyl transpeptidase-positive foci and
induced glutathione-linked detoxification enzymes in rat livers in
the name of its anti tumoral activity. This agent also showed anti-
inflammatory and carcinogen detoxifying effects; it also demon-
strated anti-metastatic and anti-developmental influences in rat liver
tumors [200]. The antiangiogenic activity of curcumin in hepatocel-
lular carcinoma cells was found to be mediated through the reduc-
tion of COX-2 and VEGF in mice model [200]. In a pilot clinical
trial on twelve patients with hepatic metastases from colorectal
cancer the curcumin concentration in normal and malignant liver
tissue after receiving 450-3600 mg of curcumin daily for 1 week
before the surgery were not enough to elicit pharmacologic activity,
which might be due to the extensive metabolizabilty of curcumin in
the intestine [178].
Curcumin was also shown to have anticarcinogenic effects in
various pancreatic tumors through numerous mechanisms; for ex-
ample, NF-B suppression in human pancreatic tumoral tissues and
cell lines [22, 201-203], down-regulation of COX-2, EGFR,
ERK1/2 [204], and Notch-1 [205]. When coupled with gemcitabine,
curcumin showed synergistic anti-proliferative effects in pancreatic
cancers [206]. In vivo studies also showed anti-cancerous impacts
of curcumin such as chemosensitization, anti-angiogenic, anti-
inflammatory, and anti-proliferative effects [24, 186]. In a clinical
trial on 25 patients, the anti pancreatic tumor activity of curcumin
was examined; despite the poor bioavailability of this agent in most
of the cases, those who demonstrated sufficient biological activity
revealed down-regulation of NF-B, COX-2 and phosphorylated
STAT3 in favor of anti tumoral activity of curcumin [207].
- Cancers of Urinary and reproductive systems: Curcumin was
assumed to be effective against bladder cancer both in vitro, for
example by suppression of NF-B [208], down regulation of cyclin
A and up-regulation of p21, and in vivo , by inhibiting implantation
and growth of the tumoral masses [178]. A clinical study revealed
that oral curcumin administration led to histological improvement
in precancerous lesions in 1 out of 2 patients [186]. Tharakan et al.
showed that curcumin alone has anti tumoral effects against human
bladder cancer; it further potentiated the gemictabine effects, possi-
bly through modulation of NF-B signaling pathway [209].
Curcumin showed apoptosis-inducing impact as well as anti-
proliferative effect against renal cell carcinoma in vitro and in vivo,
through up-regulation of TRAIL-induced apoptosis and ROS pro-
duction [210], inhibition of microsomal lipid peroxidation and
DNA damage, COX 1 and 2 inhibition [211], and downregulation
of Bcl-2, Bcl-XL, and IAP proteins [212]. An experimental study
revealed that curcumin also possesses anti metastasis and tumor
preventive effects in rats [213]. Efficacy of curcumin by modulat-
ing NF-B expression, AP-1, cyclin D1, and etc. were also demon-
strated in treatment of prostate cancer [178]. Curcumin showed
preventive effect in PC-3 prostatic tumor xenograft in mice [214],
and also led to reduction of MMP-2 and MMP-9 activity on the
tumor bearing site as well as metastasis prevention in vivo [215].
Curcumin was reported to have anti cancerous activity by al-
most the same mechanisms as other types of cancers against malig-
nancies of cervix, ovaries and uterus both in vivo and in vitro [186].
- Brain tumors: Curcumin was reported to block brain tumor
formation [216]. The efficacy of curcumin in various human malig-
nant glioblastoma cells, for example by inhibiting NF-B signaling
pathways, has been established [217, 218]. Numerous other mecha-
Noorafshan and Ashkani-Esfahani
nisms, such as the inhibition of MMP transcriptions [219], the in-
duction of histone hypoacetylation leading to apoptosis in a PARP
and caspase 3-mediated manner [220], TRAIL-induced apoptosis
[221], and the induction of non-apoptotic autophagic cell death
[222, 223] have also been suggested. In rats, curcumin significantly
decreased the incidence of radiation-induced pituitary tumors [178].
Curcumin inhibited tumor growth by three folds and induced auto-
phagy in the subcutaneous xenograft model of glioblastoma cells
[223].
- Cancers of respiratory system: Previous studies showed the
anti-tumoral activity of curcumin against lung cancer [186] for
example by inhibiting AP-1 transcription and lymph node metasta-
sis and also by modulating the NF-B DNA binding, IB
kinase
activation, and COX-2 downregulation [178, 186, 224]. Apoptosis
induction via Bcl-XL, Bax and Bcl-2 as well as ROS production
were also reported as mechanisms of anti tumoral activity of cur-
cumin [225]. In an animal study, dietary curcumin was found to
inhibit the lung metastasis of melanoma and increased the life span
of the subjects [178]. Moreover, inhibiting the signal transducer and
activator of transcription 3 (Stat3), which was seen to be activated
in nearly half of lung cancers, was reported as another mechanism
of chemopreventive activity of curcumin in lung cancer [226].
- Bone tumors: Curcumin was reported to induce apoptosis by
inhibiting NF-B, IL-6, IL-11, MMP-9 and VEGF [227, 228]in
fibrosarcoma. Further, in human osteosarcoma, curcumin was
found to inhibit the ERK gene expression and to induce apoptosis
by down-regulating the Bcl-2 expression [178, 186, 229, 230].
CONCLUSION
The wisdom and scientific knowledge of curcumin, a highly
pleiotropic agent, which were used for its therapeutic effects par-
ticularly in Chinese, Iranian and Ayurvedic traditional medicine,
have been corroborated by numerous investigations conducted in
the last thirty years, especially the last decade. Of the most notice-
able therapeutic influences of curcumin, researchers mostly pointed
at the anti-oxidant potential, anti-inflammatory, and anti tumoral
activities through its regulatory impacts on molecular targets in-
volved in development of cancerous cells as well as anti-
angiogenic, anti-proliferative, and chemopreventive effects on the
cancerous cell lines. Curcumin, due to its ability to affect a wide
range of molecular targets and an excellent safety profile, was dem-
onstrated to be a potential candidate for the prevention and/or treat-
ment of a number of diseases.
CONFLICT OF INTEREST
The authors confirm that this article content has no conflicts of
interest.
ACKNOWLEDGEMENT OF FUNDING
Histomorphometry & Stereology Research Center.
REFERENCES
[1] Milobedzka J, v. Kostanecki S, Lampe V. Curcumin. Ber Dtsch
Chem Ges 1910; 43: 2163-70.
[2] Lampe V, Milobedzka J. Curcumin. Ber Dtsch Chem Ges 1913;
46: 2235-40.
[3] Ammon H, Wahl MA. Pharmacology of Curcuma longa. Planta
Med 1991; 57: 1-7.
[4] Tilak J, Banerjee M, Mohan H, Devasagayam TPA. Antioxidant
availability of turmeric in relation to its medicinal and culinary
uses. Phytotherapy Research 2004; 18(10): 798-804.
[5] Aggarwal BB, Sundaram C, Malani N, Ichikawa H. Curcumin: The
Indian solid gold. Adv Exp Med Biol 2007; 595: 1-75.
[6] Thakur R, Puri HS, Husain A. Major medicinal plants of India.
Medicinal plants; Materia medica, Vegetable; Traditional
medicine; India. Lucknow: Central Institute of Medicinal and
Aromatic Plants 1989. p. 585.
[7] Pandeya NK. Old Wives’ Tales: Modern Miracles—Turmeric as
Traditional Medicine in India. Trees for Life J 2005; 1: 3.
The Therapeutic Effects of Curcumin
[8] Jaruga E, Salvioli S, Dobrucki J, et al. Apoptosis-like, reversible
changes in plasmamembrane asymmetry and permeability, and
transient modifications in mitochondrial membrane potential
induced by curcumin in rat thymocytes. FEBS Lett 1998; 433(3):
287-93.
[9] Jarugaa E, Sokala A, Chrulb S, Bartosza G. Apoptosis-independent
alterations in membrane dynamics induced by curcumin. Exp Cell
Res 1998; 245(2): 303-12.
[10] Ireson C, Orr S, Jones DJ, et al. 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
2001; 61: 1058-64.
[11] Ireson CR, Jones DJ, Orr S, et al. Metabolism of the cancer
chemopreventive agent curcumin in human and rat intestine.
Cancer Epidemiol Biomarkers Prev 2002; 11: 105-11.
[12] Ramsewak RS, DeWitt DL, Nair MG. Cytotoxicity, antioxidant
and anti-inflammatory activities of curcumins I-III from Curcuma
longa. Phytomedicine 2000; 7(4): 303-8.
[13] Sreejayan MNA. Curcuminoids as potent inhibitors of lipid
peroxidation. J Pharm Pharmacol 1994; 46(12): 1013-6.
[14] Ruby A, Kuttan G, Babu KD, Rajasekharan KN, Kuttan R. Anti-
tumour and antioxidant activity of natural curcuminoids. Cancer
Lett 1995; 94(1): 79-83.
[15] Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB.
Bioavailability of curcumin: problems and promises. Mol Pharm
2007; 4(6): 807-18.
[16] Payton F, Sandusky P, Alworth WL. NMR study of the solution
structure of curcumin. J Nat Prod 2007; 70(2): 143-6.
[17] Weber WM, Hunsaker LA, Roybal CN, et al. Activation of NF
B
is inhibited by curcumin and related enones. Bioorg Med Chem
2006; 14(7): 2450-61.
[18] Ishida J, Ohtsu H, Tachibana Y, et al. Antitumor Agents. Part 214:
+ Synthesis and Evaluation of Curcumin Analogues as Cytotoxic
Agents. Bioorg Med Chem 2002; 10(11): 3481-7.
[19] Ohori H, Yamakoshi H, Tomizawa M, et al. Synthesis and
biological analysis of new curcumin analogues bearing an
enhanced potential for the medicinal treatment of cancer. Mol
Cancer Ther 2006; 5(10): 2563-71.
[20] Selvam C, Jachak SM, Thilagavathi R, Chakraborti AK. Design,
synthesis, biological evaluation and molecular docking of curcumin
analogues as antioxidant, cyclooxygenase inhibitory and anti-
inflammatory agents. Bioorg Med Chem Lett 2005; 15(7): 1793-7.
[21] Sun A, Shoji M, Lu YJ, Liotta DC, Snyder JP. Synthesis of EF24-
tripeptide chloromethyl ketone: a novel curcumin-related
anticancer drug delivery system. J Med Chem 2006; 49(11): 3153-
8.
[22] Arezzini B, Ferrali M, Ferrari E, Grandi R, Monti S, Saladini M.
Glycosyl-curcuminoids as potential new chelating agents in iron
overload chelation therapy. Eur J Inorg Chem 2004; 2004(3): 646-
52.
[23] Bharat BA, Harikumar KB. Potential therapeutic effects of
curcumin, the anti-inflammatory agent, against neurodegenerative,
cardiovascular, pulmonary, metabolic, autoimmune and neoplastic
diseases Int J Biochem Cell Biol 2009; 41: 40-59.
[24] Li L, Braiteh FS, Kurzrock R. Liposomeencapsulated curcumin: In
vitro and in vivo effects on proliferation, apoptosis, signaling, and
angiogenesis. Cancer Epidemiol Biomarkers Prev 2005; 104(6):
1322-31.
[25] Maiti K, Mukherjee K, Gantait A, Saha BP, Mukherjee PK.
Curcumin-phospholipid complex: Preparation, therapeutic
evaluation and pharmacokinetic study in rats. Int J Pharm 2007;
330(1-2): 155-63.
[26] Lin L, Shi Q, Nyarko AK, et al. Antitumor agents. 250. Design and
synthesis of new curcumin analogues as potential anti-prostate
cancer agents. J Med Chem 2006; 49(13): 3963-72.
[27] Ohtsu H, Xiao Z, Ishida J, et al. Antitumor agents. 217. Curcumin
analogues as novel androgen receptor antagonists with potential as
anti-prostate cancer agents. J Med Chem 2002; 45(23): 5037-42.
[28] Adams BK, Ferstl EM, Davis MC, et al. Synthesis and biological
evaluation of novel curcumin analogs as anti-cancer and anti-
angiogenesis agents. Bioorg Med Chem 2004; 12(14): 3871-83.
[29] Nakano K, Nakayachi T, Yasumoto E, et al. Induction of apoptosis
by beta-diketones in human tumor cells. Anticancer Res 2004; 24:
711-7.
Current Pharmaceutical Design, 2013, Vol. 19, No. 11 2041
[30] Benassi R, Ferrari E, Grandi R, Lazzari S, Saladini M. Synthesis
and characterization of new beta-diketo derivatives with iron
chelating ability. J Inorg Biochem 2007; 101(2): 203-13.
[31] Woo HB, Shin WS, Lee S, Ahn CM. Synthesis of novel curcumin
mimics with asymmetrical units and their anti-angiogenic activity.
Bioorg Med Chem Lett 2005; 15(16): 3782-6.
[32] Shankar T, Shantha NV, Ramesh HP, Murthy IA, Murthy VS.
Toxicity studies on turmeric (Curcuma longa): Acute toxicity
studies in rats, guinea pigs and monkeys. Indian J Exp Biol 1980;
18(1): 73-5.
[33] Soni K, Kuttan R. Effect of oral curcumin administration on serum
peroxides and cholesterol levels in human volunteers. Indian J
Physiol Pharmacol 1992; 36(4): 273-5.
[34] Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB.
Bioavailability of curcumin: problems and promises. Mol Pharm
2007; 4: 807-18.
[35] Sharma RA, Steward WP, Gescher AJ. Pharmacokinetics and
pharmacodynamics of curcumin. Adv Exp Med Biol 2007; 595:
453-70.
[36] Cheng AL, Hsu CH, Lin JK, et al. Phase I clinical trial of
curcumin, a chemopreventive agent, in patients with high-risk or
pre-malignant lesions. Anticancer Res 2001; 21(4B): 2895-900.
[37] Lao CD, M.T.T. R, Normolle D, et al. Dose escalation of a
curcuminoid formulation. BMC Complement Altern Med 2006; 6:
10.
[38] Sharma RA, Euden SA, Platton SL, et al. Phase I clinical trial of
oral curcumin: biomarkers of systemic activity and compliance.
Clin Cancer Res 2004; 10(20): 6847-54.
[39] Yang KY, Lin LC, Tseng TY, Wang SC, Tsai TH. Oral
bioavailability of curcumin in rat and the herbal analysis from
Curcuma longa by LC-MS/MS. Journal of Chromatography B
2007; 853(1-2): 183-9.
[40] Wahlstrom B, Blennow G. A study on the fate of curcumin in the
rat. Acta Pharmacol Toxicol (Copenh) 1978; 43(2): 86-92.
[41] Lopez-Lazaro M. Anticancer and carcinogenic properties of
curcumin: considerations for its clinical development as a cancer
chemopreventive and chemotherapeutic agent. Mol Nutr Food Res
2008; 52(S1): S103-S27.
[42] NTP. NTP Toxicology and Carcinogenesis Studies of Turmeric
Oleoresin (CAS No. 8024-37-1) (Major Component 79-85%
Curcumin, CAS No. 458-37-7) in F344/N Rats and B6C3F1 Mice
(Feed Studies). Natl Toxicol Program Tech Rep Ser 1993; 427: 1-
275.
[43] Shishodia S, Sethi G, Aggarwal BB. Curcumin: Getting back to the
roots. Ann N Y Acad Sci 2005; 1056: 206-17.
[44] Amit S, Ben-Neriah Y. NF-kappaB activation in cancer: A
challenge for ubiquitination- and proteasomebased therapeutic
approach. Semin Cancer Biol 2003; 13(1): 15-28.
[45] Hatcher H, Planalp R, Cho J, Torti FM, Torti SV. Curcumin: From
ancient medicine to current clinical trials. Cell Mol Life Sci 2008;
65(11): 1631 - 52.
[46] Thangapazham R, Sharma A, Maheshwari RK. Multiple molecular
targets in cancer chemoprevention by curcumin. AAPS J 2006;
8(3): E443-9.
[47] Mann J, DuBois RN. Cyclooxygenase-2 and gastrointestinal
cancer. Cancer J 2004; 10(3): 145-52.
[48] Prescott S. Is cyclooxygenase-2 the alpha and the omega in cancer?
J Clin Invest 2000; 105(11): 1511-3.
[49] Gao X, Kuo J, Jiang H, et al. Immunomodulatory activity of
curcumin: Suppression of lymphocyte proliferation, development
of cell-mediated cytotoxicity, and cytokine production in vitro.
Biochem Pharmacol 2004; 68(1): 51 -61.
[50] Surh YJ. Anti-tumor promoting potential of selected spice
ingredients with antioxidative and anti-inflammatory activities: a
short review. Food Chem Toxicol 2002; 40(8): 1091-7.
[51] Hanai H, Sugimoto K. Curcumin has Bright Prospects for the
Treatment of Inflammatory Bowel Disease. Curr Pharm Des 2009;
15(18): 2087-94(8).
[52] Chan MM-Y, Huang H-I, Fenton MR, Fong D. In vivo Inhibition of
Nitric Oxide Synthase Gene Expression by Curcumin, a Cancer
Preventive Natural Product with Anti-inflammatory Properties.
Biochemical Pharmacol 1998; 55(12): 1955-62.
[53] Ebrahimi S, Esfahani SA, Kohkiloezadeh M, et al. A model of
cerebral ischemia induction in neonatal rabbits. Journal of Applied
Animal Research 2012 40(1): 37-42.
2042 Current Pharmaceutical Design, 2013, Vol. 19, No. 11
[54] Antunes LMG, Araujo MCP, da Luz Dias F, Takahashi CS. Effects
of H2O2, Fe2+ and Fe3+ on curcumin-induced chromosomal
aberrations in CHO cells. Genet Mol Biol 2005; 28(1): 161-4.
[55] Patro BS, Rele S, Chintalwar GJ, Chattopadhyay S, Adhikari S,
Mukherjee T. Protective activities of some phenolic 1,3-diketones
against lipid peroxidation: Possible involvement of the 1,3-diketone
moiety. ChemBio-Chem 2002; 3(4): 364-70.
[56] Jovanovic S, Boone CW, Steenken S, Trinoga M, Kaskey RB. How
curcumin works preferentially with water soluble antioxidants. J
Am Chem Soc 2001; 123(13): 3064-8.
[57] Vajragupta O, Boonchoong P, Berliner LJ. Manganese complexes
of curcumin analogues: Evaluation of hydroxyl radical scavenging
ability, superoxide dismutase activity and stability towards
hydrolysis. Free Radic Res 2004; 38(3): 303-14.
[58] Barik A, Mishra B, Kunwar A, et al. Comparative study of
copper(II)-curcumin complexes as superoxide dismutase mimics
and free radical scavengers. . Eur J Med Chem 2007; 42(4): 431-9.
[59] Sreejayan RM. Nitric oxide scavenging by curcuminoids. J Pharm
Pharmacol 1997; 49(1): 105-7.
[60] Joe B, Lokesh BR. 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 1994; 1224(2):
255-63.
[61] Lin J, Shih CA. Inhibitory effect of curcumin on xanthine
dehydrogenase/oxidase induced by phorbol-12-myristate-13-
acetate in NIH3T3 cells. Carcinogenesis 1994; 15(8): 1717-21.
[62] Jefremov V, Zilmer M, Zilmer K, Bogdanovic N, Karelson E.
Antioxidative effects of plant polyphenols: From protection of G
protein signaling to prevention of age-related pathologies. Ann NY
Acad Sci 2007; 1095: 449-57.
[63] Bemis DL, Katz AE, Buttyan R. Clinical trials of natural products
as chemopreventive agents for prostate cancer. Expert Opin
Investig Drugs 2006; 15(10): 1191-200.
[64] Bengmark S. Curcumin, an atoxic antioxidant and natural
NFkappaB, cyclooxygenase-2, lipooxygenase, and inducible nitric
oxide synthase inhibitor: a shield against acute and chronic
diseases. JPEN J Parenter Enteral Nutr 2006; 30(1): 45-51.
[65] Bengmark S, Mesa MD, Gil A. Plant-derived health: the effects of
turmeric and curcuminoids. Nutr Hosp 2009; 24(3): 273-81.
[66] Kunnumakkara AB, Anand P, Aggarwal BB. Curcumin inhibits
proliferation, invasion, angiogenesis and metastasis of different
cancers through interaction with multiple cell signaling proteins.
Cancer Lett 2008; 269(2): 199-225.
[67] Shanmugam MK, Kannaiyan R, Sethi G. Targeting cell signaling
and apoptotic pathways by dietary agents: role in the prevention
and treatment of cancer. Nutr Cancer 2011; 63(2): 161-73.
[68] Thomasset SC, Berry DP, Garcea G, Marczylo T, Steward WP,
Gescher AJ. Dietary polyphenolic phytochemicals-promising
cancer chemopreventive agents in humans? A review of their
clinical properties. Int J Cancer 2007; 120(3): 451-8.
[69] Aggarwal BB, Sethi G, Ahn KS, et al. Targeting signal-transducer-
and-activator-of-transcription-3 for prevention and therapy of
cancer: modern target but ancient solution. . Ann N Y Acad Sci
2006; 1091: 151-69.
[70] Kakarala M, Wicha MS. Implications of the cancer stem-cell
hypothesis for breast cancer prevention and therapy. J Clin Oncol
2008; 26(17): 2813-20.
[71] Kakarala M, Brenner DE, Korkaya H, et al. Targeting breast stem
cells with the cancer preventive compounds curcumin and piperine.
Breast Cancer Res Treat 2010; 122(3): 777-85.
[72] Sandur SK, Ichikawa H, Pandey MK, et al. Role of pro-oxidants
and antioxidants in the anti-inflammatory and apoptotic effects of
curcumin (diferuloylmethane). Free Radic Biol Med 2007; 43(4):
568-80.
[73] Yamaguchi H, Wang HG. The protein kinase PKB/Akt regulates
cell survival and apoptosis by inhibiting Bax conformational
change. Oncogene 2001; 20(53): 7779-86.
[74] Jee S, Shen SC, Tseng CR, Chiu HC, Kuo ML. Curcumin induces a
p53-dependent apoptosis in human basal cell carcinoma cells. J
Invest Dermatol 1998; 111(4): 656-61.
[75] Jiang M, Yang-Yen HF, Lin JK, Yen JJ. Differential regulation of
p53, c-Myc, Bcl-2 and Bax protein expression during apoptosis
induced by widely divergent stimuli in human hepatoblastoma
cells. Oncogene 1996; 13(3): 609-16.
Noorafshan and Ashkani-Esfahani
[76] Choudhuri T, Pal S, Agwarwal ML, Das T, Sa G. Curcumin
induces apoptosis in human breast cancer cells through p53-
dependent Bax induction. FEBS Lett 2002; 512(1-3): 334-40.
[77] Choudhuri T, Pal S, Das T, Sa G. Curcumin selectively induces
apoptosis in deregulated cyclin D1-expressed cells at G2 phase of
cell cycle in a p53-dependent manner. J Biol Chem 2005; 280:
20059-68.
[78] Chen Y, Kuo TC, Lin-Shiau SY, Lin JK. Induction of HSP70 gene
expression by modulation of Ca(12) ion and cellular p53 protein by
curcumin in colorectal carcinoma cells. Mol Carcinogenesis 1996;
17: 224-34.
[79] Bush J, Cheung K-JJ, Li G. Curcumin induces apoptosis in human
melanoma cells through a Fas receptor/ caspase-8 pathway
independent of p53. Exp Cell Res 2001; 271(2): 305-14.
[80] Arbiser J, Klauber N, Rohan R, et al. Curcumin is an in vivo
inhibitor of angiogenesis. Mol Med 1998; 4(6): 376-83.
[81] Mohan R, Sivak J, Ashton P, et al. Curcuminoids inhibit the
angiogenic response stimulated by fibroblast growth factor-2,
including expression of matrix metalloproteinase gelatinase B. J
Biol Chem 2000; 275: 10405-12.
[82] Gururaj A, Belakavadi M, Venkatesh DA, Marme D, Salimath BP.
Molecular mechanisms of antiangiogenic effect of curcumin.
Biochem Biophys Res Commun 2002; 297(4): 934-42.
[83] Bhandarkar SS, Arbiser JL. Curcumin as an inhibitor of
angiogenesis. Adv ExpMed Biol 2007; 595: 185-95.
[84] Aggarwal BB, Sung B. Pharmacological basis for the role of
curcumin in chronic diseases: an age-old spice with modern targets.
Trends in Pharmacological Sciences 2008; 30(2): 85-94.
[85] Purkayastha S, Berliner A, Fernando SS, et al. Curcumin blocks
brain tumor formation. Brain Research 2009; 1266: 130-8.
[86] Jing Lim K, Bisht S, Bar E, Maitra A, Eberhart C. A polymeric
nanoparticle formulation of curcumin inhibits growth,
clonogenicity and stem-like fraction in malignant brain tumors.
Cancer Biol Ther 2011; 11(5): 464-73.
[87] Kundu P, Mohanty C, Sahoo S. Antiglioma activity of curcumin-
loaded lipid nanoparticles and its enhanced bioavailability in brain
tissue for effective glioblastoma therapy. Acta Biomaterialia 2012;
8(7): 2670-87.
[88] Hsieh M-Y, Ponsford J, Wong D, McKay A. Exploring variables
associated with change in cognitive behaviour therapy (CBT) for
anxiety following traumatic brain injury. Disability and
Rehabilitation 2012; 34(5): 408-15.
[89] Sharma S, Zhuang Y, Ying Z, Wu A, Gomez-Pinilla F. Dietary
curcumin supplementation counteracts reduction in levels of
molecules involved in energy homeostasis after brain trauma.
Neuroscience 2009; 161(4): 1037-44.
[90] Kakkar V, Kau I. Evaluating potential of curcumin loaded solid
lipid nanoparticles in aluminium induced behavioural, biochemical
and histopathological alterations in mice brain. Food Chemical
Toxicol 2011; 49(11): 2906-13.
[91] Tian M, Wang L, Yu G, Liu B, Yu L. Curcumin promotes
cholesterol efflux from brain through LXR/RXR-ABCA1-apoA1
pathway in chronic cerebral hypoperfusion aging-rats. Molecular
Neurodegeneration 2012; 7(1): S7.
[92] Mutsuga M, Chambers JK, Uchida K, et al. Binding of curcumin to
senile plaques and cerebral amyloid angiopathy in the aged brain of
various animals and to neurofibrillary tangles in Alzheimer's brain.
J Vet Med Sci 2012; 74(1): 51-7.
[93] Liu L, Zhang P, Li Y, Yu G. Curcumin protects brain from
oxidative stress through inducing expression of UCP2 in chronic
cerebral hypoperfusion aging-rats. Molecular Neurodegeneration
2012; 7(Suppl 1): S10.
[94] Agrawala R MB, Tyagia E,Nathb C,Shukla R. Effect of curcumin
on brain insulin receptors and memory functions in STZ (ICV)
induced dementia model of rat. Pharmacological Research 2010;
61(3): 247-52.
[95] Shukla PK KV, Ali MM, Khan MY ,Srimal RC. Anti-ischemic
Effect of Curcumin in Rat Brain. Neurochemical Research 2008;
33(6): 1036-43.
[96] Huanga Z ZX, Lia Z, Fenga C, Pana A, Mao Q. Curcumin reverses
corticosterone-induced depressive-like behavior and decrease in
brain BDNF levels in rats. Neuroscience Letters 2011; 493(3): 145-
8.
[97] Pillai GR, Srivastava AS, Hassanein TI, Chauhan DP, Carrier E.
Induction of apoptosis in human lung cancer cells by curcumin.
Cancer Letters 2004; 208(2): 163-70.
The Therapeutic Effects of Curcumin
[98] Alexandrow MG, Song LJ, Altiok S, Gray J, Haura EB, Kumar
NB. Curcumin: a novel Stat3 pathway inhibitor for
chemoprevention of lung cancer. European Journal of Cancer
Prevention 2011; In Press.
[99] Deryugina EI, Quigley JP. The Role of Matrix Metalloproteinases
in Cellular Invasion and Metastasis. Biology of Extracellular
Matrix 2011; 2: 145-19.
[100] Song-Shei, Lai KC, Shu-Chun Hsu, et al. Curcumin inhibits the
migration and invasion of human A549 lung cancer cells through
the inhibition of matrix metalloproteinase-2 and -9 and Vascular
Endothelial Growth Factor (VEGF). Cancer Letters 2009; 285(2):
127-33.
[101] Lee JC, Kinniry PA, Arguiri E, et al. Dietary Curcumin Increases
Antioxidant Defenses in Lung, Ameliorates Radiation-Induced
Pulmonary Fibrosis, and Improves Survival in Mice. Radiation
Research 2010; 173(5): 590-601.
[102] Lüer S, Troller R, Jetter M, Spaniol V, Aebi C. Topical curcumin
can inhibit deleterious effects of upper respiratory tract bacteria on
human oropharyngeal cells in vitro: potential role for patients with
cancer therapy induced mucositis? Supportive Care in Cancer
2011; 19(6): 799-806.
[103] Farhangkhoee H, Khan ZA, Mukherjee S, et al. Heme oxygenase in
diabetes-induced oxidative stress in the heart. J Mol Cell Cardiol
2003; 35(12): 1439-48.
[104] Brouet I, Ohshima H. Curcumin,an anti-tumour promoter and
antiinflammatory agent, inhibits induction of nitric oxide synthase
in activated macrophages. Biochem Biophys Res Commun 1995;
206(2): 533-40.
[105] Farhangkhoee H, Khan ZA, Chen S, Chakrabarti S. Differential
effects of curcumin on vasoactive factors in the diabetic rat heart.
Nutr Metab (Lond) 2006; 3: 27.
[106] Venkatesan N. Curcumin attenuation of acute adriamycin
myocardial toxicity in rats. Br J Pharmacol 1998; 124(3): 425-7.
[107] Daosukho C, Chen Y, Noel T, et al. Phenylbutyrate, a histone
deacetylase inhibitor, protects against adriamycin-induced cardiac
injury. Free Radic Biol Med 2007; 42(12): 1818-25.
[108] Gusterson RJ, Jazrawi E, Adcock IM, Latchman DS. The
transcriptional co-activators CREB-binding protein (CBP) and
p300 play a critical role in cardiac hypertrophy that is dependent on
their histone acetyltransferase activity. J Biol Chem 2003; 278(9):
6838-47.
[109] Yanazume T, Hasegawa K, Morimoto T, et al. Cardiac p300 is
involved in myocyte growth with decompensated heart failure. Mol
Cell Biol 2003; 23(10): 3593-606.
[110] Li HL, Liu C, Couto G, et al. Curcumin prevents and reverses
murine cardiac hypertrophy. J Clin Invest 2008; 118(3): 879-93.
[111] Morimoto T, Sunagawa Y, Kawamura T, et al. The dietary
compound curcumin inhibits p300 histone acetyltransferase activity
and prevents heart failure in rats. J Clin Invest 2008; 118(3): 868-7.
[112] Marcu M.G., Jung Y, Lee S, et al. Curcumin is an inhibitor of p300
histone acetylatransferase. Med Chem 2006; 2(2): 169-74.
[113] Virani SS, Polsani VR, Nambi V. Novel markers of inflammation
in atherosclerosis. Curr Atheroscler Rep 2008; 10(2): 164-70.
[114] Schoonderwoerd BA, Smit MD, Pen L, Van Gelder IC. New risk
factors for atrial fibrillation: causes of ‘not-so-lone atrial
fibrillation'. Europace 2008; 10(6): 668-73.
[115] Goel A, Kunnumakkara AB, Aggarwal BB. Curcumin as
“Curecumin”: from kitchen to clinic. Biochem Pharmacol 2008;
75(4): 787-809.
[116] Shishodia S, T S. Chaturvedi MM. Modulation of transcription
factors by curcumin. Adv Exp Med Biol 2007; 595: 127-48.
[117] Pae HO, Jeong GS, Jeong SO, et al. Roles of heme oxygenase-1 in
curcumin-induced growth inhibition in rat smooth muscle cells.
Exp Mol Med 2007; 39(3): 267-77.
[118] Durante W. Heme oxygenase-1 in growth control and its clinical
application to vascular disease. J Cell Physiol 2003; 195(3): 373-
82.
[119] Li Y, Chen ZQ, Li YD. Effects of curcumin on the epithelial
mesenchymal transition and TGF-beta/Smads signaling pathway in
unilateral ureteral obstruction rats. Zhongguo Zhong Xi Yi Jie He
Za Zhi 2011; 31(9): 1224-8.
[120] Ahmed MH, Ashton N, Balment RJ. Renal function in a rate model
of analgesic nephropathy: Effect of chloroquine. J Pharmacol Exp
Ther 2003; 305(1): 123-30.
[121] Yousef MI, Omar SAM, El-Guendi MI, Abdelmegid LA. Potential
protective effects of quercetin and curcumin on paracetamol-
Current Pharmaceutical Design, 2013, Vol. 19, No. 11 2043
induced histological changes, oxidative stress, impaired liver and
kidney functions and haematotoxicity in rat. Food and Chemical
Toxicol 2010; 48(11): 3246-61.
[122] Shahed AR, Jones E, Shoskes D. Quercetin and curcumin up-
regulate antioxidant gene expression in rat kidney after ureteral
obstruction or ischemia/reperfusion injury. Transplantation
Proceedings 2001; 33( 6): 2988.
[123] El-Nahas AF, El-Ashmawy IM. Reproductive and cytogenetic
toxicity of metronidazole in male mice. Basic Clin Pharmacol
Toxicol 2004; 94(5): 226-33.
[124] Noorafshan A, KarbalayDoust S, Valizadeh A, Aliabadi E.
Ameliorative effects of curcumin on the structural parameters of
seminiferous tubules and Leydig cells in metronidazole-treated
mice: A stereological approach. Exp Toxicologic Pathol 2011; 63:
627- 33.
[125] Farombi EO, Abarikwu SO, Adedara IA, Oyeyemi MO. Curcumin
and Kolaviron Ameliorate Di-n-Butylphthalate-Induced Testicular
Damage in Rats. Basic & Clinical Pharmacology Toxicol 2007;
100(1): 43-8.
[126] Tsutsumi T, Ichihara T, Kawabe M, et al. Renal toxicity induced
by folic acid is associated with the enhancement of male
reproductive toxicity of di (n-butyl)phthalate in rats. Reprod
Toxicol 2004; 18(1): 35-42.
[127] Mathuria N, Verma RJ. Curcumin ameliorates aflatoxin-induced
toxicity in mice spermatozoa. Fertil Steril 2008; 90(3): 775-80.
[128] Giannessi F, Giambelluca MA, Grasso L, Scavuzzo MC, Ruffoli R.
Curcumin protects Leydig cells of mice from damage induced by
chronic alcohol administration. Med Sci Monit 2008; 14(11): 237-
42.
[129] Giannessi F, Giambelluca MA, Grasso L, Scavuzzo MC, Ruffoli R.
Curcumin protects Leydig cells of mice from damage induced by
chronic alcohol administration. Med Sci Monit 2008; 14(11): 237-
42.
[130] Ilbey YO, Ozbek E, Cekmen M, Simsek A, Otunctemur A, Somay
A. Protective effect of curcumin in cisplatin-induced oxidative
injury in rat testis: mitogen-activated protein kinase and nuclear
factor-kappa B signaling pathways. Hum Reprod 2009; 24(7):
1717-25.
[131] Hong JH, Ahn KS, Bae E, Jeon SS, Choi HY. The effects of
curcumin on the invasiveness of prostate cancer in vitro and in
vivo. Prostate Cancer and Prostatic Diseases 2006; 9: 147-52.
[132] Chendil D, Ranga RS, Meigooni D, Sathishkumar S, Ahmed MM.
Curcumin confers radiosensitizing effect in prostate cancer cell line
PC-3. Oncogene 2004; 23: 1599-607.
[133] Nonn L, Duong D, Peehl DM. Chemopreventive anti-inflammatory
activities of curcumin and other phytochemicals mediated by MAP
kinase phosphatase-5 in prostate cells Carcinogenesis 2007; 28(6):
1188-96.
[134] Ohtsu H, Xiao Z, Ishida J, et al. Antitumor Agents. 217. Curcumin
Analogues as Novel Androgen Receptor Antagonists with Potential
as Anti-Prostate Cancer Agents. J Med Chem 2002; 45(23): 5037-
42.
[135] Jones RE, López KH. Human Reproductive Biology. Oxford:
Academic Press; 2006.
[136] Madhavi K, Kumar R. In vivo Toxicological Evaluation Of
Organophosphate Pesticide On Female Albino Mice: Therapeutic
Effects Of Curcumin. Int J Pharm Sci Res 2010; 1(9): 86-92.
[137] El-Sayed ESM. The Uterine Relaxant Effect Of Curcumin In Rats;
An In vitro Study. J Basic Applied Sci 2008; 4(1): 45-8.
[138] Itthipanichpong C, Ruangrungsi N, Kemsri W, Sawasdipanich A.
Antispasmodic effects of curcuminoids on isolated guinea-pig
ileum and rat uterus. J Med Assoc Thai 2003; 86(2): 299-309.
[139] Liduan Z, Qiangsong T, Cuihuan W. Growth-inhibitory effects of
curcumin on ovary cancer cells and its mechanisms. Journal of
Huazhong University of Science and Technology 2004; 24(1): 55-
8.
[140] Shi M, Cai Q, Yao L, Mao Y, Ming Y, Ouyang G.
Antiproliferation and apoptosis induced by curcumin in human
ovarian cancercells. Cell Biology International 2006; 30(3): 221-6.
[141] Singh M, Singh N. Curcumin counteracts the proliferative effect of
estradiol and induces apoptosis in cervical cancer cells. Molecular
and Cellular Biochemistry 2011; 347(1-2).
[142] Thapa BR, Walia A. Liver function tests and their interpretation.
Indian J Pediatr 2007; 74 (7): 663-71.
2044 Current Pharmaceutical Design, 2013, Vol. 19, No. 11
[143] Yousef MI, El-Demerdash FM, Radwan FME. Sodium arsenite-
induced biochemical perturbations in rats: Ameliorating effect of
curcumin. Food Chem Toxicol 2008; 46(11): 3506-11.
[144] Messner DJ, Sivam G, Kowdley KV. Curcumin reduces the toxic
effects of iron loading in rat liver epithelial cells. Liver
International 2008; 29(1): 63-72.
[145] Schrader C, Schiborr C, Frank J, Rimbach G. Curcumin induces
paraoxonase 1 in cultured hepatocytes in vitro but not in mouse
liver in vivo. British Journal of Nutrition 2011; 28(105): 167-70
[146] Seehofer D, Schirmeier A, Bengmark S, et al. Inhibitory Effect of
Curcumin on Early Liver Regeneration Following Partial
Hepatectomy in Rats. Journal of Surgical Research 2009; 155(2):
195-200.
[147] Farombi EO, Shrotriya S, Na HK, Kim SH, Surh YJ. Curcumin
attenuates dimethylnitrosamine-induced liver injury in rats through
Nrf2-mediated induction of heme oxygenase-1. Food and Chemical
Toxicology 2008; 46(4): 1279-87.
[148] Fu Y, Zheng S, Lin J, Ryerse J, Chen A. Curcumin Protects the Rat
Liver from CCl4-Caused Injury and Fibrogenesis by Attenuating
Oxidative Stress and Suppressing Inflammation Molecular
Pharmacology 2008; 73(2): 399-409
[149] Wang L, Shen Y, Song R, Sun Y, Xu J, Xu Q. An Anticancer
Effect of Curcumin Mediated by Down-Regulating Phosphatase of
Regenerating Liver-3 Expression on Highly Metastatic Melanoma
Cells Molecular Pharmacology 2009 76 (6): 1238-45
[150] Bruck R, Ashkenazi M, Weiss S, et al. Prevention of liver cirrhosis
in rats by curcumin. Liver International 2007; 27(3): 373-83.
[151] Irving GR, Karmokar A, Berry DP, Brown K, Steward WP.
Curcumin: the potential for efficacy in gastrointestinal diseases.
Best Pract Res Clin Gastroenterol 2011; 25(4-5): 519-34.
[152] Ali T, Shakir F, Morton J. Curcumin and Inflammatory Bowel
Disease: Biological Mechanisms and Clinical Implication.
Digestion 2012 85(4): 249-55.
[153] Taylor RA, Leonard MC. Curcumin for inflammatory bowel
disease: a review of human studies. Altern Med Rev 2011; 16(2):
152-6.
[154] Maheshwari R, Singh AK, Gaddipati J, Srimal RC. Multiple
biological activities of curcumin: A short review. Life Sci 2006;
78(18): 2081-7.
[155] S. Darvesh A, B. Aggarwal B, Bishayee A. Curcumin and Liver
Cancer: A Review. Curr Pharm Biotechnol 2012; 13(1): 218-
28(11).
[156] Onodera S, Kaneda K, Mizue Y, Koyama Y, Fujinaga M, Nishihira
J. Macrophage migration inhibitory factor up-regulates expression
of matrix metalloproteinases in synovial fibroblasts of rheumatoid
arthritis. J Biol Chem 2000; 275(1): 444-50.
[157] Lev-Ari S, Strier L, Kazanov D, et al. Curcumin synergistically
potentiates the growth-inhibitory and pro-apoptotic effects of
celecoxib in osteoarthritis synovial adherent cells. . Rheumatology
(Oxford) 2006; 45(2): 171-7.
[158] Avci G, Kadioglu H, Sehirli AO, et al. Curcumin Protects Against
Ischemia/Reperfusion Injury in Rat Skeletal Muscle. Journal of
Surgical Research 2012; 172(1): e39-e46.
[159] Vazeille E, Slimani L, Claustre A, et al. Curcumin treatment
prevents increased proteasome and apoptosome activities in rat
skeletal muscle during reloading and improves subsequent recovery
The Journal of Nutritional Biochemistry 2012; 23(3): 245-51.
[160] Poylin V, Fareed MU, O'Neal P, et al. The NF-kappaB Inhibitor
Curcumin Blocks Sepsis-Induced Muscle Proteolysis. Mediators
Inflamm 2008; 2008: 317851.
[161] Na LX, Zhang YL, Li Y, et al. Curcumin improves insulin
resistance in skeletal muscle of rats. Nutrition, Metabolism and
Cardiovascular Diseases 2011; 21(7): 526-33.
[162] Davis JM, Murphy EA, Carmichael MD, et al. Curcumin effects on
inflammation and performance recovery following eccentric
exercise-induced muscle damage. AJP - Regu Physiol 2007;
292(6): R2168-R73.
[163] Davis M. Effects of Curcumin and Quercetin on Inflammation and
Fatigue with Muscle Damage, Cancer and Infection. Med Sci
Sports Exercise 2009; 41 (5): 53.
[164] Maheshwari RK, Singh AK, Gaddipati J, Srimal RC. Multiple
biological activities of curcumin: a short review. Life Sci 2006;
78(18): 2081-7.
[165] Kurd SK, Smith N, VanVoorhees A, et al. Oral curcumin in the
treatment of moderate to severe psoriasis vulgaris: a prospective
clinical trial. J Am Acad Dermatol 2008; 58(4): 625-31.
Noorafshan and Ashkani-Esfahani
[166] Ashkani-Esfahani S, Imanieh MH, Khoshneviszadeh M, et al. The
Healing Effect of Arnebia Euchroma in Second Degree Burn
Wounds in Rat as an Animal Model. Iran Red Crescent Med J
2012; 14(2): 70-4.
[167] Ashkani-Esfahani S, Emami Y, Esmaeilzadeh E, Bagheri F,
Namazi MR. Glucosamine Enhances Tissue Regeneration in the
Process of Wound Healing in Rats as Animal Model: A
Stereological Study. J Cytol Histol 2012; 3: 150.
[168] Jagetia GC, Rajanikant GK. Acceleration of wound repair by
curcumin in the excision wound of mice exposed to different doses
of fractionated
radiation. Int Wound J 2012 9(1): 76-92.
[169] López-Jornet P, Camacho-Alonso F, Jiménez-Torres MJ, Orduña-
Domingo A, Gómez-García F. Topical curcumin for the healing of
carbon dioxide laser skin wounds in mice. Photomed Laser Surg
2011; 29(12): 809-14.
[170] Pari L, Murugan P. Antihyperlipidemic effect of curcumin and
tetrahydrocurcumin in experimental type 2 diabetic rats. Ren Fail
2007; 29(7): 881-9.
[171] Pari L, Murugan P. Tetrahydrocurcumin prevents brain lipid
peroxidation in streptozotocin-induced diabetic rats. J Med Food
2007; 10(2): 323-9.
[172] Mahesh T, Sri-Balasubashini MM, Menon VP. Photo-irradiated
curcumin supplementation in streptozotocin-induced diabetic rats:
effect on lipid peroxidation. Therapie 2004; 59(6): 639-44.
[173] Nishiyama T, Mae T, Kishida H, et al. Curcuminoids and
sesquiterpenoids in turmeric (Curcuma longa L.) suppress an
increase in blood glucose level in type 2 diabetic KK-Aymice. J
Agric Food Chem 2005; 53(4): 959-63.
[174] Suryanarayana P, Satyanarayana A, Balakrishna N, Kumar PU,
Reddy GB. Effect of turmeric and curcumin on oxidative stress and
antioxidant enzymes in streptozotocin-induced diabetic rat. Med
Sci Monit 2007; 13(12): BR286-92.
[175] Sharma S, Kulkarni SK, Chopra K. Curcumin, the active principle
of turmeric (Curcuma longa), ameliorates diabetic nephropathy in
rats. Clin Exp Pharmacol Physiol 2006 b; 33(10): 940-5.
[176] Farhangkhoee H, Khan ZA, Chen S, Chakrabarti S. Differential
effects of curcumin on vasoactive factors in the diabetic rat heart. .
Nutr Metab (Lond) 2006; 3: 27.
[177] Feng B, Chen S, Chiu J, George B, Chakrabarti S. Regulation of
cardiomyocyte hypertrophy in diabetes at the transcriptional level.
Am J Physiol Endocrinol Metab 2008.; 294(6): E1119-E26.
[178] Aggarwal BB, Bhatt ID, Ichikawa H, et al. Curcumin - biological
and medicinal properties. In: Ravindran PN, Babu KN, Sivaraman
K, editors. Turmeric the Genus Curcuma. NY: CRC Press; 2007. p.
297-368.
[179] Shao ZM, Shen ZZ, Liu CH, et al. Curcumin exerts multiple
suppressive effects on human breast carcinoma cells. Int J Cancer
2002; 98(2): 234-40.
[180] Schindler R, Mentlein R. Flavonoids and vitamin E reduce the
release of the angiogenic peptide vascular endothelial growth factor
from human tumor cells. J Nutr 2006; 136(6): 1477-82.
[181] Ramachandran C, Fonseca HB, Jhabvala P, Escalon EA, Melnick
SJ. Curcumin inhibits telomerase activity through human
telomerase reverse transcriptase in MCF-7 breast cancer cell line.
Cancer Lett 2002; 184(1): 1-6.
[182] Di GH, Li HC, Shen ZZ, Shao ZM. Analysis of antiproliferation of
curcumin on human breast cancer cells and its mechanism.
Zhonghua Yi Xue Za Zhi 2003; 83(20): 1764-8.
[183] Yoon H, Liu RH. Effect of selected phytochemicals and apple
extracts on NF-kappaB activation in human breast cancer MCF-7
cells. J Agric Food Chem 2007; 55(8): 3167-73.
[184] Xia X, Cheng G, Pan Y, Xia ZH, Kong LD. Behavioral,
neurochemical, neuroendocrine effects of the ethanolic extract from
Curcuma longa L.in the mouse forced swimming test. J
Ethnopharmacol 2007; 110(2): 356-63.
[185] Poma P, Notarbartolo M, Labbozzetta M, et al. The antitumor
activities of curcumin and of its isoxazole analogue are not affected
by multiple gene expression changes in an MDR model of the
MCF-7 breast cancer cell line: analysis of the possible molecular
basis. Int J Mol Med 2007; 20(3): 329-35.
[186] Anand P, Sundaram C, Jhurani S, Kunnumakkara AB, Aggarwal
BB. Curcumin and cancer: an "old-age" disease with an "age-old"
solution. Cancer Letters 2008; 267(1): 133-64.
[187] Rafiee P, Ogawa H, Heidemann J, et al. Isolation and
characterization of human esophageal microvascular endothelial
The Therapeutic Effects of Curcumin
cells: mechanisms of inflammatory activation. Am J Physiol
Gastrointest Liver Physiol 2003; 285: G1277-G92.
[188] Wax A, Pyhtila JW, Graf RN, et al. Prospective grading of
neoplastic change in rat esophagus epithelium using angle-resolved
low-coherence interferometry. J Biomed Opt 2005; 10(5): 051604.
[189] Wei SC, Lin YS, Tsao PN, Wu-Tsai JJ, Wu CH, Wong JM.
Comparison of the anti-proliferation and apoptosis-induction
activities of sulindac, celecoxib, curcumin, and nifedipine in
mismatch repair-deficient cell lines. J Formos Med Assoc 2004;
103(8): 599-606.
[190] Scott DW, Loo G. Curcumin-induced GADD153 gene up-
regulation in human colon cancer cells. Carcinogenesis 2004;
25(11): 2155-64.
[191] Rashmi R, Kumar S, Karunagaran D. Human colon cancer cells
lacking Bax resist curcumin-induced apoptosis and Bax
requirement is dispensable with ectopic expression of Smac or
downregulation of Bcl-xL. Carcinogenesis 2005; 26(4): 713-23.
[192] Du B, Jiang L, Xia Q, Zhong L. Synergistic inhibitory effects of
curcumin and 5-fluorouracil on the growth of the human colon
cancer cell line HT-29. Chemotherapy 2006; 52(1): 23-8.
[193] Moussavi M, Assi K, Gomez-Munoz A, Salh B. Curcumin
mediates ceramide generation via the de novo pathway in colon
cancer cells. Carcinogenesis 2006; 27(8): 1636-44.
[194] Wijnands MV, Erk MJv, Doornbos RP, Krul CA, Woutersen RA.
Do aberrant crypt foci have predictive value for the occurrence of
colorectal tumours? Potential of gene expression profiling in
tumours. Food Chem Toxicol 2004; 42(10): 1629-39.
[195] Volate SR, Davenport DM, Muga SJ, Wargovich MJ. Modulation
of aberrant crypt foci and apoptosis by dietary herbal supplements
(quercetin, curcumin, silymarin, ginseng and rutin). Carcinogenesis
2005; 26(8): 1450-6.
[196] Li L, Ahmed B, Mehta K, Kurzrock R. Liposomal curcumin with
and without oxaliplatin: effects on cell growth, apoptosis, and
angiogenesis in colorectal cancer. Mol Cancer Ther 2007; 6(4):
1276-82.
[197] Vietri M, Pietrabissa A, Mosca F, Spisni R, Pacifici GM. Curcumin
is a potent inhibitor of phenol sulfotransferase (SULT1A1) in
human liver and extrahepatic tissues. Xenobiotica 2003; 33(4):
357-63.
[198] Chen YN, Cheng CC, Chen JC, Tsauer W, Hsu SL.
Norcantharidin-induced apoptosis is via the extracellular signal-
regulated kinase and c-Jun-NH2-terminal kinase signaling
pathways in human hepatoma HepG2 cells. Br J Pharmacol 2003;
140(3): 461-70.
[199] Bae MK, Kim SH, Jeong JW, et al. Curcumin inhibits hypoxia-
induced angiogenesis via down-regulation of HIF-1. Oncol Rep
2006; 15(6): 1557-62.
[200] Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of
curcumin: preclinical and clinical studies. Anticancer Res 2003;
23(1A): 363-98.
[201] Wang W, Abbruzzese JL, Evans DB, Larry L, Cleary KR, Chiao
PJ. The nuclear factor-kappa B RelA transcription factor is
constitutively activated in human pancreatic adenocarcinoma cells.
Clin Cancer Res 1999; 5(1): 119-27.
[202] Khanbolooki S, Nawrocki ST, Arumugam T, Andtbacka R, Pino
MS, Kurzrock R, et al. Nuclear factor-kappaB maintains TRAIL
resistance in human pancreatic cancer cells. Mol Cancer Ther 2006;
5: 2251-60.
[203] Jutooru I, Chadalapaka G, Lei P, Safe S. Inhibition of NF
B and
Pancreatic Cancer Cell and Tumor Growth by Curcumin Is
Dependent on Specificity Protein Down-regulation. J Biological
Chem 2010; 285(33): 25332-44. .
[204] Lev-Ari S, Starr A, Vexler A, et al. Inhibition of pancreatic and
lung adenocarcinoma cell survival by curcumin is associated with
increased apoptosis, downregulation of COX-2 and EGFR and
inhibition of Erk1/2 activity. Anticancer Res 2006; 26(6B): 4423-
30.
[205] Wang Z, Zhang Y, Banerjee S, Li Y, Sarkar FH. Notch-1 down-
regulation by curcumin is associated with the inhibition of cell
growth and the induction of apoptosis in pancreatic cancer cells.
Cancer Lett 2006; 106(11): 2503-13.
[206] Lev-Ari S, Vexler A, Starr A, et al. Curcumin augments
gemcitabine cytotoxic effect on pancreatic adenocarcinoma cell
lines. Cancer Invest 2007; 25(6): 411-8.
Current Pharmaceutical Design, 2013, Vol. 19, No. 11 2045
[207] Dhillon N, Aggarwal BB, Newman RA, et al. Curcumin and
pancreatic cancer: phase II clinical trial experience. J Clin Oncol
2007; 25: 4599.
[208] Kamat AM, Sethi G, Aggarwal BB. Curcumin potentiates the
apoptotic effects of chemotherapeutic agents and cytokines through
down-regulation of nuclear factor-kappaB and nuclear factor-
kappaB-regulated gene products in IFN-alpha-sensitive and IFN-
alpha-resistant human bladder cancer cells. Mol Cancer Ther 2007;
6(3): 1022-30.
[209] Tharakan ST, Inamoto T, Sung B, Aggarwal BB, Kamat AM.
Curcuminpotentiates the antitumor effects of gemcitabine in an
orthotopic model of human bladder cancer through suppression of
proliferative and angiogenic biomarkers. Biochemical
Pharmacology 2010; 79(2): 218-28.
[210] Jung EM, Lim JH, Lee TJ, Park JW, Choi KS, Kwon TK.
Curcumin sensitizes tumor necrosis factor-related apoptosis-
inducing ligand (TRAIL)-induced apoptosis through reactive
oxygen species-mediated upregulation of death receptor 5 (DR5).
Carcinogenesis 2005; 26: 1905-13.
[211] Iqbal M, Okazaki Y, Okada S. In vitro curcumin modulates ferric
nitrilotriacetate (Fe-NTA) and hydrogen peroxide (H2O2)-induced
peroxidation of microsomal membrane lipids and DNA damage.
Teratog Carcinog Mutagen 2003; 23(S1): 151-60.
[212] Woo JH, Kim YH, Choi YJ, et al. Molecular mechanisms of
curcumin induced cytotoxicity: induction of apoptosis through
generation of reactive oxygen species, down-regulation of Bcl-XL
and IAP, the release of cytochrome c and inhibition of Akt.
Carcinogenesis 2003; 24(7): 1199-208.
[213] Frank N, Knauft J, Amelung F, Nair J, Wesch H, Bartsch H. 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 2003; 523-524: 127-35.
[214] Khor TO, Keum YS, Lin W, et al. Combined inhibitory effects of
curcumin and phenethyl isothiocyanate on the growth of human
PC-3 prostate xenografts in immunodeficient mice. Cancer Res
2006; 66: 613-21.
[215] Hong JH, Ahn KS, Bae E, Jeon SS, Choi HY. The effects of
curcumin on the invasiveness of prostate cancer in vitro and in
vivo. Prostate Cancer Prostatic Dis 2006; 9: 147-52.
[216] Purkayastha S, Berliner A, Fernando SS, et al. Curcumin blocks
brain tumor formation. Brain Research 2009; 1266: 130-8.
[217] Karmakar S, Banik NL, Ray SK. Curcumin suppressed anti-
apoptotic signals and activated cysteine proteases for apoptosis in
human malignant glioblastoma U87MG cells. Neurochem Res
2007; 32(12): 2103-13.
[218] Dhandapani KM, Mahesh VB, Brann DW. Curcumin suppresses
growth and chemoresistance of human glioblastoma cells via AP-1
and NF
B transcription factors. J Neurochem Res 2007; 102(2):
522-38.
[219] Kim SY, Jung SH, Kim HS. Curcumin is a potent broad spectrum
inhibitor of matrix metalloproteinase gene expression in human
astroglioma cells. Biochem Biophys Res Commun 2005; 337: 510-
6.
[220] Kang SK, Cha SH, Jeon HG. Curcumin-induced histone
hypoacetylation enhances caspase-3-dependent glioma cell death
and neurogenesis of neural progenitor cells. Stem Cells Dev 2006;
15(2): 165-74.
[221] Gao X, Deeb D, Jiang H, Liu YB, Dulchavsky SA, Gautam SC.
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 2005; 5: 39-48.
[222] Shinojima N, Yokoyama T, Kondo Y, Kondo S. Roles of the
Akt/mTOR/p70S6K and ERK1/2 signaling pathways in curcumin-
induced autophagy. Autophagy 2007; 3(6): 635-7.
[223] Aoki H, Takada Y, Kondo S, Sawaya R, Aggarwal BB, Kondo Y.
Evidence that curcumin suppresses the growth of malignant
gliomas in vitro and in vivo through induction of autophagy: role of
Akt and extracellular signal-regulated kinase signaling pathways.
Mol Pharmacol 2007; 72(1): 29-39.
[224] Chen YS, Ho CC, Cheng KC, et al. Curcumin inhibited the
arylamines N-acetyltransferase activity, gene expression and DNA
adduct formation in human lung cancer cells (A549). Toxicol In
vitro 2003; 17(3): 323-33.
[225] Wu SH, Hang LW, Yang JS, et al. Curcumin Induces Apoptosis in
Human Non-small Cell Lung Cancer NCI-H460 Cells through ER
 2046 Current Pharmaceutical Design, 2013, Vol. 19, No. 11
Stress and Caspase Cascade- and Mitochondria-dependent
Pathways. Anticancer Res 2010; 30(6): 2125-33
[226] Alexandrow MG, Song LJ, Altiok S, Gray J, Haura EB, Kumar
NB. Curcumin: a novel Stat3 pathway inhibitor for chemo-
prevention of lung cancer. European Journal of Cancer Prevention
2011; Publish Ahead of Print: 10.1097/CEJ.0b013e32834ef194.
[227] Anto RJ, Maliekal TT, Karunagaran D. L-929 cells harboring
ectopically expressed RelA resist curcumininduced apoptosis. J
Biol Chem 2000; 275: 15601-4.
Received: August 31, 2012 Accepted: October 22, 2012
View publication stats
Noorafshan and Ashkani-Esfahani
[228] Kondo A, Mogi M, Koshihara Y, Togari A. Signal transduction
system for interleukin-6 and interleukin-11 synthesis stimulated by
epinephrine in human osteoblasts and human osteogenic sarcoma
cells. Biochem Pharmacol 2001; 61(3): 319-26.
[229] Ravindran J, Prasad S, Aggarwal BB. Curcumin and Cancer Cells:
How Many Ways Can Curry Kill Tumor Cells Selectively? . The
AAPS J 2009; 11(3): 495-510.
[230] Walters DK, Muff R, Langsam B, Born W, Fuchs B. Cytotoxic
effects of curcumin on osteosarcoma cell lines. Invest New Drugs
2008; 26(4): 289-97.