Cancer Letters 362 (2015) 814

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Cancer Letters
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / c a n l e t

Mini-review

Garcinol: Current status of its anti-oxidative, anti-inflammatory and

anti-cancer effects
Chaoqun Liu a,b, Paul Chi-Lui Ho b, Fang Cheng Wong a, Gautam Sethi c, Ling Zhi Wang a,c,*,
Boon Cher Goh a,c,d,**
a

Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599

Department of Pharmacy, National University of Singapore, Singapore 117543
c
Department of Pharmacology, National University Health System, Singapore 117597
d Department of Haematology-Oncology, National University Health System, Singapore 119228
b

A R T I C L E

I N F O

Article history:
Received 16 January 2015
Received in revised form 12 March 2015
Accepted 12 March 2015
Keywords:
Garcinia indica
Garcinol
Pharmacodynamics
Pharmacokinetics
Toxicology

A B S T R A C T

Garcinol is the main medicinal component of the dried fruit rind of Garcinia indica (G. indica), which has
traditionally been extensively used to treat gastric ailments and skin irritation. In vitro studies of garcinol
revealed its potential therapeutic effects, such as its anti-oxidative, anti-inflammatory and anti-cancer
properties. Similarly, in vivo studies in animal models also demonstrated the ecacy of garcinol for the
treatment of various inflammatory and cancerous conditions. Despite being well tolerated in preclinical studies, the toxicological profile of garcinol remains elusive. More importantly, systematic
pharmacokinetics (PK) studies of garcinol to establish an appropriate route of administration and its effective concentration range under physiological conditions have not yet been performed. PK studies play
an essential role in translating the preclinical findings of garcinol from cell line models and animal species
to humans, thereby facilitating dose selection, the characterization of the therapeutic index, identification of a metabolic pathway, and the determination of garcinols potency and tolerability. This paper reviews
the current studies of garcinol as a potential anti-oxidant, anti-inflammatory and anti-cancer agent and
highlights the importance of performing preclinical PK and toxicological studies on garcinol for its development pipeline.
2015 Elsevier Ireland Ltd. All rights reserved.

Introduction
Garcinia indica (G. indica, also known as kokum) is a small tropical evergreen tree that was first discovered in the Western Ghats
of India [1]. Natural compounds that have been isolated from the

Abbreviations: G. indica, Garcinia indica; PD, pharmacodynamics; PK, pharmacokinetics; ADME, absorption, distribution, metabolism and elimination; OH,
hydroxyl radical; ROS, reactive oxygen species; DPPH, 1,1-diphenyl-2-picrylhydrazyl;
NFB, nuclear factor-k B; iNOS, inducible nitric oxide synthase; NO, nitric oxide;
ERK1/2, extracellular signal-regulated kinase; MAPK, P38/Mitogen-activated protein
kinase; cPLA2, cytosolic phospholipases A2; PGs, prostaglandins; COX-2,
cyclooxygenase-2; 5-LOX, 5-Lipoxygenase; LTs, leukotrienes; PI3K, phosphoinositide
3-kinase; Akt, serine/threonine-specific protein kinase; CDKIs, cyclin-dependent
kinases inhibitors; HAT, histone acetyltransferase; p300/PCAF, P300/CBP-associated
factor; miRNAs, micro RNAs; MMPs, metalloproteinases; VEGFs, vascular endothelial growth factors; ACF, aberrant crypt foci; Cmax, maximum concentration; Tmax,
time to maximum concentration; t1/2, elimination half-life; HCC, hepatocarcinoma;
HNSCC, head and neck squamous cell carcinoma).
* Corresponding author. Tel.: +6565168925; fax: +6568739664.
E-mail addresses: csiwl@nus.edu.sg (L.Z. Wang).
** Corresponding author. Tel.: +6565168925; fax: +6568739664.
E-mail addresses: phcgbc@nus.edu.sg (B.C. Goh).
http://dx.doi.org/10.1016/j.canlet.2015.03.019
0304-3835/ 2015 Elsevier Ireland Ltd. All rights reserved.

rind of the fruit of garcinol include hydroxycitric acid, hydroxycitric

acid lactone, citric acid, oxalic acid, malic acid, ascorbic acid, polyphenols and anthocyanin [2,3]. The development of various analytical
techniques has recently facilitated the extraction of garcinol, a
polyisoprenylated benzophenone derivative, from the rinds [4]. The
extraction of pure garcinol from G. indica enables its use in in vitro
experiments to delineate its potential therapeutic indications [5].
By subjecting multiple cell lines to garcinol, molecular targets were
captured and mechanistic explanations for its pharmacological
actions could be inferred. The effects of garcinol observed in animal
studies provide evidence to justify or nullify its potential as a therapeutic agent. According to the drug development pipeline, garcinol
is now at the stage of preclinical development, at which point pharmacodynamics (PD), toxicology and pharmacokinetic (PK) studies
should be performed before the drug can proceed to the clinical
testing phase. However, the absence of information on its absorption, distribution, metabolism and elimination (ADME) as well as
the absence of toxicity profiles impedes the use of garcinol in clinical studies. This current research gap in the toxicological and PK
studies warrants further investigations to rationalize and accelerate the development of garcinol as a drug candidate for clinical trials.
The objectives of the present review are to summarize the data from

C. Liu et al./Cancer Letters 362 (2015) 814

in vitro and in vivo studies of garcinol as a potential therapeutic agent

and highlight the importance of performing preclinical toxicological and PK studies that could be the basis for future ecacy and
safety investigations.
Uses of G. indica
Many uses have been reported for G. indica since historical times.
In the culinary field, the dried fruit rind can be used as a garnish
to impart an acidic flavor to curries, while extracts from the fruit
can be ground, steeped in syrup and consumed as a refreshing beverage [6]. In addition to the fruit rind, the oil-rich seed of G. indica,
known as kokum butter, have also been used in the cosmetics and
confectionery industries [6]. In the Indian traditional system of medicine, Ayurveda, G. indica has long been established as a multipurpose herbal medicine in treating ailments. The leaves and fruits
are ground and administered to patients to treat indigestion. The
rinds are used for inflammatory conditions, and the fruit extract is
purported to be a natural antacid used to relieve gastric reflux [7].
Chemical structure and properties of garcinol
Garcinol (molecular mass: 602.39) was first extracted in 1981
from the dried fruit rind of G. indica using hexane [4]. It was precipitated as yellow needle-like crystals with a concentration of 1.5%
in hexane [4]. A physical analysis of garcinol identified a melting
point of 122 C and optical rotation of [] 22D 143 (1% chloroform). The molecular formula, C38H50O6, was suggested to have
structural similarities to xanthochymol (molecular mass: 602.82 and
[] 22D +141 (1% chloroform), a prenylated chalconoid previously
discovered from Garcinia xanthochymus [4]. However, based on its
optical rotation sign, garcinol may be more closely associated with
cambogin (molecular mass: 602.27 and [] 22D 132.9 (1% chloroform) [8,9], an isoprenylated benzophenone derivative isolated
from G. cambogia and characterized by Venkatsuamy et al. [4,5]. The
highly similar physical properties between cambogin and garcinol
spurred researchers to structurally distinguish the two compounds. The structural analysis confirmed the structure of garcinol
as an isoprenylated benzophenone with an enolizable 1,3-diketone
group conjugated to a 3,4-dihydroxybenzoyl moiety and two unsaturated carbonyl groups. Hence, the molecular masses of garcinol
and cambogin are the same, but their chemical structures differ
[4,5,10], as depicted in Fig. 1, which also shows the structure of
xanthochymol.

Current studies on PD actions

Numerous in vitro cell-based and in vivo animal model studies
have been carried out to elucidate the mechanisms of action of
garcinol. A summary of these studies will be given later.
In vitro studies on anti-oxidant properties
Given the growing interest in the potential health benefits of consuming dietary antioxidants, numerous studies have examined the
use of traditional herbs for the treatment of human disease [11,12].
In general, phytochemicals may act as antioxidants by either eradicating free radicals or inhibiting pro-oxidants. They mitigate the
interaction between reactive oxygen species (ROS) with deoxyribonucleic acid (DNA) bases, lipids, proteins, and other biomolecules
[13] and hence retard the onset and progression of various diseases, including neurodegenerative diseases and cancer [1416]. The
free radical, superoxide anion (O2) scavenging activity of garcinol
was shown to be as potent as that of gallic acid and stronger than
that of (+)-catechin [16]. Furthermore, garcinol scavenges the free
radical DPPH (1,1-diphenyl-2-picrylhydrazyl) with three times greater
potency than DL--tocopherol, a lipid-soluble natural anti-oxidant
[15]. In addition, garcinol was shown to be able to quench OH at
an IC50 of 0.32 M [16], thus preventing OH-induced DNA damage.
Similarly, 100 M peroxynitrite was quenched with 0.2 M garcinol
[17]. The free radical quenching activities displayed by garcinol suggest
that it may play a role in the protection against neurodegenerative
diseases that are associated with a surplus of ROS [18].
Despite promising in vitro results, the determination of garcinols
in vivo concentration is crucial because the anti-oxidative effect displayed by garcinol was demonstrated using cell-free assays. Although
garcinol was found to be more potent than DL--tocopherol in an
aqueous ethanol solution, it displayed poorer anti-oxidative properties than tocopherol when tested in a micellar system [15].
Therefore, the cellular uptake of garcinol through the amphiphilic
phospholipid bilayer that surrounds the cell requires investigation. The observed differences in the anti-oxidant ecacy may be
reconciled by performing a PK analysis of garcinol in animal studies
to account for its tissue uptake and consequently, its physiological
anti-oxidative significance.
In vitro studies on anti-inflammatory effects
The anti-inflammatory effects of certain herbs have been studied
in detail; the most prominent example is aspirin, which is derived

Fig. 1. A: Chemical structure of garcinol extracted from Garcinia indica. B: Structure of cambogin extracted from Garcinia cambogia. C: Structure of xanthochymol extracted
from Garcinia xanthochymus [10].

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C. Liu et al./Cancer Letters 362 (2015) 814

from the bark of the willow tree and one of the most important antiinflammatory drugs in clinical use. Current studies have shown that
garcinol exhibits an anti-inflammatory effect by interfering with
various inflammatory cascades. First, garcinol was found to affect
the nuclear factor NFkB signaling pathway. A study showed that
garcinol suppressed inducible nitric oxide synthase (iNOS) synthesis most effectively at 5 M by inhibiting NFkB activation, leading
to reduced nitric oxide (NO) generation [19], a known physiologic
free radical believed to be elevated in neurodegenerative diseases,
diabetes and rheumatoid arthritis [20]. Moreover, extracellular signalregulated kinase 1/2 (ERK1/2), a protein kinase of the P38/Mitogenactivated protein kinase (MAPK) family, can also mediate the
inflammation process [21]. Under normal physiological conditions, phosphorylated ERK1/2 activates cytosolic phospholipases A2
(cPLA2) and leads to the formation of COX-2, an enzyme that produces prostaglandins (PGs) [22]. In lipopolysaccharide-activated
macrophages, 1 M garcinol inhibited the production of COX-2 and
PGs. The proposed mechanism of action involves interference with
the LPS-mediated phosphorylation of ERK1/2, which reduces the
level of COX-2 products in LPS-stimulated cells [23]. The third antiinflammatory pathway of garcinol was found to be related to
5-lipoxygenase (5-LOX) activation, which is responsible for producing inflammatory molecules, such as leukotrienes (LTs) [22].
Garcinol inhibited the activation of 5-LOX at IC50 values of 0.1 M
in in vitro cell-free assays and 1.9 M in cellular studies [24]. This
difference could be due to the lower activity of garcinol on intracellular 5-LOX [24]. Furthermore, garcinol inhibited isolated COX-1
activation with an IC50 of 12 M, but this effect was not observed
in human whole blood [24]. The loss of potency in human whole
blood could be due to the strong albumin-binding of garcinol [24].

Together, these results suggest the urgent need to determine the

concentration of garcinol attainable in in vivo systems.
Chronic inflammation has been shown to be involved in the
pathogenesis of various cancer models [25]. The elucidation of
garcinols anti-inflammatory action has in turn inspired studies of
inflammation-related cancers, which will be discussed in detail in
Section Anti-inflammation.
Anti-cancer activities
Various PD studies of garcinol and different cancer types have
been conducted, and the results are summarized in Table 1. In addition to reducing inflammation, garcinol displayed in vitro and in
vivo anti-cancer effects in various cancers. The mechanisms that underlie garcinols anti-cancer effect include the induction of apoptosis,
inhibition of cell growth and proliferation, stimulation of cell cycle
arrest and prevention of cancer cell metastasis.
In vitro studies
Anti-inflammation. Garcinols anti-cancer effects were tested in
cancer cell models whose carcinogenesis is known to be affected
by inflammation. The pathways and major targets of garcinol in the
inflammatory cascade are exemplified in Fig. 2. The up-regulation
of COX-2 expression has been observed in lung and colon cancers,
while increases in 5-LOX, COX-2 and PGE2 are observed in early pancreatic cancer [4850]. In human lung carcinoma cell lines and
human pancreatic BxPC-3 cell lines, garcinol inhibited COX-2 expression and the downstream prostanoid synthesis at IC50 values
of 10 M and 20 M, respectively [24,41], resulting in reduced tumorigenic cell proliferation.

Table 1
Summary of results from in vitro and in vivo studies to investigate mechanisms of action of garcinol in different cancer types.
Cancer type

Study type

Mechanisms

In vitro concentration(s)/M in vivo dose/mg/kg

Reference

Breast
Breast

In vitro
In vitro

Apoptosis
Apoptosis and reduced angiogenesis

[26]
[27]

Breast
Breast
Colon

In vivo (p.o.)
In vitro
In vitro
In vitro

Reduced cell proliferation

HAT inhibition
Cell cycle arrest
Apoptosis

Lung

In vitro
In vivo (p.o.)
In vivo (p.o.)
In vitro
In vitro
In vitro
In vitro
In vitro
In vitro
In vivo (i.p.)
In vitro

Apoptosis
Anti-inflammatory
Anti-inflammatory
Apoptosis
Apoptosis
Apoptosis
Apoptosis
Apoptosis
Apoptosis and cell cycle arrest
Apoptosis
Cell cycle arrest

Lung
Pancreatic

In vitro
In vitro

HAT inhibition
Apoptosis and reduced angiogenesis

Pancreatic

In vitro

Apoptosis, cell cycle arrest and reduced angiogenesis

Pancreatic

In vitro

Apoptosis and gene modulation

Breast, prostate pancreatic

In vitro
In vivo (p.o.)
In vivo (topical)
In vivo (p.o.)
In vitro
In vivo (i.p.)

Cell cycle arrest and gene modulation

Cell cycle arrest and gene modulation
Anti-inflammatory
Cell cycle arrest and anti-inflammatory
Apoptosis, cell cycle arrest, and reduced angiogenesis
Reduced cell proliferation

MDA-MB-231: 35 (IC50)
MDA-MB-231: 10
MCF-7: 20 (IC50)
Mice: 285.71
MCF7: 10
MDA-MB-231: 20
HT-29: 11.4 (IC50)
HCT-116: 12 (IC50)
HT-29: 20
Mice: 500 ppma
Rat: 6.53
HCT116: 15
U937, and K562: 20 (IC50)
HL-60: 9.42 (IC50)
HL-60: 16 (IC50)
Hep3B: 20 (IC50)
C3A: 25
Mice: 1
H460: 7.5 (IC50)
H1299: 7.5 (IC50)
A549: 12 (IC50)
BxPC-3: 20 (IC50)
Panc-1: 10 (IC50)
BxPC-3: 15 (IC50)
Panc-1: 7 (IC50)
BxPC-3: 5
Panc-1: 5
MDA-MB-231: 10
Mice: 285.71
Hamster: 0.5 mM
Rat: 26.05
CAL27 and UMSCC1: 10
Mice: 1

Colon
Colon
Colon
Colon
Leukaemia
Leukaemia
Leukaemia
Liver
Liver

Oral
Tongue
Head and neck

[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[10]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]

IC50 concentrations are given if reported in the respective paper. When not reported, the lowest concentration at which garcinol demonstrated observed activities in the
respective cell lines are reported.
a
Oral dose given to each animal could not be determined due to insucient information on dietary intake of garcinol.
i.p.: intraperitoneal injection; p.o.: oral gavage.

C. Liu et al./Cancer Letters 362 (2015) 814

11

Fig. 2. Pharmacodynamic effects and mechanisms of action of garcinol reported in in vitro and in vivo studies.

Induction of apoptosis. Garcinol interferes with multiple signaling

cascades to induce apoptosis in several cancer cell lines. The known
mechanisms of action of garcinol in apoptosis involve the
inactivation of the signal transducer and activator of transcription
3 (STAT-3), NFB and phosphoinositide 3-kinase (PI3K)/serine/
threonine-specific protein kinase (Akt) signaling pathways
[31,38,44]. This inactivation increases the expression of pro-apoptotic
gene products (Bax, Bak) over pro-survival gene products (Bcl-xL,
Bcl-2, Mcl-1, survivin), the release of cytochrome c into the cytosol,
the activation of caspase-3, and thus, the induction of apoptosis [51].
In vitro studies of human liver cancer cells showed that garcinol
inhibited the phosphorylation and dimerization of STAT-3 in a
dose-dependent manner, thus interfering with the pSTAT-3 nuclear
translocation that mediates the transcription of STAT-3-responsive
genes, including Bcl-xL, Mcl-1 and survivin [38]. Furthermore, NFB,
a molecule constitutively active in pancreatic adenocarcinoma cells
[52], was effectively depleted by garcinol in a dose-dependent
manner, leading to cancer cell apoptosis [41]. Based on its ability
to down-regulate NF-B, garcinol has been studied in human breast
cancer cell lines that are known to demonstrate NF-kB activation
[53]. Garcinol was more potent against oestrogen-receptor positive
(MCF-7 cells) than triple-negative breast cancer cell lines (MDAMB-231 cells), with IC50 values of 20 M and 35 M, respectively
[26]. Garcinol also affects focal adhesion kinase, which utilizes the
Src, ERK and the PI3K/Akt axis to activate cell survival and
proliferation in colorectal carcinoma cells [31,34]. Garcinol was found
to induce apoptosis in the human colorectal cancer cell line HT-29
at a relatively low IC50 of 10 M [31,34].
Inhibition of cell cycle. Garcinol also exerts anti-cancer effects by inhibiting the cell cycle, which is dysregulated in many cancers. The
cyclin-dependent kinase inhibitors (CDKIs) p21Waf1/Cip1 and p27KIP1

target the key cell cycle checkpoint molecules CDKs, specifically the
CDK2 and CDK4/cyclin complex, to induce G1 cell cycle arrest and
inhibit cell division [54,55]. In p53-null H1299 lung cancer cells,
10 M garcinol was shown to cause cell cycle arrest at the G1 phase
by up-regulating p21Waf1/Cip1 gene expression [39]. Interestingly, p53
wild-type A549 cells treated with less than 4 M garcinol continued to divide, suggesting that garcinol may not be able to induce
cell cycle arrest in p53 wild-type cells or that the dose was insufficient to induce cell cycle arrest in this cell type [39]. A PK evaluation
of garcinol is critical to determine its effective dose for both in vitro
and/or in vivo studies.
Modulation of gene expression. Growing interest in histone
acetyltransferase (HAT) inhibitors as potential agents to treat cancer
has also led to anti-cancer studies of histone acetylation in response to garcinol [56]. Several members of the HAT family have
been implicated in hematological malignancies [57]. Specifically,
P300/CBP-associated factor (p300/PCAF) dysfunction in the HAT
family is associated with the onset of acute leukemia [58]. In vitro
studies showed that p300/PCAF is one of the molecular targets of
garcinol (IC50 7 M for p300 and IC50 5 M for PCAF) [8]. Recent functional studies of micro RNAs (miRNAs) revealed that the highly
conserved and non-protein-coding short RNA products may participate in carcinogenesis by acting as tumor suppressors or
oncogenes [59]. For instance, preclinical studies of breast cancer
tissues confirm the function of miRNA let-7 as a tumor suppressor gene [60]. In MDA-MB-231 and BT-549 breast cancer cells,
garcinol up-regulated the expression levels of let-7, further elucidating the mechanism by which it inhibits breast cancer [27].
Moreover, elevated oncogenic miRNA-21 levels are observed in
breast, colon and pancreatic cancers [6163]. Garcinol also downregulated the expression level of miRNA-21 in the human pancreatic

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C. Liu et al./Cancer Letters 362 (2015) 814

cancer cell lines BxPC-3 and Panc-1 [42]. Taken together, these novel
discoveries of garcinols ability to inhibit p300/PCAF and downregulate oncogenic miRNA make it an attractive agent to modulate
gene expression and affect downstream PD events in various cancer
types. Thus, these studies may serve as a motivation to study the
PK profile of garcinol in order to explore its effective tumor uptake
concentration in xenografted mouse models.
Reduction in tumor angiogenesis and metastasis. The role of matrix
metalloproteinases (MMPs) and vascular endothelial growth factors
(VEGFs) in promoting the metastatic potential of cancer cells is well
established in breast, pancreatic and colon cancer [64,65]. In
colorectal cancer, the expression levels of VEGF and MMP-7 strongly
correlate with metastatic potential [66]. Garcinol reduces the MMP-7
levels in HT-29 cells [45]. In addition to MMP-7, MMP-9 has recently been identified as a key regulator of angiogenesis in the
metastatic pancreatic islets of transgenic mice [57]. The ability of
garcinol to reduce MMP-9 levels in the pancreatic cancer cell models
BxPC-3 and Panc-1 indicates the potential effect of garcinol on the
function of MMPs [43].
Overall, the concentrations used in different cell culture assays
varied dramatically, from 5 M in pancreatic cancer cells to 35 M
in breast cancer cells [26,43]. Despite these differences, micromolar concentrations of garcinol were effective in almost all studies
conducted thus far [67]. However, this phenomenon is common for
most natural products, which require higher consumption in order
to observe beneficial effects [68]. Based on the reported IC50 values,
garcinol appears to be more effective in inducing apoptosis and cell
cycle arrest in pancreatic cancer, lung cancer and leukaemia cells
than in colon, liver and breast cancer cells. Thus, the use of garcinol
for the former malignancies should be explored further.
In vivo studies
Current in vivo anti-cancer studies of garcinol focused on its
chemoprevention and chemotherapeutic actions. First, the
chemopreventive effect of garcinol against inflammation-induced
cancer was explored in 4 in vivo studies, which examined varied
doses, administration frequencies and administration routes for
garcinol. The dietary administration of 6.53 mg/kg of garcinol to a
rat with inflammation-induced colonic aberrant crypt foci (ACF) (precursor lesions for colon carcinoma) for 5 weeks was found to reduce
the incidence of colon carcinogenesis by 40.2%. This effect could be
attributed to an increase in glutathione S-transferase and quinone
reductase detoxifying enzymes observed in the rat livers [33]. In addition, 22 weeks of dietary intake equivalent to 26.05 mg/kg garcinol
for a rat resulted in COX-2 suppression and cell cycle arrest at the
G1 phase. These effects decreased the incidence of inflammationinduced neoplastic tongue carcinoma by 44.4% [46]. In the third
study, a thrice weekly topical application of 0.5 mM garcinol for 25
weeks to the chemically treated cheeks of hamsters decreased the
occurrence of inflammation-induced oral carcinogenesis by 19.0%,
likely by down-regulating the 5-LOX enzyme and LTB4 [45]. Another
study showed a 44.4% reduction of inflammation-induced colorectal
tumor formation after feeding mice food supplemented with
500 ppm garcinol for 24 weeks. Garcinol was shown to interrupt
the MAPK/ERK, Pl3K/Akt and Wnt pathways in this study [32]. These
results reflect the beneficial effect of garcinol against inflammationinduced colon cancer.
Other in vivo evidence suggested that garcinol could reduce tumor
growth and metastasis. The oral administration of 285.71 mg/kg
garcinol to mice bearing MDA-MB-231 breast cancer xenografts at
a dosing frequency of 5 days per week for 4 weeks reduced breast
tumor weight by 42.9%. Garcinol was shown to interrupt the STAT-3
signaling cascade, which was also demonstrated in vitro by the same
group [26,44]. Moreover, the group used the same mouse model and
garcinol dose (285.71 mg/kg) but increased the frequency to 6 days

per week for 4 weeks. This regiment significantly decreased the level
of the tumor proliferation biomarker Ki-67, which indicated a reduction in breast tumor proliferation in garcinol-treated mice [44].
Furthermore, the relative level of miRNA let-7 was also found to be
1.11 times higher in the garcinol-treated group compared with the
control [27]. These studies further support the in vitro experiments conducted with MDA-MB-231 cells described in Section
Modulation of gene expression, which indicated that garcinol could
inhibit breast tumor proliferation. A 1 mg/kg dose of garcinol administered intraperitoneally (i.p.) 5 days per week for 3 weeks to
mice carrying hepatocarcinoma (HCC) xenografts reduced the liver
tumor volume by 200 mm3, at least in part by interrupting STAT-3
phosphorylation, reducing the level of the pro-survival protein Bcl-2
and activating cleaved-caspase-3 [38]. In another head and neck
squamous cell carcinoma (HNSCC) xenograft mouse model, 1 mg/kg
of garcinol administered i.p. 5 days per week for 4 weeks reduced
the tumor volume by 100 mm3 [47]. Garcinol also suppressed STAT-3
phosphorylation in mice in this study [47]. These results suggest
that garcinol inhibits cancers, such as HCC and HNSCC, via a STAT3-mediated pathway [69].
However, the lack of PK studies may call the reliability of data
collected from both in vitro and in vivo studies into question. Therefore, the effective concentration range of garcinol needs to be
determined with a PK analysis to complement existing ecacy
studies of garcinol against different types of cancer.

Importance of PK and toxicological studies

Although accumulating evidence from in vitro and in vivo studies
indicated that garcinol exerts multiple pharmacological effects, such
as anti-oxidant, anti-inflammatory and anti-cancer effects, the development of garcinol into a drug candidate has progressed slowly.
PK and toxicological studies are needed to accelerate this process
and bridge the current research gap between in vitro and in vivo
findings. Interpretation based only on in vitro data has failed to consider the PK properties of garcinol, the presence of active metabolites
and the safety of dosage ranges to be employed in in vivo studies.
These considerations are important for garcinol because many natural
products and their derivatives are pro-drugs that must undergo metabolic conversion either by the intestinal microflora or mammalian
phase I and/or II metabolism before becoming an active pharmacological agent (metabolite) [70]. For instance, CPT-11 (Irinotecan),
a derivative of camptothecin, is a prodrug of SN-38, which is approximately 100- to 1000-fold more cytotoxic than the parent drug.
CPT-11 has shown a broad spectrum of clinical antitumor activities against many cancer types, including colorectal, lung, cervical,
and ovarian cancers [71].
Oral bioavailability is another key factor to ensure an effective
drug concentration is physiologically achievable. PK studies can
indicate the bioavailability of a drug, which can in turn help to
optimize the administration route and schedule to achieve
therapeutic ecacy [72]. Although curcumin, a dietary polyphenol
with diverse pharmacological effects, has been demonstrated as
substantially ecacious and safe, its poor bioavailability (1% in rats)
[73] restricts its clinical application. Therefore, extensive formulation
strategies have been employed to improve its bioavailability [74].
Garcinol, like curcumin, is a natural compound that has been
extensively studied and suggested to have beneficial therapeutic
effects [28]. Thus, lessons must be learned from previous examples
in order to progress studies of garcinol to the clinical phase. PK
studies performed with robust and sensitive bio-analytical methods
allow us to identify ADME constraints and better understand the
bioavailability and other important PK parameters of garcinol, such
as the Cmax (maximum peak concentration), t1/2 (half-life), clearance,
volume of distribution and linearity [75].

C. Liu et al./Cancer Letters 362 (2015) 814

While PK is an integral part of the drug development, the

toxicological aspects of garcinol are equally important because
ecacy and safety are not mutually exclusive [76]. A previous study
showed that feeding 285.71 mg/kg garcinol did not result in systemic
toxicity and mortality in a mouse model inflammation-induced
colon cancer [27,44]. Despite the lack of apparent toxicity
demonstrated in animal studies, the systemic exposure with
repeated doses of garcinol should be thoroughly investigated to
identify the maximum tolerated dose (MTD) and non-observed
adverse effect limit. The lack of toxicological studies of garcinol has
precluded the identification of the toxicity profiles of garcinol as a
therapeutic agent. Nevertheless, the development of a natural
compound into a clinically employed therapy is not an unrealistic
expectation. For example, galantamine, an alkaloid extracted from
Galanthus nivalis, is now being used as the first-line clinical therapy
for Alzheimers disease. It has been shown to have favorable PK
features, including linear elimination kinetics, an appropriate
half-life and high oral bioavailability, in addition to its desirable
ecacy and safety profile [77]. Overall, PK and toxicological studies
play a vital role in elucidating the ecacy and safety of garcinol and
translating the research findings from the preclinical to clinical stage.
Without this information, the significance of current preclinical
findings is elusive and can be misleading.

Conclusion and future perspectives

Advances in analytical sciences have accelerated the commercialization of purified garcinol, which has greatly improved the
evaluation of the various properties of garcinol, especially its antioxidant, anti-inflammatory and anti-cancer activities. The antioxidant nature of garcinol largely depends on its polyphenolic
structure, while its anti-inflammatory effects could be attributed
to its inhibition of COX-2, 5-LOX and iNOS synthesis. In addition,
the anti-cancer activities of garcinol involve anti-inflammation,
the induction of apoptosis and cell cycle arrest, the inhibition of
angiogenesis and the modulation of gene expression. However,
the development of garcinol has lacked systematic PK evaluation
to determine the effects of the concentration on its pharmacodynamics characteristics. To the best of our knowledge, a sensitive
bio-analytical method to determine the effective plasma and intracellular concentrations of garcinol is currently lacking, which is
the main obstacle to understanding garcinols biologically relevant concentrations in animal models. The PK parameters of garcinol
must be evaluated in order to precisely define its PK linearity,
effective dose, route of administration, administration schedule,
and ADME. Because the extracts derived from G. indica have been
used extensively for centuries, the safety of these products is
generally not an issue of concern. However, a systematic toxicological study of purified garcinol has not yet been conducted.
Clearly, further examining the pharmacological profile of garcinol
can help to reconcile the results gathered from in vitro and in vivo
studies in order to elucidate the benefit of garcinol for the treatment of specific diseases and ultimately advance the use of garcinol
from empirical studies to evidence-based, clinically applicable
pharmacotherapy.

Acknowledgements
The study was sponsored by the National Research Foundation
of Singapore (Experimental Therapeutics Program/R-713-001-011271) and the National Medical Research Council of Singapore
(NMRC/CSA/021/2010). The authors thank the NUHS Medical
Publications Support Unit, Singapore, for assistance in the
preparation of this manuscript.

13

Conflict of interest statement

None declared.
References
[1] H.D. Ramachandran, Plant profile, phytochemistry and pharmacology of garcinia
indica: a review, Int. J. Pharm. Sci. Rev. Res. 27 (2) (2014) 376381.
[2] G.K. Jayaprakasha, K.K. Sakariah, Determination of organic acids in leaves and
rinds of Garcinia indica (Desr.) by LC, J. Pharm. Biomed. Anal. 28 (2) (2002)
379384.
[3] C. Lakshmi, K. Kumar, T. Dennis, T.S.S.P.N.S. Kumar, Antibacterial activity of
polyphenols of Garcinia indica, Indian J. Pharm. Sci. 73 (4) (2011) 470473.
[4] N. Krishnamurthy, Y.S. Lewis, B. Ravindranath, On the structures of garcinol,
isogarcinol and camboginol, Tetrahedron Lett. 22 (8) (1981) 793796.
[5] A.V. Rama Rao, G. Venkatswamy, D. Pendse, Camboginol and cambogin,
Tetrahedron Lett. 21 (20) (1980) 19751978.
[6] S. Padhye, A. Ahmad, N. Oswal, F.H. Sarkar, Emerging role of Garcinol, the
antioxidant chalcone from Garcinia indica Choisy and its synthetic analogs, J.
Hematol. Oncol. 2 (2009) 38.
[7] M.S. Baliga, H.P. Bhat, R.J. Pai, R. Boloor, P.L. Palatty, The chemistry and medicinal
uses of the underutilized Indian fruit tree Garcinia indica Choisy (kokum): a
review, Food Res. Intern. 44 (7) (2011) 17901799.
[8] K. Balasubramanyam, M. Altaf, R.A. Varier, V. Swaminathan, A. Ravindran, P.P.
Sadhale, et al., Polyisoprenylated benzophenone, garcinol, a natural histone
acetyltransferase inhibitor, represses chromatin transcription and alters global
gene expression, J. Biol. Chem. 279 (32) (2004) 3371633726.
[9] J.B. Bharate, R.A. Vishwakarma, S.B. Bharate, M. Kushwaha, A.P. Gupta,
Quantification of anticancer polyisoprenylated benzophenones garcinol and
isogarcinol using multiple reaction monitoring Lc-Esi-Ms-Ms in ultra-sound
assisted extracts of Garcinia indica fruits, J. Liq. Chromatogr. Relat. Technol.
131231090727009 (2013).
[10] S. Sang, C.-H. Liao, M.-H. Pan, R.T. Rosen, S.-Y. Lin-Shiau, J.-K. Lin, et al., Chemical
studies on antioxidant mechanism of garcinol: analysis of radical reaction
products of garcinol with peroxyl radicals and their antitumor activities,
Tetrahedron 58 (51) (2002) 1009510102.
[11] K.B. Pandey, S.I. Rizvi, Plant polyphenols as dietary antioxidants in human health
and disease, Oxid. Med. Cell. Longev. 2 (5) (2009) 270278.
[12] A. Scalbert, I.T. Johnson, M. Saltmarsh, Polyphenols: antioxidants and beyond,
Am. J. Clin. Nutr. 81 (1) (2005) 215S217S.
[13] M.S. Cooke, M.D. Evans, M. Dizdaroglu, J. Lunec, Oxidative DNA damage:
mechanisms, mutation, and disease, FASEB J. 17 (10) (2003) 11951214.
[14] W. Drge, Free radicals in the physiological control of cell function, Physiol. Rev.
82 (1) (2002) 4795.
[15] F. Yamaguchi, T. Ariga, Y. Yoshimura, H. Nakazawa, Antioxidative and antiglycation activity of garcinol from garcinia indica fruit rind, J. Agric. Food Chem.
48 (2) (2000) 180185.
[16] F. Yamaguchi, M. Saito, T. Ariga, Y. Yoshimura, H. Nakazawa, Free radical
scavenging activity and antiulcer activity of garcinol from garcinia indica fruit
rind, J. Agric. Food Chem. 48 (6) (2000) 23202325.
[17] J. Kolodziejczyk, M. Masullo, B. Olas, S. Piacente, B. Wachowicz, Effects of garcinol
and guttiferone K isolated from Garcinia cambogia on oxidative/nitrative
modifications in blood platelets and plasma, Platelets 20 (7) (2009) 487
492.
[18] V. Calabrese, D. Boyd-Kimball, G. Scapagnini, D.A. Butterfield, Nitric oxide and
cellular stress response in brain aging and neurodegenerative disorders: the
role of vitagenes, In Vivo 18 (3) (2004) 245268.
[19] C.H. Liao, S. Sang, Y.C. Liang, C.T. Ho, J.K. Lin, Suppression of inducible nitric
oxide synthase and cyclooxygenase-2 in downregulating nuclear factor-kappa
B pathway by Garcinol, Mol. Carcinog. 41 (3) (2004) 140149.
[20] V. Cattell, A. Jansen, Inducible nitric oxide synthase in inflammation, Histochem.
J. 27 (10) (1995) 777784.
[21] T. Zarubin, J. Han, Activation and signaling of the p38 MAP kinase pathway,
Cell Res. 15 (1) (2005) 1118.
[22] S.Y. Kim, T.-B. Kim, K.-A. Moon, T.J. Kim, D. Shin, Y.S. Cho, et al., Regulation of
pro-inflammatory responses by lipoxygenases via intracellular reactive oxygen
species in vitro and in vivo, Exp. Mol. Med. 40 (2008) 461476.
[23] J. Hong, S. Sang, H.J. Park, S.J. Kwon, N. Suh, M.T. Huang, et al., Modulation of
arachidonic acid metabolism and nitric oxide synthesis by garcinol and its
derivatives, Carcinogenesis 27 (2) (2006) 278286.
[24] A. Koeberle, H. Northoff, O. Werz, Identification of 5-lipoxygenase and
microsomal prostaglandin E2 synthase-1 as functional targets of the antiinflammatory and anti-carcinogenic garcinol, Biochem. Pharmacol. 77 (9) (2009)
15131521.
[25] S. Rakoff-Nahoum, Why cancer and inflammation?, Yale J. Biol. Med. 79 (34)
(2006) 123130.
[26] A. Ahmad, Z. Wang, R. Ali, M.Y. Maitah, D. Kong, S. Banerjee, et al., Apoptosisinducing effect of garcinol is mediated by NF-kappaB signaling in breast cancer
cells, J. Cell. Biochem. 109 (6) (2010) 11341141.
[27] A. Ahmad, S.H. Sarkar, B. Bitar, S. Ali, A. Aboukameel, S. Sethi, et al., Garcinol
regulates EMT and wnt signaling pathways in vitro and in vivo, leading to
anticancer activity against breast cancer cells, Mol. Cancer Ther. 11 (10) (2012)
21932201.

14

C. Liu et al./Cancer Letters 362 (2015) 814

[28] H.M. Collins, M.K. Abdelghany, M. Messmer, B. Yue, S.E. Deeves, K.B. Kindle,
et al., Differential effects of garcinol and curcumin on histone and p53
modifications in tumour cells, BMC Cancer 13 (2013) 37.
[29] C.S. Chen, C.H. Lee, C.D. Hsieh, C.T. Ho, M.H. Pan, C.S. Huang, et al., Nicotineinduced human breast cancer cell proliferation attenuated by garcinol through
down-regulation of the nicotinic receptor and cyclin D3 proteins, Breast Cancer
Res. Treat. 125 (1) (2011) 7387.
[30] J. Hong, S.J. Kwon, S. Sang, J. Ju, J.N. Zhou, C.T. Ho, et al., Effects of garcinol and
its derivatives on intestinal cell growth: inhibitory effects and autoxidationdependent growth-stimulatory effects, Free Rad. Biol. Med. 42 (8) (2007)
12111221.
[31] C.H. Liao, S. Sang, C.T. Ho, J.K. Lin, Garcinol modulates tyrosine phosphorylation
of FAK and subsequently induces apoptosis through down-regulation of Src,
ERK, and Akt survival signaling in human colon cancer cells, J. Cell. Biochem.
96 (1) (2005) 155169.
[32] M.-L. Tsai, Y.-S. Chiou, L.-Y. Chiou, C.-T. Ho, M.-H. Pan, Garcinol suppresses
inflammation-associated colon carcinogenesis in mice, Mol. Nutr. Food Res.
(2014) 16134133 Electronic.
[33] T. Tanaka, H. Kohno, R. Shimada, S. Kagami, F. Yamaguchi, S. Kataoka, et al.,
Prevention of colonic aberrant crypt foci by dietary feeding of garcinol in male
F344 rats, Carcinogenesis 21 (6) (2000) 11831189.
[34] S. Prasad, J. Ravindran, B. Sung, M.K. Pandey, B.B. Aggarwal, Garcinol potentiates
TRAIL-induced apoptosis through modulation of death receptors and
antiapoptotic proteins, Mol. Cancer Ther. 9 (4) (2010) 856868.
[35] K. Matsumoto, Y. Akao, E. Kobayashi, T. Ito, K. Ohguchi, T. Tanaka, et al., Cytotoxic
benzophenone derivatives from garcinia species display a strong apoptosisinducing effect against human leukemia cell lines, Biol. Pharm. Bull. 26 (4)
(2003) 569571.
[36] M.-H. Pan, W.-L. Chang, S.-Y. Lin-Shiau, C.-T. Ho, J.-K. Lin, Induction of apoptosis
by garcinol and curcumin through cytochrome c release and activation of
caspases in human leukemia HL-60 cells, J. Agric. Food Chem. 49 (3) (2001)
14641474.
[37] A.C. Cheng, M.L. Tsai, C.M. Liu, M.F. Lee, K. Nagabhushanam, C.T. Ho, et al.,
Garcinol inhibits cell growth in hepatocellular carcinoma Hep3B cells through
induction of ROS-dependent apoptosis, Food Funct. 1 (3) (2010) 301307.
[38] G. Sethi, S. Chatterjee, P. Rajendran, F. Li, M.K. Shanmugam, K.F. Wong, et al.,
Inhibition of STAT3 dimerization and acetylation by garcinol suppresses the
growth of human hepatocellular carcinoma in vitro and in vivo, Mol. Cancer
13 (2014) 66.
[39] S.Y. Yu, C.H. Liao, M.H. Chien, T.Y. Tsai, J.K. Lin, M.S. Weng, Induction of
p21(Waf1/Cip1) by garcinol via downregulation of p38-MAPK signaling in
p53-independent H1299 lung cancer, J. Agric. Food Chem. 62 (9) (2014)
20852095.
[40] T. Oike, H. Ogiwara, K. Torikai, T. Nakano, J. Yokota, T. Kohno, Garcinol, a histone
acetyltransferase inhibitor, radiosensitizes cancer cells by inhibiting nonhomologous end joining, Int. J. Radiat. Oncol. Biol. Phys. 84 (3) (2012) 815821.
[41] M.A. Parasramka, S.V. Gupta, Garcinol inhibits cell proliferation and promotes
apoptosis in pancreatic adenocarcinoma cells, Nutr. Cancer 63 (3) (2011)
456465.
[42] M.A. Parasramka, S.V. Gupta, Synergistic effect of garcinol and curcumin on
antiproliferative and apoptotic activity in pancreatic cancer cells, J. Oncol. 2012
(2012) 709739.
[43] M.A. Parasramka, S. Ali, S. Banerjee, T. Deryavoush, F.H. Sarkar, S. Gupta, Garcinol
sensitizes human pancreatic adenocarcinoma cells to gemcitabine in association
with microRNA signatures, Mol. Nutr. Food Res. 57 (2) (2013) 235248.
[44] A. Ahmad, S.H. Sarkar, A. Aboukameel, S. Ali, B. Biersack, S. Seibt, et al.,
Anticancer action of garcinol in vitro and in vivo is in part mediated through
inhibition of STAT-3 signaling, Carcinogenesis 33 (12) (2012) 24502456.
[45] X. Chen, X. Zhang, Y. Lu, J.-Y. Shim, S. Sang, Z. Sun, et al., Chemoprevention of
7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster cheek pouch
carcinogenesis by a 5-Lipoxygenase inhibitor, garcinol, Nutr. Cancer 64 (8) (2012)
12111218.
[46] K. Yoshida, T. Tanaka, Y. Hirose, F. Yamaguchi, H. Kohno, M. Toida, et al., Dietary
garcinol inhibits 4-nitroquinoline 1-oxide-induced tongue carcinogenesis in rats,
Cancer Lett. 221 (1) (2005) 2939.
[47] F. Li, M.K. Shanmugam, L. Chen, S. Chatterjee, J. Basha, A.P. Kumar, et al., Garcinol,
a polyisoprenylated benzophenone modulates multiple proinflammatory
signaling cascades leading to the suppression of growth and survival of head
and neck carcinoma, Cancer Prevention Research 6 (8) (2013) 843854.
[48] L.M. Knab, P.J. Grippo, D.J. Bentrem, Involvement of eicosanoids in the
pathogenesis of pancreatic cancer: the roles of cyclooxygenase-2 and
5-lipoxygenase, World J. Gastroenterol. 20 (31) (2014) 1072910739.
[49] J.R. Brown, R.N. DuBois, Cyclooxygenase as a target in lung cancer, Clin. Cancer
Res. 10 (12) (2004) 4266s4269s.

[50] M. Kondo, T. Hla, Expression of Cyclooxygenase-1 and -2 in human colorectal

cancer, Cancer Res. 55 (17) (1995) 37853789.
[51] S. Xiong, T. Mu, G. Wang, X. Jiang, Mitochondria-mediated apoptosis in
mammals, Protein Cell 5 (10) (2014) 737749.
[52] B. Hoesel, J. Schmid, The complexity of NF-kappaB signaling in inflammation
and cancer, Mol. Cancer 12 (1) (2013) 86.
[53] D.K. Biswas, Q. Shi, S. Baily, I. Strickland, S. Ghosh, A.B. Pardee, et al., NF-B
activation in human breast cancer specimens and its role in cell proliferation
and apoptosis, Proc. Natl. Acad. Sci. U.S.A. 101 (27) (2004) 1013710142.
[54] I. Collins, M.D. Garrett, Targeting the cell division cycle in cancer: CDK and cell
cycle checkpoint kinase inhibitors, Curr. Opin. Pharmacol. 5 (4) (2005) 366373.
[55] J. Cicenas, M. Valius, The CDK inhibitors in cancer research and therapy, J. Cancer
Res. Clin. Oncol. 137 (10) (2011) 14091418.
[56] F. Manzo, F.P. Tambaro, A. Mai, L. Altucci, Histone acetyltransferase inhibitors
and preclinical studies, Expert Opin. Ther. Pat. 19 (6) (2009) 761774.
[57] G. Bergers, R. Brekken, G. McMahon, T.H. Vu, T. Itoh, K. Tamaki, et al., Matrix
metalloproteinase-9 triggers the angiogenic switch during carcinogenesis, Nat.
Cell Biol. 2 (10) (2000) 737744.
[58] J. Borrow, V.P. Stanton, J.M. Andresen, R. Becher, F.G. Behm, R.S.K. Chaganti, et al.,
The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative
acetyltransferase to the CREB-binding protein, Nat. Genet. 14 (1) (1996) 3341.
[59] N. Lynam-Lennon, S.G. Maher, J.V. Reynolds, The roles of microRNA in cancer
and apoptosis, Biol. Rev. Camb. Philos. Soc. 84 (1) (2009) 5571.
[60] Y. Zhao, C. Deng, J. Wang, J. Xiao, Z. Gatalica, R. Recker, et al., Let-7 family miRNAs
regulate estrogen receptor alpha signaling in estrogen receptor positive breast
cancer, Breast Cancer Res. Treat. 127 (1) (2011) 6980.
[61] B. Zhang, X. Pan, G.P. Cobb, T.A. Anderson, MicroRNAs as oncogenes and tumor
suppressors, Dev. Biol. 302 (1) (2007) 112.
[62] F. Sicard, M. Gayral, H. Lulka, L. Buscail, P. Cordelier, Targeting miR-21 for the
therapy of pancreatic cancer, Mol. Ther. 21 (5) (2013) 986994.
[63] I.A. Asangani, S.A.K. Rasheed, D.A. Nikolova, J.H. Leupold, N.H. Colburn, S. Post,
et al., MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor
suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in
colorectal cancer, Oncogene 27 (15) (2007) 21282136.
[64] L.M. Coussens, B. Fingleton, L.M. Matrisian, Matrix metalloproteinase inhibitors
and cancer trials and tribulations, Science 295 (5564) (2002) 23872392.
[65] A. Rapisarda, G. Melillo, Role of the VEGF/VEGFR axis in cancer biology and
therapy, in: O.D. Ira (Ed.), Advances in Cancer Research, vol. 114, Academic Press,
2012, pp. 237267.
[66] S. Koskensalo, J. Louhimo, S. Nordling, J. Hagstrm, C. Haglund, MMP-7 as a
prognostic marker in colorectal cancer, Tumor Biol. 32 (2) (2011) 259264.
[67] C. Qin, K.L. Tan, C.L. Zhang, C.Y. Tan, Y.Z. Chen, Y.Y. Jiang, What does it take to
synergistically combine sub-potent natural products into drug-level potent
combinations?, PLoS ONE 7 (11) (2012) e49969.
[68] C. Gupta, D. Prakash, Phytonutrients as therapeutic agents, J. Complement. Integr.
Med., 11, (2014), 151.
[69] D.A. Frank, STAT3 as a central mediator of neoplastic cellular transformation,
Cancer Lett. 251 (2) (2007) 199210.
[70] S.V. Kumar, D. Saravanan, B. Kumar, A. Jayakumar, An update on prodrugs from
natural products, Asian Pac. J. Trop. Med. 7 (Suppl. 1 (0)) (2014) S54S59.
[71] R.H.J. Mathijssen, R.J. van Alphen, J. Verweij, W.J. Loos, K. Nooter, G. Stoter, et al.,
Clinical pharmacokinetics and metabolism of Irinotecan (CPT-11), Clin. Cancer
Res. 7 (8) (2001) 21822194.
[72] US Food and Drug Administration, Bioavailability and bioequivalence studies
for orally administered drug products general considerations, in: US
Department of Health and Human Services, C. a. C. (Ed.), US Department of
Health and Human Services CaC, e. R., MD 2003., Bioavailability and
Bioequivalence Studies for Orally Administered Drug Products General
Considerations, Rockville, MD, 2003.
[73] K.Y. Yang, L.C. Lin, T.Y. Tseng, S.C. Wang, T.H. Tsai, Oral bioavailability of curcumin
in rat and the herbal analysis from Curcuma longa by LCMS/MS, J. Chromatogr.
B 853 (12) (2007) 183189.
[74] P. Anand, A.B. Kunnumakkara, R.A. Newman, B.B. Aggarwal, Bioavailability of
curcumin: problems and promises, Mol. Pharm. 4 (6) (2007) 807818.
[75] L. Li, I. Brunner, A.-R. Han, M. Hamburger, A.D. Kinghorn, R. Frye, et al.,
Pharmacokinetics of -mangostin in rats after intravenous and oral application,
Mol. Nutr. Food Res. 55 (S1) (2011) S67S74.
[76] J.B. Calixto, Ecacy, safety, quality control, marketing and regulatory guidelines
for herbal medicines (phytotherapeutic agents), Braz. J. Med. Biol. Res. 33 (2000)
179189.
[77] M. Heinrich, H. Lee Teoh, Galanthamine from snowdrop the development of
a modern drug against Alzheimers disease from local Caucasian knowledge,
J. Ethnopharmacol. 92 (23) (2004) 147162.