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Contents lists available at ScienceDirect

PharmaNutrition
journal homepage: www.elsevier.com/locate/phanu

Clinical applications of curcumin

Yoichi Sunagawaa,b,c , Yasufumi Katanasakaa,b,c , Koji Hasegawab , Tatsuya Morimotoa,b,c,*
a
Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuok, Shizuoka, Japan
b
Division of Translational Research, Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, Kyoto, Japan
c
Shizuoka General Hospital, Shizuoka, Japan

A R T I C L E I N F O A B S T R A C T

Article history: The morbidity of lifestyle-related diseases such as heart disease, cancer, and diabetes mellitus is
Received 28 July 2015 increasing in industrialized countries including Japan each year, and dealing with this increased
Received in revised form 4 August 2015 morbidity is a problem that needs prompt attention. Curcumin is a natural polyphenol derived from the
Accepted 10 August 2015
root of Curcuma longa and has multiple actions, such as anti-inflammatory action, anti-cancer action,
Available online xxx
anti-oxidant action, anti-viral action, and cytoprotective action. It is expected that curcumin has
therapeutic potency to prevent various lifestyle-related diseases. However, curcumin is not readily
Keywords:
soluble in water and has an extremely low level of bioavailability. Over the past decade, preparation
Curcumin
Pleiotropic effect
techniques such as nanoparticles and micelles have led to the development of highly absorbable
Bioavailability curcumin preparations, paving the road for human use of curcumin. This article summarizes a number of
Clinical study basic studies and clinical trials involving curcumin and discusses the potential for clinical use of
curcumin.
ã 2015 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Approaches to clinical use of curcumin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.1. Cancer . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.2. Heart failure . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.3. Type 2 diabetes . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.4. Knee osteoarthritis . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. Conclusion . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Introduction addition, mono-target drugs are extremely difficult and expensive,

and they also have the possibility to produce unexpected adverse
As a result of lifestyle changes such as dietary life, exercise effects. Recently, it is revealed that ingredients in food act to
habits, rest, smoking, and alcohol consumption, patients with prevent various developing diseases with abnormalities in
lifestyle-related diseases such as heart diseases, cancer, and biological regulatory system in the body. Foods with these actions
metabolic syndromes are increasing each year in industrialized are known as functional foods and have garnered attention.
countries including Japan. Over the past several decades, advances Functional foods with multi-faceted actions and a low price have
in drug research have led to the development of numerous mono- become more important than mono-target drugs in terms of
target drugs. However, numerous diseases are caused by abnor- preventing various diseases [2].
malities in multiple signaling pathways, so blocking only one Curcumin is a polyphenol and derived from the rhizome of
signaling pathway might be insufficiency and inefficiency [1]. In Curcuma longa. Curcumin has long been used as a spice in curry, a
natural coloring agent, and Chinese and Indian traditional
medicines. In the US, the FDA has approved curcumin as a safe
* Corresponding author at: 52-1, Yata, Suruga-ku, Shizuoka 422-8526, Japan. ingredient in food. In Japan, curcumin is used in foods such as
E-mail address: morimoto@u-shizuoka-ken.ac.jp (T. Morimoto). curry, pickled radishes, and Japanese confectioneries. The latest

http://dx.doi.org/10.1016/j.phanu.2015.08.001
2213-4344/ ã 2015 Elsevier B.V. All rights reserved.

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research has revealed that curcumin has various physiologic complexed with curcumin to produce micelles. A human clinical
activities, and worldwide attention has focused on curcumin. trial revealed that Meriva resulted in a 29-fold improvement in
Curcumin has been found to have multiple actions such as anti- absorption efficiency in comparison to natural curcumin [7]. In our
inflammatory action through inhibition of NF-kB; anti-cancer previous study, Theracurmin is produced by preparing nano-
action through cell-cycle arrest, induction of apoptosis, and particles of curcumin with gum ghatti coating [8]. In a trial that
inhibition of angiogenesis; anti-oxidant action through removal orally administered Theracurmin 30 mg to humans, the area under
of free radicals and an increased intracellular concentration of the blood concentration-time curve (AUC) of Theracurmin was
glutathione; anti-viral action; and cytoprotective action. Moreover, 27.5 times higher than those of natural curcumin. The maximum
numerous studies using biotechnology techniques have reported concentration of curcumin in the blood was 29.5 ng/ml. This level is
that curcumin regulates intracellular signaling pathways associat- comparable to those of natural curcumin intake in gram doses.
ed with various chronic diseases (Table 1) [3]. Naturally derived Curcumin preparations such as BCM-95, Meriva, and Theracurmin
curcumin is a pleiotropic molecule and might be effective at can easily achieve a satisfactory concentration of curcumin in the
treating various diseases such as cancer, heart disease, and blood at low doses intake compared to natural curcumin powder.
metabolic syndrome. Numerous human clinical trials involving Thus, these curcumin preparation may be useful for clinical setting
curcumin are undergoing in Japan and elsewhere around the to treat various diseases in the future. Our current study
world. At the current point in time, 23 clinical trials involving demonstrated a double-blind crossover human trial to compare
curcumin are registered in UMIN-CTR (http://www.umin.ac.jp/ctr/ these 3 preparations and revealed that Theracurmin resulted in an
), and 108 clinical trials are registered in ClinicalTrial.gov (https:// AUC 16.1 and 5.6 times higher than those of BCM-95 and Meriva,
clinicaltrials.gov/), a website where foreign clinical trials are respectively [9]. Theracurmin is highly orally absorbable in
registered (Table 2) [4]. This article has summarize numerous basic comparison to the other curcumin preparations and may be the
studies and human clinical trials of curcumin in Japan and the most effective curcumin preparation to exhibit its various actions.
world and discuss the potency for clinical use of curcumin. Until the present time, various clinical trials involving Theracurmin
are undergoing in Japan and the US (Table 2).
2. Approaches to clinical use of curcumin
2.1. Cancer
Because curcumin is highly lipophilic, poor gastrointestinal
absorption, and mostly eliminated without being absorbed at oral In various physiologic activities of curcumin, its anti-cancer
administration, curcumin has an extremely low level of bioavail- action has been investigated. A search of PubMed (a website for
ability. According to a study by Lao et al., the maximum searching life science literature) for journal articles related to
concentrations of curcumin in the blood when orally taking curcumin and cancer resulted in over 2700 articles since 1983.
10 or 12 g of curcumin were 50.5 and 57.6 ng/ml, respectively [5]. These articles has doubled over the last 5 years. The reason for the
Thus, the approach to improve absorption efficiency of curcumin is efficiency of curcumin against cancer is because curcumin targets
required for exhibiting therapeutic potency of curcumin in multiple signaling pathways. Curcumin acts multiple-molecules
humans. Some studies demonstrated that the preparation of associated with the progression of cancer by inducing apoptosis
curcumin nanoparticles or curcumin in micelles and liposomes (Bcl-2 and STAT3) and inhibiting cell proliferation (c-myc and
improve curcumin absorption on oral intake in humans. One of Cyclin D1), angiogenesis (VEGF and IL-6), and metastasis (MMP)
these approaches is BCM-95, a preparation that mixes micro- [10]. In vitro experimental systems using cultured cells and animal
particles of curcumin with essential oil of turmeric. The relative experiments demonstrated that curcumin has effective in the
bioavailability of BCM-95 exhibited a 6.9-fold increase in humans treatment of colon cancer, pancreatic cancer, liver cancer, prostate
compared to natural curcumin [6]. Meriva is a preparation cancer, breast cancer, and thymus cancer [4]. Clinical trials
containing soybean lecithin (a mixture of phospholipids) involving use of curcumin for patients with various cancers are
going. Kanai et al. performed a phase I/II clinical trial using
curcumin for patients with gemcitabine-resistant pancreatic
Table 1
cancer [11]. Although this trial analyzed only 21 patients, taking
Molecular targets of curcumin.
curcumin 8 g/day resulted in a median survival of 161 days (95%
Inflammation IL-1, -2, -6, -8# confidence interval: 109–223 days) and a 1-year survival rate of
TNF-a#
19% (4.4–41.4%). Because the prognosis of patients with gemcita-
Kinase activity EGFR kinase#
MAPK# bine-resistant pancreatic cancer is generally close to 60 days, these
PKA#, PKB#, PKC# finding are promising. At present, a phase II clinical trial involving
JAK# use of Theracurmin for patients with pancreatic cancer have been
Transcriptional factor AP-1# going (Table 1). In the US, the M D Anderson Cancer Center also
b-Catenin#
CREB#
conducted a phase II clinical trial in patients with advanced
NF-kB# pancreatic cancer, and this trial indicated that taking curcumin
PPARg" 8 g/day resulted in reduced phosphorylation of NF-kB, COX2, and
STAT3# STAT3 in peripheral blood mononuclear cells from patients [12]. It
p53#
is noted that one patient had 73% tumor reduction. This institution
c-myc#
HIF1# currently have performed a phase I clinical trial using Theracurmin
Enzyme activity COX-2# for the patients with various cancers in order to determine its
iNOS# safety and maximum tolerated dose. Further research using
MMP# Theracurmin may lead that curcumin therapy contribute to
p300#
Etc Cyclin D, Cyclin E#
improve quality of life and a prognosis for patients with cancer.
Bax", Bcl-2#
VEGF# 2.2. Heart failure
Adiponectin"
GST", Glutathione"
Hemodynamic stresses including hypertension or myocardial
ROS#
infarction activate neurohumoral factors such as the sympathetic

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Table 2
Clinical trials using Theracurmin.

Condition Status Location Identifier (reference)

Mild-to moderate Crohn’s disease Open public recruiting Hamamatsu Minami Hospital, Shizuoka, Japan UMIN000015770
Therapy-resistant cancer Enrolling by invitation Keio University Hospital, Tokyo, Japan UMIN000014335
Hypertensive heart disease Enrolling by invitation Kyoto Medical Center, Kyoto, Japan UMIN000014232
Phase III
Non-small-cell lung cancer Not yet recruiting Saitama Medical Center, Saitama, Japan UMIN000013424
Phase I,II
Osteochondropathy and knee osteoarthritis Open public recruiting Kyoto Medical Center, Kyoto, Japan UMIN000011075
Knee osteoarthritis Active, not recruiting Kyoto Medical Center, Kyoto, Japan UMIN000011074
(26)
Unresectable advanced pancreatic cancer Enrolling by invitation Kyoto University Hospital, Kyoto, Japan UMIN000010326
Phase II
Chronic obstructive pulmonary disease Active, not recruiting Kyoto Medical Center, Kyoto, Japan UMIN000009139
Impaired glucose tolerance Active, not recruiting Kyoto Medical Center, Kyoto, Japan UMIN000007361
Non-alcoholic fatty hepatitis and steatohepatitis Not yet recruiting Kyoto University Hospital, Kyoto, Japan UMIN000007015
Recurrent or advanced non-small-cell lung cancer Enrolling by invitation Keio University Hospital, Tokyo, Japan UMIN000006892
Hypertensive heart disease Completed Kyoto Medical Center, Kyoto, Japan UMIN000006227
Phase II UMIN000003851
UMIN000002098
Gemcitabine-resistant pancreatic cancer Completed Kyoto University Hospital, Kyoto, Japan UMIN000001386
Phase I, II (12)
Malignant tumor Completed M D Anderson Cancer Center, Houston, TX, United States NCT01201694
Phase I
Mild cognitive impairment Active, not recruiting UCLA Longevity Center, NCT01383161
Phase II Los Angeles, California, United State
Schizophrenia Recruiting VA Greater Los Angeles Healthcare System, Los Angeles, NCT02104752
Phase I, II California, United State

nervous system and renin-angiotensin system, and lead the 2.3. Type 2 diabetes
progression of heart failure. Established pharmacological agents
such as angiotensin II receptor blockers (ARBs), angiotensin- Type 2 diabetes is caused by disorder of the lifestyle such as
converting enzyme (ACE) inhibitors, and b-blockers target extra- aging, obesity, and lack of exercise and increasing in industrialized
cellular molecules and receptors on the cell membrane. They have countries. In Japan, the total number of patients with diabetes
proven effective thus far, but the 5-year survival rate for patients mellitus and “pre-diabetes” reach 20.5 million [19]. Though its
with severe heart failure remains lower than 50%. It is required subjective symptoms are often poor, diabetes increases the risk of
that another pharmacological approach should be developed. cardiovascular events. The prompt and appropriate care and
Because intracellular signaling pathways that lead to the therapy are crucial to prevent the progression of diseases.
development of heart failure are complex and wide-ranging, Curcumin acts to improve pancreatic b-cell function, glucose
targeting common nuclear pathways might be more effective tolerance, and insulin resistance [20–22] and may be effective
target than targeting extracellular molecules and receptors. Our agent to prevent the development of type 2 diabetes. Chuengsa-
previous studies demonstrated that the transcriptional co- marn et al. conducted the clinical trial in pre-diabetics adminis-
activator, p300, and its histone acetyltransferase (HAT) activity tered 250 mg of curcuminoids or a placebo for 9 months [23]. The
play a key role in left ventricular remodeling and the develop- result showed that the 16.4% subjects developed diabetes in
ment of heart failure [13,14]. Based on these findings, the placebo group while curcuminoids treatment could not develop
inhibition of p300 HAT activity is expected as a therapeutic diabetes and had improved b-cell function and insulin resistance.
potency for heart failure. Balasubramanyam et al. reported that In the clinical trial to verify the effect of curcumin on vascular
curcumin is a p300-specific HAT inhibitor [15]. And then, we endothelial function in diabetics, oral administration of curcumin
demonstrated that curcumin prevented the development of heart for 8 weeks resulted in the improvement of vascular endothelial
failure using 2 rat models of chronic heart failure, hypertensive function and the reductions in oxidative stress and inflammatory
heart disease and myocardial infarction [16]. Furthermore, cytokines [24]. These effects of curcumin were comparable to the
combined therapy with enalapril, an ACE inhibitor, and curcumin treatment of atorvastatin. These findings indicate that curcumin
resulted in the additive therapeutic effect compared to a may prevent the onset of diabetes mellitus and decrease the risk of
monotherapy in rats with myocardial infarction [17]. Low dosage diabetes-associated events. At present, our clinical trial involving
of Theracurmin, one-hundredth of native curcumin, prevented use of Theracurmin to treat patients with impaired glucose
myocardial infarction-induced development of heart failure [18]. tolerance is ongoing (UMIN000007361).
These findings indicate that Theracurmin may be an attractive
and therapeutic agent for heart failure in clinical settings. A phase 2.4. Knee osteoarthritis
II clinical trial in patients with hypertension and left ventricular
hypertrophy showed that oral administration of Theracurmin Knee osteoarthritis is the most common form of arthritis and
twice a day in a total dose of 60 mg for 24 weeks resulted in leads the cause of chronic disability in older people. Yoshimura
significant improvement in E/E0 , an index of left ventricular et al. conducted a large-scale cohort study and reported that an
diastolic function. A dose-ranging study in patients with estimated 25.3 million people had arthritis of the knee in Japan.
hypertensive heart disease is ongoing. It is hoped that further Osteoarthritis of the knee is a mechanical abnormality involving
clinical studies on heart failure patients using Theracurmin are functional depression of the knee due primarily to aging, obesity,
conducted in the future, and curcumin could be useful agent for the induction of inflammation triggered by a reduction in knee
heart failure therapy targeting p300 HAT activity in the nucleus of cartilage and deformation of the menisci. Osteoarthritis of the
cardiomyocytes. knee also involves excessive pooling of synovial fluid and pain.

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Please cite this article in press as: Y. Sunagawa, et al., Clinical applications of curcumin, PharmaNutrition (2015), http://dx.doi.org/10.1016/j.
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