Chapter

Medicinal properties and health benefits of curcumin

Abstract

Preparations of turmeric (Curcuma longa, Linn.; family: Zingiberaceae) rhizome have been used in several Asian countries for hundreds of years as a traditional medicine. Chemical investigations have concluded that medicinal properties of this preparation are due to its major polyphenolic compound (~5-10% of dry weight), the curcumin (diferuloylmethane). This vivacious yellow compound has been also used as a spice, approved as food additive to flavor various types of curries and mustards. Biomedical investigations of curcumin have evidenced a wide range of molecular and cellular activities, most related to redox reactions and signal transduction. Many of the activities are related to its ability to suppress acute and chronic inflammation. Moreover, curcumin inhibits cancer development and progression. It has activity as a blocking agent, inhibiting the initiation of cancer and also as a suppressing agent, inhibiting malignant cell proliferation, thus, the progression of carcinogenesis (a clinical trial in Phase I about curcumin for the prevention of colon cancer has been completed). Another interesting aspect of curcumin's activity is the ability to exert both radioprotective effects in normal cells and radiosensitizing effects in cancer cells. Curcumin is remarkably well tolerated, but its bioavailability is poor (a clinical trial concerning pharmacokinetics of curcumin in healthy volunteers had been completed in 2007). Hence, its bioavailability has been tried to improve by dissolving curcumin in ambivalent solvents. However, all these promising results should be taken in caution because of some undesirable effects of curcumin have been detected. The present review tries to summarize different studies on the medicinal properties and health benefits of curcumin.
ISBN 978-1-ó1942-481-4
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ISBN: 978-l-61942-481-4
Published by Nova Science Publishers, Inc. * New York
ln: Curcumin: Biosynthesis, Medicinal Uses and Health Benefits ISBN: 978-l-61942-481-4
Editors: Jun Sasaki and Masaki Kichida @ 2012 Nova Science Publishers. Inc.
Chapter XI
Medicinal Properties
and Health Benefits of Curcumin
Natividad Sebostido, José Miguel Sorianoo,
Jordi Moñeso and Alegría Montorob
'Department of Preventive Medicine. Faculty of Pharmacy. University of Valencia
Av. Vicent Andrés Estellés s/n. 46100 Burjassot. Spain
bServicio de Protección Radiológica, Hospital Universitario La Fe,
46009 Valencia, Spain
Abstract
Preparations of turmeric (Curcuma longa, Lirn; family: Zingiberaceae) rhizome
have been used in several Asian countries for hundreds ofyears as a traditional medicine.
Chemical investigations have concluded that medicinal properties of this preparation a¡e
due to its major polyphenolic compound (-5-10% of dry weight), the curcumin
(diferuloylmethane). This vivacious yellow compound has been also used as a spice,
approved as food additive to flavor various types of curries and mustards. Biomedical
investigations of curcumin have evidenced a wide range of molecular and cellular
actiüties, most related to redox reactions and signal transduction. Many of the activities
are related to its ability to suppress acute and chronic inflammation. Moreover, curcumin
inhibits cancer development and progression. It has activity as a blocking agent,
inhibiting the initiation of cancer and also as a suppressing agent, inhibiting malignant
cell proliferation, thus, the progression ofcarcinogenesis (a clinical trial in Phase I about
curcumin for the prevention of colon cancer has been completed). Another interesting
aspect of curcumin's activity is the ability to exert both radioprotective effects in normal
cells and radiosensitizing effects in cancer cells. Curcumin is remarkably well tolerated,
but its bioavailability is poor (a clinical trial concerning pharmacokinetics of curcumin in
healthy volunteers had been completed in2007). Hence, its bioavailability has been tried
to improve by dissolving curcumin in ambivalent solvents. However, all these promising
results should be taken in caution because ofsome undesirable effects ofcurcumin have
been detected. The present review tries to summarize different studies on the medicinal
properties and health benefits of curcumin.
236 Natividad Sebastiá, José Miguel Soriano, Jordi Mañes et al.
Introduction
Curcumin (diferuloylmethane) is one of the principal curcuminoids presents in the
rhizomes of the common known turmeric plafi (Curcuma longa). The turmeric plant had
been described as a treatment for inflammatory diseases in Ayurveda, the Indian system of
holistic medicine which uses mainly plant-based drugs or formulations to treat various
ailments. Although the turmeric plant is known for thousands of years, the use of curcumin as
a plant drug has been emphasizedby the modern medicine in the few last decades. In fact, the
60 %o of the small molecule drugs introduced in worldwide medicine between l98l and 2002
have their origins in natural products [1], probably in an attempt to mimic their actions in
higher plants as a natural defense against disease and infection. Furthermore, the use of
natural products should not be dismissed because the health of 80% of individuals in
developing countries depends primarily on natural products.
Curcumin was first isolated in 1815 by Vogel and Pelletier. It was crystallized by Daube
and finally its structure was elucidated in 1910 by Lampe and co-workers [].
Traditional Medicinal Uses
Curcumin has been used mainly in three main areas for more than 2000 years [2]
foodstuff, cosmetic and medicine.
I. Foodstuff: as a food ingredient curcumin has been used mainly as a spice, to provide
characteristic yellow color and flavor to curry. It has been also used as a coloring
agent in cheese and butter.
Cosmetic: curcumin is used in combination with other plant extracts to manufacture
herbal cosmetics which reduce skin oxidative stress and improve its appearance.
Medicine
a. In folk medicine, curcumin and other curcuminoids have been applied a
therapeutic preparations over the world.
b. In Ayurvedic medicine, curcumin has been used to treat different respiratory
conditions as well as for liver disorders, anorexia, rheumatism, diabetes, runny
nose, cough and sinusitis.
c. In Chinese medicine, it is used in diseases related with abdominal pain.
d. In ancient Hindu medicine, it was used to treat sprains and swelling, probably as
an anti-inflammatory agent.
e. Throughout the Orient, it has been used as an anti-inflammatory medicine.
As it can be seen, the East zones were those where the plant Curcuma longa atd its
curcuminoids have been used traditionally. In fact, the early European explorers to the Asian
continent were who introduced this important food ingredient to the Westem world in the 14'h
century [2].
2.
-)-
Medicinal Properties and Health Benefits of Curcumin 237
Studies in Modern Medicine
Since the first article on curcumin published tn The Lancet n 1g3i, only 17 articles were
published until 1980, 65 in the next 10 years, and 452 n thenext 10. Since 2000, almost 2000
more publications have appeared in the National lnstitutes of Health pubMed [3]. The large
amount of studies suggests that curcumin is a gold molecule because it has a diverse and wiáe
range of molecular targets. Nearly 100 molecules are included in this large range among
which are transcriptional factors, inflammatory cytokines, several enzymes, kinases, growth
factors, receptors, adhesion molecules or antiapoptotic proteins [4]. Curcumin is capable of
directly binds and modulates molecular targets activity or modulates their activity in an
indirect or secondary way.
The extensive investigations had indicated that curcumin possess health benefits because
of it reduces blood cholesterol, prevents low-density lipoprotein oxidation, inhibits platelet
aggregation, suppresses thrombosis and myocardial infarction, suppresses symptoms
associated with type II diabetes, rheumatoid arthritis, multiple sclerosis, and Alzheirner's
disease, inhibits HIV replication, enhances wound healing, protects from liver injury,
prevents cataract formation, protects from pulmonary toxicity and ñbrosis, has theraplutic
effects in leishmaniasis, has antiatherosclerotic activity, and has anticancer activities.
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Medicinal Properties and Health Benefits of Curcumin
Almost 2500 preclinical studies in vitro and in vivo have prompted various clinical trials
in human subjects. In the service of the U.S. National Institutes of Health a number of 62
clinical trials including curcumin are registered, among which 21 are already completed.
Table I shows different clinical trials that are being conducted or already completed. In trials
conducted with humans only minor side effects of curcumin, namely diarrhoea, have been
reported, and it is considered safe and well tolerated.
In order to understand the health benefits of curcumin it is necessary to well known its
mechanisms of action based on the modulation of several molecular targets (Figure l). At this
time it is described the molecular action of curcumin on the main molecular targets:
Curcu min Inhibits Transcription Factors
Curcumin is a potent inhibitor of the activation of various hanscription factors including
nuclear factor-rB (NF-KB), activated protein-l (AP-l), signal transducer and activator of
transcription (STAT) proteins, peroxisome proliferator-activated receptor-g (PPAR-g), and B-
catenin [5]. These transcription factors regulate the expression of genes that contribute to
tumorigenesis, inflammation, cell survival, cell proliferation, invasion, and angiogenesis.
NF-KB. Is one of the key transcription factors responsive to curcumin; many of the
observed biological effects of curcumin involve processes that are NF'-rB-dependent.
For example, curcumin is capable to inhibit the survival and proliferation of diveses
human tumor cell lines (myeloid leukaemia, B non-Hodgkin,s lymphoma sHL),
embryonic kidney, mouse macrophage) by suppressing NF-rB-regulated gene
products [6].
STAT proteins. They have an ubiquitous role in tumourigenesis; curcumin concretely
inhibits srAT3 activation in human multiple myeloma [7] and Hodgkin and Reed-
Sternberg lymphoma cells [8]. This protein is involved in dysregulation of cell
growth, invasion, angiogenesis, metastasis and resistance to apoptosis.
PPAR-g. Is a transcription factor that exerts anti-inflammatory, anti-cancer and
insulin-sensitising actions. Curcumin is capable to induce the action of this receptor
in rat liver cells [9].
AP-l. Is a transcription factor that is frequently associated with activation of NF-rB.
curcumin has been shown to inhibit the activation of Ap-l induced by tumour
promoters [0].
Response Element-Binding Protein. Along with histone acetyltransferases (HAT),
have been implicated in cancer cell growth and survival. It has been proved that
curcumin is a selective HAT inhibitor in vitro and in vivo [11].
Egr-I. curcumin suppresses the induction of Egr-I, involved in angiogenesis, and
thereby modulates the expression of Egr-l-regulated genes invirro studies [12].
B-catenin. Is a central component of the cadherin cell adhesion complex. Curcumin
induces activation of caspase-3, which in tum mediates cleavage of B -catenin and
therefore impairs cell-cell adhesion pathways, resulting in cell cycle arrest at the
G2lM phase and induction of apoptosis in in vitro models [13].
241
242 Natividad Sebastiá, José Miguel Soriano, Jordi Mañes et al.
¡ Nrf-2. Its activation initiates the transcription of genes coding for detoxiffing
enzymes and cytoprotective proteins. In a study of renal epithelial cells Curcumin
stimulates the expression of Nrf-2 in a concentration- and time-dependent manner
tl4l.
Curcumin Down-regulates the Expression of p53
p53 is a tumor suppressor and transcription factor. It plays an important role as regulator
of many cellular processes, including cell signal transduction, cellular response to DNA
damage, genomic stability, cell cycle control, and apoptosis. Curcumin has been shown to be
a potent inhibitor of p53. In this molecular target the role of curcumin in complex, it has been
shown that curcumin can inhibits p53 in immature B cell lymphoma mouse cell lines, a colon
cancer cell line and myeloid leukaemic cells. On the contrary, other experiments show
induction of p53 by curcumin. Therefore, it should take into account the different activity of
curcumin in different types of cancer [6].
Curcumin Suppress the Action of the Tumour Necrosis Factor
Tumour necrosis factor (TNF) is a cltokine that mediates tumor initiation, promotion,
and metastasis. Its effects as pro-inflammation are mediated by its capacity to activate NF-KB,
promoting the expression of inflammatory genes such as COX-2, LOX-2, cell adhesion
molecules, inflammatory cytokines, chemokines, and inducible nitric oxide synthase. In a
study of Shisodia et al. [5] in mantle cell lymphoma cell lines, curcumin inhibits the
expression of both TNF mRNA and TNF protein.
Inflammatory Enzymes
. Cyclooxygenase-2 (COX-2). Is a form of prostaglandin H synthase regulated by
mitogens, tumor promoters, cytokines, and growth factors. Curcumin exerts
significant Cox-2-inhibiting activity through suppression of NF-rB [4].
. Lipoxygenases (LOX). The family of lipoxygenases is responsible for several
inflammatory processes such as asthma or allergy. Curcumin inhibits the activity of
some LOX lisoenzymes and inhibits the release of compounds by LOX which
promote inflammatory responses [15].
Cyclin
Cyclin D1 is a rate-limiting factor in progression of cells through the first gap (G1) phase
of the cell cycle. Therefore, the loss of its regulation is a risk factor for cancer development.
Curcumin down-regulates the expression of cyclin D1 at the transcriptional and
posthanscriptional levels I I 6]
Medicinal Properties and Health Benefits of Curcumin 243
Table 2. Effects of curcumin in animal models
Depression Effect of curcumin in animal models
re
Asthma Metabolic disease
Epilepsy Arthritis
Diabetes Gall-stones formation
Cardiotoxicity Allergy
Parkison's disease Wound healing
Nephrotoxicity Colitis
Infl ammatory bowel disease Renal ischemia
HIV replication Psoriasis
Neoplasic disease Lung fibrosis
Multiple sclerosis Fatigue
Alzheimer's disease Cardiovascular disease
curcumin Downregulates the Activity of Numerous Kinases
A variety of tyrosine kinases are activated by mutations that conkibute to the malignant
transformation, growth, and metastasis of human cancers. Cellular experiments in vitrohave
shown that curcumin completely inhibits the activity of several protein kinases including
phosphorylase kinase, protein kinase C (PKC), protamine kinase (cPK), autophosphorylationi
activated protein kinase (AK), pp60c-src tyrosine kinase, epidermal growth facior ieceptor
(EGFR), mitogen-activated protein kinases (MAPK) I4l.
Curcumin Downregulates Adhesion Molecules Expression
Cell adhesion molecules are transmembrane proteins that are required for binding of cells
to other cells or other extracellular molecules. In cancer metastasis the expressionlf th"r"
molecules is a critical and essential process. Curcumin can inhibit cell adhesion process by
modi$'ing cell receptor binding. In a study of Kumar et al. [17] curcumin could block the ceil
surface expression of adhesion molecules in endothelial cells treated with fumour necrosis
factor.
Medicinal propert¡es of Curcum¡n
The wealth of in vitro and pre-clinical data has provided a strong basis from which to
progress to the hialling of curcumin in human subjects. In addition to the modulation of
numerous metabolic pathways by curcumin in vitro assays, numerous sfudies carried out in
rodents show that curcumin is active in numerous animal models for chronic diseases (Table
2). Epstein et al. [6] affirmed that many of the molecular efficacies of curcumin demonstrated
in cell culture systems and animal models are comparable to those seen in human subjects.
244 Natividad Sebastiá, José Miguel Soriano, Jordi Mañes et al.
Certainly, pharmacokinetics and pharmacodynamics of curcumin have been also studied; first
in rodents, probably for the f,rrst time in 1978 by Wahlstrom and Blennow in Sprague-Dawley
rats [4] and later in humans producing generally similar data. Results show that curcumin
does not appear to be toxic to animals or humans even at high doses [2]. This safety allowed
to conduct quite a lot human hials to test curcumin for chronic disease, several studies have
been already completed and others are nowadays in development (Table 1). Findings
evidence that curcumin has the following benefits.
Anti-I nfla m matory Activity
Research shows curcumin is a highly pleiohopic molecule capable of interacting with
numerous molecular targets involved in inflammation. Modulation of the inflammatory
response by curcumin is carried out by down-regulating the activity of cyclooxygenase-2
(COX-2), lipoxygenase and inducible nitric oxide synthase (iNOS) enzymes; also by
inhibiting the production of the inflammatory cl4okines tumor necrosis factor-alpha (TNF-a),
interleukin (IL) -1, -2, -6, -8 and -12, monocyte chemoattractant protein (MCP), and
migration inhibitory protein and down-regulating mitogen-activated and Janus kinases [8].
The anti-inflammatory activity of curcumin improves status of of rheumatoid arthdtis.
psoriasis, tropical pancreatitis [4], post-operative inflammation, chronic anterior uveitis and
orbital inflammatory pseudo-tumours [6].
Curcumin Reduces Serum Cholesterol and Lipid Peroxide Levels in Healthy
Individuals
A study of Soni et al. [19] observed that a daily administration of curcumin (500 mg) for
7 days to healthy subjects led to a significant 33olo decrease in serum lipid peroxides, a29Yo
increase in serum HDL cholesterol, and a nearly l2o/o decrease in total serum cholesterol.
Moreover, in patients with arterioscleoris curcumin was capable to reduce LDL levels and
increase HDL values [20].
Curcumin as Palliative Therapy for Cancerous Skin Lesions
Curcumin could act similarly to corticosteroids in extemal sebaceous neoplasms. It
improves lesions itching; odor, drying, pain and lesion size [4].
Curcumin Possibly Prevents Gallstone Formation
A potential risk of gall bladder cancer is gallstone formation. Therefore, the emptying of
gall bladder is a key factor in cancer prevention. Curcumin had shown this ability in a
randomized, double-blind, crossover study involving 12 healthy volunteers [21]. Another
study indicated that doses of 40 and 80 mg curcumin produced 50Yo arrd 72Yo contaction of
the gall bladder volume, respectively.
Medicinal Properties and Health Benefits of Curcumin
Curcumin Exerts Chemoprevent¡ve Effects in Multiple Humans Cancer
Apparently, curcumin can also safely exert chemopreventive effects on premalignant
lesions [4]. Several patients with precancerous lesions showed histologic improvement of
their lesions when different doses of curcumin, ranging from 0.5 to 8 mg/day, were
administered. It is thought that chemopreventive effects are due, at least in part, by the
capacity of curcumin to induce the activity or expression of phase II carcinogen detoxiffing
enrymes [5].
Curcumin has been Shown to Suppress Transformat¡on, Proliferation, and
Metastasis of Tumors
All these effects are mediated by the fact that, as is mentioned above and well-known,
curcumin can modulate a wide range of molecular targets. The anti cancer properties of
curcumin are mediated through its regulation of various transcription factors, growth factors,
inflammatory cytokines, protein kinases, and other enzymes.
Carcinogen bioactivation is inhibited via suppression of specific cytochrome P450
isozymes. Curcumin is also capable of arresting cancerous cells in various phases of the cell
cycle by supressing the cell cycle regulatory proteins [5] and moreover, it produces apoptosis
[22].Angiogenesis, which is essential for tumour growth and metastasis, has been down-
regulated by curcumin when it suppressed the proliferation of human vascular endothelial
cells in vitro [23] and to abrogate the FGF-2-induced angiogenic response in vivo [24].
Once a cancer is in metastasic stage, curcumin can act; is known that curcumin is highly
metastastic in nature [5].
Abundant studies over the last two decades have demonstrated that curcumin targets
several steps in biochemical pathways, consequently showing immense promise for the
treatment ofcancers (prostate cancer, colon cancer, pancreas cancer).
Curcumin Diminish Symptoms of Irritable Bowel Syndrome
Two pilot sudies demonstrated that curcumin, when given orally, reported benef,rt to
patients with proctitis and Crohn's disease [25] or improved symptoms of irritable bowel
disease after treatment [26].
Curcumin May Improve Cognitive Function in the Elderly
Nowadays, several diseases in the elder stage of the life which diminish cognitive fuction
are desafortunately becoming common. One of these diseases is the Aláeimer's disease
(AD). Some natural antioxidants have been tested to treat AD without a great success.
Curcumin is several times more potent than vitamin E as a free radical scavenger, protects the
brain from lipid peroxidation and scavenges NO-based radicals produced during
inflammation. In the study of Limm et al.l27l they reported that the Indian spice curcumin
245
246 Natividad Sebastiá, José Miguel Soriano, Jordi Mañes et al.
suppresses indices of inflammation and oxidative damage in the brains of mice, factors that
have been implicated in AD pathogenesis.
Curcumin Acts as Radiosensitizing and Radioprotect¡ve
Curcumin have demonstrated to exert a dual mode of action after irradiation, depending
on its dose. Curcumin could be useful in cancer treatment because of it protects various
systems against the deleterious effects induced by ionizing radiation [28] and enhaces the
effect ofthis radiation in cancerous cells [29].
Curcumin aga¡nst Diabetes
Curcumin is a potent antioxidant. It has been shown that curcumin is useful in preventing
glucose-induced oxidative stress in the endothelial cells and in the heart of diabetic animals. It
has also been observed that short-term treatment of diabetic rats with curcumin prevents
diabetes-induced decreased antioxidant enzyme levels and kidney dysfunction; an important
activity by the fact that diabetic nephropathy is a major cause of morbidlty in diabetic patients
[30]. Another work from Kowluru et al. [31] suggested that curcumin could have potential
benefits in inhibiting the development of retinopathy in diabetic patients
Acknowledgments
This research was supported by the Consejo de Seguridad Nuclear (2696/SRO).
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