Pooja Ri 2014

Drug Evaluation
Embelin -- a drug of antiquity:

shifting the paradigm towards
modern medicine
1. Introduction
Radhika Poojari
2. Phytochemistry
Indian Institute of Technology Bombay, Department of Biosciences and Bioengineering,
3. Pharmacodynamics (in vitro Mumbai, India
and in vivo preclinical trials)
4. Clinical efficacy
Introduction: Embelia ribes or Embelia tsjeriam-cottam, more commonly
known as vidanga, is a type of ayurvedic medicine that has been used to treat
Expert Opin. Investig. Drugs Downloaded from informahealthcare.com by University of Washington on 08/23/14
5. Safety and tolerability

various diseases for a number of years. Bright orange embelin-rich fruits have
(toxicology)
been well established as ethnomedicinals, for a number of years with their
6. Pharmacokinetics and pharmacological actions attributed to their hydroxybenzoquinone active
metabolism
constituent. Embelin has become known specifically for its antihelminthic
7. Regulatory affairs and contraceptive use.
8. Conclusion Areas covered: This drug evaluation provides a historical summary of embelin
9. Expert opinion along with its therapeutic use, phytochemistry and toxicology. Embelin’s
pharmacotherapeutical properties are also discussed along with its molecular
targets. It is hoped that this article will help to draw the attention of researchers
and biopharmaceutical companies to the untapped potential in bioprospection
for the development of new drugs.
For personal use only.
Expert opinion: Embelin is the only known non-peptide small-molecule

X-linked inhibitor of the apoptosis protein (XIAP) -- an anti-apoptotic protein
considered a promising cancer therapeutic target. Embelin acts as an NF-kB
blocker and potential suppressor of tumorigenesis. It also exhibits potent
cytotoxic, antioxidant and cancer chemopreventive effects. Given the potential
uses of embelin, it is recommended that further investigations take place to
properly explore its pharmacological and clinical effects.
Keywords: embelin, ethnomedicinal uses, molecular targets, pharmacotherapeutics, vidanga
Expert Opin. Investig. Drugs (2014) 23(3):427-444
1. Introduction
The genus Embelia is a group of shrubs belonging to the Myrsinaceae family, a

group more commonly known as vidanga. For many years, this indigenous drug
has been recommended for a number of diseases, with its use recorded in historical
texts, including the Charaka Samhita in 1949, Sushruta Samhita in 1942 and
Ashtanga Hridaya in 1950 in great detail. Embelia ribes Burm. f. (Syn. E. gladulifera
Wight), Embelia tsjeriam-cottam (Syn. E. robusta, Roxb), is a rambling shrub distrib-
uted along the Malabar Coast of Sri Lanka, through Sylhet, Singapore and China, as
well as Assam to Cochin and the hilly parts of Maharashtra and Konkan in India
(Figure 1). Embelin (Box 1) gained mention in 1934 in the British Pharmaceutical
Codex, followed by the Indian Pharmaceutical Codex in 1953, and was included
as an official drug in 1966 in Pharmacopoeia of India as vidanga, although its
botanical origin was described as fruits of E. ribes only [1]. The bright orange
hydroxybenzoquinone embelin-rich fruits have become well established within eth-
nomedicine and their pharmacological action is attributed to this constituent. These
fruits have been described as a number of things, including acrid, astringent, bitter,
pungent, expectorant, depurative, digestive and carminative with antibacterial, sto-
machic, diuretic, vermifuge, contraceptive, rejuvenating, alternative, stimulant,
10.1517/13543784.2014.867016 © 2014 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 427
All rights reserved: reproduction in whole or in part not permitted
R. Poojari
Box 1. Drug summary.

Drug name Embelin
Phase Preclinical
Indication A number of indications including contraceptive
Pharmacology description A XIAP inhibitor and potent NF--kB blocker
Route of administration Oral
Chemical structure O
OH
HO CH3
O
Pivotal trial(s) [4,25-27]
febrifuge, colic and tonic properties. These fruits are consid- Cherutoi et al. first described the reaction of zinc(II) and
ered to be beneficial in chronic skin diseases as well as respira- copper(II) ions with embelin in a 1:2 ratio to yield six-
tory disorders, helminthiasis and gastrointestinal disorders. coordinate complexes [8]. The embelin molecule, on loss of
They are also thought to promote immune functions, improve protons, produced a bidentate ligand with five-membered
blood circulation and possess anti-aging effects [2,3]. chelate rings. Further, acidification of this molecule led to
While there have been a number of papers published on the the regeneration of the embelin molecule. A recent synthesis
therapeutic effects of the fruit extracts of the Embelia species, approach for hydrophilic analogues of embelin was developed
updated literature on embelin -- the major active constituent to improve the water solubility and biodisponibility of
of vidanga -- is unavailable. The aim of this review is to sum- embelin. Three amines with different carbon chain lengths
marise the history, therapeutic uses, phytochemistry and tox- bearing a protected benzoquinone were prepared for its
icology of embelin as well as its molecular aspects in the hydrophilicity. Such a modification would provide useful
hope of increasing the awareness of bioprospection for the information on the influence of polarity of the side chain
development of new drugs. It is also hoped that this review for the development of a comprehensive structure--activity
would encourage further research on the pharmacological relationship of embelin analogues for anti-cancer activity [9].
effects of embelin, both in vitro and in vivo, in order to pro- X-ray crystal structural analysis of plasminogen activator
vide a more in-depth insight into the mechanisms associated inhibitor-1 (PAI-1) in complex with antagonist embelin as
with the therapeutic effects of embelin. The clinical aspects drug-designing PAI-1 targets was reported by Lin et al. [10].
of embelin certainly warrant further investigation before its Nikolovska-Coleska et al. [11] discovered that embelin is
integration into medicinal practices as well as for its use in the only known small molecular inhibitor of X-linked inhibi-
the formulations for commercialisation. tor of apoptosis protein (XIAP), identified through a novel,
structure-based computational screening of an herbal medi-
2. Phytochemistry cine-based compound library. The design, synthesis and eval-
uation of new embelin analogues as potent inhibitors of XIAP
Embelin (2,5 dihydroxy-3-undecyl-1,4 benzoquinone) (Figure 2) have been reported [12]. For example, compound 6 g exhibited
is the major active constituent (2.3%) in the fruits commonly a Ki value of 180 nM binding to XIAP BIR3 in a competitive
known as vidanga. This naturally occurring hydroxybenzoqui- binding assay which represented a promising lead compound
none consists of a dihydroxyquinone core; its long hydrophobic for further optimisation. Very recently, a novel protocol based
tail is a characteristic feature of the genus Embelia, which was first on the dihydropyran and dihydropyridin embelin derivatives
chemically investigated by Scott in 1888. Its other constituents synthesised through a three-component reaction with embe-
include quercitol (1.0%), an alkaloid christembine; tannin; lin, with aldehydes and with cyclic enaminones as synthetic
vilangin (methylene-bis-2-5-dihydroxy-4-undicyl 3-6-benzo- imputs for antibacterial activity, has been evaluated [13].
quinone) (Figure 3) and fatty ingredients (5.2%), including res- Embelin has been extracted colourimetrically and gravimet-
inoid; fixed oil and traces of volatile oil [3,4]. So far, the chemical rically [14]. There have been reports on optimisation, quantita-
examination of E. ribes has led to its isolation, a better under- tive estimation of embelin in the fruits of E. ribes and in
standing of its synthesis and its bare constituents. Further, formulations (market tinctures, tablets) spectrophotometri-
investigations of its analogues and its condensation reactions cally Stability and quality control studies of embelin in ayur-
with primary amines have also taken place, in addition to inves- vedic iron formulations (Navayasa Churna used for anaemia,
tigations in the synthesis of embelin derivatives (diamines and jaundice and piles and Krimimudgara Rasa, an antihelminthic
bisquinones) and isolation of vilangin [5-7]. drug) were carried out using high-performance thin layer
428 Expert Opin. Investig. Drugs (2014) 23(3)

Embelin
mechanism of action has been summarised in this review. An

overview of the current status of pharmacotherapeutics of
embelin and its molecular targets has been depicted in Figures
4 and 5, respectively.
3.1 Analgesic and anti-inflammatory activity

Gupta et al. [4], Zutshi et al. [25] and Chitra et al. [26] reported
a promising lead compound, embelin, and its disalt deriva-
tives for designing a new class of potent analgesic and anti-
Figure 1. Embelia tsjeriam-cottam: flowering, fruiting inflammatory agents. Kalyan Kumar et al. [27] reported that
branch in habitat and dried fruits are shown. topical application of embelin (0.1, 0.3 and 1%) exhibited
anti-inflammatory activities in acute (1 h) and chronic models
(10 days) of psoriasis using 12-O-tetradecanoylphorbol-

13-acetate (TPA, 50 µg/ml) in induced mouse ear oedema.
Embelin inhibited TPA-stimulated tumour necrosis factor-a
(TNF-a) in human keratinocytes and showed dose-
dependent decrease in bacterial LPS (Escherichia coli sero-
type 055:B5)-induced TNF-a levels in mice with an ED50
of 9.28 mg/kg. It inhibited topical oedema in the mouse ear
with substantial reductions in skin thickness, tissue weight,
Figure 2. Illustration of embelin.
inflammatory cytokine production, neutrophil-mediated
myeloperoxidase activity and ameliorated various histopatho-
logical indicators. The inhibitory effect of embelin may be
due to the inhibition of pro-inflammatory cytokines IL-1b
and TNF-a and the subsequent blockade of leucocyte accu-

mulation. Mahendran et al. [28,29] demonstrated potent anal-
gesic and anti-inflammatory activities of embelin and its
derivatives. Embelin condensed with various aromatic substi-
tuted primary amines yielded 10 new derivatives and one pre-
Figure 3. Illustration of vilangin.
viously reported derivative along with monomethyl embelin
and a unique ninhydrin adduct of embelin. Hot plate, tail
chromatography [15-19]. The developed methods were vali-
immersion, acetic acid-induced writhing methods and
dated in terms of precision, accuracy, stability, limit of detec-
carrageenan-induced paw oedema in mice and rats were tested
tion and limit of quantification. A simple, sensitive, accurate
at 10 and 20 mg/kg intraperitoneal (i.p.) doses of embelin
and reproducible method for embelin marker-based standard-
which allowed analysis of peripheral and centrally mediated
isation and quality assurance of E. ribes and E. tsjeriam-cottam
antinociceptive responses. Potent analgesic activity higher
from the various extracts of fruits and in polyherbal formula-
than the standard pentazocine was observed. Embelin and
tions by reversed-phase high-pressure liquid chromatography
both of its derivatives almost completely abolished the acetic
(RP-HPLC) have been demonstrated [19-23] so far. A sensitive
acid-induced writhing. The p-sulphonylamine phenylamino
and accurate HPLC method for the determination of embelin
derivative of embelin showed better anti-inflammatory activ-
in plasma, urine, faeces and tissue homogenates of brain,
ity than the parent compound embelin with significant reduc-
heart, liver, kidney, spleen and lungs have been developed.
tion in the paw oedema of 19.02% in 30 min in comparison
A pharmacokinetic study of embelin 50 mg/kg after oral
to 14.74% after 120, 180 and 360 min, respectively. Kumara
administration in rats was successfully quantified up to
Swamy et al. [30] studied the wound-healing activity of embe-
24 h [24].
lin (4 mg/ml of 0.2% sodium alginate gel) which resulted in
fast epithelialisation of the incision, wound contraction, sig-
3.Pharmacodynamics (in vitro and in vivo nificant increase in tensile strength of the incision wound,
preclinical trials) weight of granulation tissue, collagenation, more fibroblasts,
blood vessels and an absence of monocytes. Topical applica-
In recent decades, there has been spurt of reports with respect to tion of embelin 5% (w/w) ointment on a cutaneous wound
the primary pharmacodynamic activities of embelin, namely, in streptozotocin (STZ)-induced diabetic rats using excision,
anti-inflammatory, analgesic, anti-fertility effects, lipid metabo- incision and dead space models exhibited a significant increase
lism, glucose metabolism, hepato-gastroenterological disorders, in wound contraction and better epithelialisation, accelerating
neurological abnormalities, molecular docking, antioxidant the healing process. Embelin has been demonstrated to
effects, anti-cancer activity and drug delivery systems. The be active by the oral route (25 and 50 mg/kg) [31].
Expert Opin. Investig. Drugs (2014) 23(3) 429

R. Poojari
Anticancer Respiratory
Radioprotective disorders
Antimitotic Contraceptive
/antispermatogenic
XIAP inhibitor
Antioxidant O Anti-infective
OH
Molecular docking
Antihyperlipidaemic
and antihyperglycemic
Nanomedicine HO C11H23
O
Anti-inflammatory Analgesic
Embelin
Antihelminthic
Antipyretic
Hepatoprotective
Gastrointestinal
Neurodegenerative disorders
disorders
Clinical
development
Figure 4. Pharmacotherapeutics of embelin are shown.
Schaible et al. [32] depicted embelin as a novel chemotype for available to date as discussed here. Powdered berries of E. ribes
the development of dual 5-lipoxygenase (IC50 0.06 µM)/ (100 mg/day) orally administered to male bonnet monkeys for
microsomal prostaglandin E2 synthase (IC50 0.2 µM)-1 inhib- 3 months adversely affected the quantity and quality of semen,
itors. A new approach of using embelin and its derivatives and testosterone levels were reduced. Ayurvedic formulations
could serve as the alternative natural source of crosslinking/ containing E. ribes, such as ROC-101 and Garbhanivarana
stabilising agents [33]. Since their development, crosslinking aushadam were reported to impair the fertility of female mice
agents like formaldehyde, glutaraldehyde and epoxy com- and rats, inducing sterility in male mice. Pippalyadi yoga,
pounds are cytotoxic which limits the clinical applications. AC-4 and Maswin tablets have been used in women for their
Docking of the quinones with type I collagen and type III col- contraceptive activities without side effects [34-36].
lagen revealed that embelin, 5-O-methyl embelin and potas- Embelin possesses anti-implantation activity of 83.33%
sium embelate possessed the best affinities with collagens. when administered post-coitally from days 1 to 5 of pregnancy
Using bioinformatics tools, such as quinone and collagen, at an oral dose of 60 and 120 mg/kg in rats [37,38]. Similar
molecular interactions could be developed as the potent cross- observations were made by Rathinam et al. [39] wherein, embe-
linking/stabilising agent of collagen preparation in wound lin anti-implantation activity of 100% at 10 mg/kg, a much
dressings for clinical applications. smaller oral dose, in rats were reported. It also exhibited highly
significant anti-ovulatory effects in rabbits. Embelin at an oral
3.2 Contraceptive activity dose of 50, 100 and 200 mg/kg was given to male rats for
There has been wide acceptance of embelin or E. ribes fruits 15 days and significant reduction in the sperm count and
incorporated in the multi-component ayurvedic formulations motility and weight of the testes were observed [40]. Embelin
(powder/extracts/tablets/capsules) tested in animal models as at subcutaneous (s.c.) dose of 0.3, 0.4 and 0.5 mg/kg was given
well as in clinical studies, but not much has been explored to male rats for 35 days, resulting in altered testicular histology
with respect to the isolated active form of embelin for its fertil- and anti-androgenic activity [41]. Embelin at s.c. daily dose of
ity regulation activities. A limited number of survey data is 20 mg/kg was given to male rats for 15 or 30 days, which

Embelin
Embelin
Cell Antioxidant Immuno- Molecular docking Drug delivery

Apoptosis Metastasis
proliferation stimulant and bioinformatics systems
Sex differentiation
in ischemic brains XIAP
COX-2 miR-23a LPO MMP-9 XIAP-BIR3 PEG-derivatized embelin
IL-1β, 6
Cyclin D1 Caspase 3,7,8,9 GSH ICAM-1 PPARγ PEG-PLA
INF α
cMyc cIAP 1, cIAP 2 GST VE GF PI3K PCL microfibers
TNF α
p21 Survivin GPχ CD 31 pAkt PEG-b-p (CB-co-LA)
Ki67 PARP SOD GLUT4 PEG-PCD lipopolymer
PCNA NF-κB CAT PAI-1 Embelin-phospholipid
p53 DNA damage PCAF complex
IκBα Bcl-2
p65 Bcl-x1
Nuclear translocation Bax
TRAF 1,2 Cyt-c
c-FLIP Mcl-1
PPARγ RIP
TRAIL c-FLIP
STAT3-PTEN Erk1/2
Erb B2
Akt/m TOR/S6K1
Figure 5. Molecular targets of embelin are shown.
revealed inhibition of the epididymal motile sperm count oestrous cycles with significant depression in the plasma oestra-
and carbohydrate metabolism enzymes. Profound morpholog- diol and progesterone. Isolated mixed ovarian cells from
ical changes in the spermatozoa such as decapitation of the embelin-treated rats produced significantly less progesterone
spermatozoal head, discontinuity of the outer membranous and estradiol than the controls in vitro. Thus, embelin probably
sheath in the mid-piece and the tail region, and alteration in interferes with the reproductive functions in female rats by
the shape of the cytoplasmic droplet in the tail were observed. suppressing the ovarian production of sex steroid hormones [47].
These changes were reversible with a 15- to 30-day recovery Hence, as deciphered from these observations, embelin
period [42]. In male dogs, embelin at an oral dose of 80 mg/kg interfered with the fertility in male and female mammals and
every alternate day for 100 days caused significant reduction consequently could be developed into a potent contraceptive
in the weight of testes and epididymis, the diameter of the sem- agent.
iniferous tubule and Leydig cells and biochemical changes in
testes and epididymis. Histologically, it showed varying degrees 3.3 Gastrointestinal and liver disorders
of spermatological alterations which were recouped after a Vidanga has been an excellent remedy for diarrhoea, dysen-
250-day recovery period [43]. Embelin administration to white tery, abdominal pain, constipation, colic and flatulence since
New Zealand male rabbits (30 mg/kg intramuscular) on alter- antiquity. For instance, Vidanga is one of the constituents of
nate days for 14 days caused a marked reduction in the testoster- Gasex formulation of the Himalaya drug company which
one concentrations within 2 days and up to 90% reduction by gave excellent results in minimising the gastrointestinal
the sixth day. The luteinising hormone level showed a corre- symptoms in a clinical trial in post-operation where the
sponding rise with the fall in testosterone levels. Similarly, there abdominal discomforts were checked [48]. Daily oral embelin
was a rapid increase in the progesterone levels with embelin (75 mg/kg/day) administration to male rats for 15 -- 30 days
administration. The observed changes in the levels of these three caused significant elevation in the uptake of D-glucose,
hormones suggested that embelin disrupted testosterone pro- L-alanine, L-leucine and calcium in small intestinal seg-
duction at the testicular level [44]. Embelin at an oral dose of ments. Embelin significantly increased the intestinal brush
100 mg/kg given to female rats from days 1 to 5 of pregnancy border membrane-associated enzymes: sucrase, lactase, malt-
failed to increase or decrease the oestrogen-sensitive parameters ase, alkaline phosphatase and leucine aminopeptidase.
like uterine weight, protein, glycogen and alkaline phosphatase A significant increase was also noted for microsomal glu-
activities of uterine. It had no oestrogenic or anti-oestrogenic cose-6-phosphatase and cytosolic lactate dehydrogenase.
effect [45]. In ovariectomised rats, embelin at an oral dose of Increases in the brush border membrane-associated total lip-
25 and 50 mg/kg from day 1 to day 10 with oestradiol 17-b ids, phospholipids, cholesterol, triacylglycerol, unesterified
0.4 µg/rat s.c. from day 8 to day 10 inhibited pregnancy and fatty acids and ganglioside sialic acid were seen but not in
possessed anti-estrogenic and weak progestational activity [46]. the cholesterol:phospholipid molar ratio. All of these changes
Embelin at an oral dose of 10 and 20 mg/kg disrupted the returned to control or near control levels with drug

R. Poojari
withdrawal [49,50]. In inflammatory bowel disease, a chronic acids were markedly elevated in methylcholantherene-induced
intestinal disorder, a protective effect has been reported fibrosarcoma transplanted rats. After 30 days, embelin
when an oral dose of embelin (25 and 50 mg/kg) and sulfa- (50 and 100 mg/kg) treatment orally for 20 days led to signif-
salazine (100 mg/kg) was given for 5 days before colitis icant alterations in these lipid profiles of serum, and liver and
induction in rats by intrarectal acetic acid (3% v/v) adminis- kidney tissues [56]. The biochemical effects of embelin admin-
tration, with continued treatment for 7 days. This treatment istration (50 mg/kg oral dose for 14 weeks) from E. ribes
significantly reduced the colonic myeloperoxidase activity, against a two-step hepatocarcinogenic regimen of N-nitroso-
lipid peroxides and serum lactate dehydrogenase and signifi- diethylamine (NDEA, 200 mg/kg single i.p.) and phenobar-
cantly increased glutathione (GSH) which had previously bital (PB, 0.05% in drinking water orally for 13 weeks) was
been reduced as an effect of inflammatory bowel disease. It studied in Wistar rats with respect to the lipid profile, renal
significantly reduced the wet weight of the colon, clinical function tests and blood glucose levels. Rats administered
activity, gross lesion score and the percentage of the affected NDEA/PB showed hypercholesterolaemia, hypertriglyceri-
area in comparison to colitis control. Histopathologically, the daemia, elevated low-density lipoproteins, free fatty acids
leucocyte infiltration, and oedema and colonic mucosa tissue and very-low-density lipoproteins levels and decreased urea
injuries were minimal following pre-treatment with embelin levels. Pre- and co-treatment with embelin for 14 weeks sig-
indicating its protective effect from ulcerative colitis [51]. In nificantly prevented these biochemical alterations induced
another study, colitis was induced in BALB/c mice by 5% by NDEA/PB, suggesting that embelin has protective and
dextran sulphate sodium in drinking water for 7 days. Embelin hypolipidaemic effects [57]. Chaudhari et al. [58] have shown
(10, 30 or 50 mg/kg) on oral administration for 7 days attenu- the preventive effects of embelin (50 mg/kg) for 21 days
ated the pathological symptoms of colitis. In addition, embelin against hyperlipidaemia and oxidative stress in rats on a
ameliorated colitis by suppressing the pro-inflammatory high-fat diet with induced obesity. Oral embelin treatment
mediators, such as TNF-a, IL-1b and IL-6 mRNA expression reduced the gain in body weight, blood pressure, visceral fat
levels [52]. pad weight, serum lipid levels, coronary artery risk and ath-
Although several ayurvedic formulations containing erogenic indices, serum glucose (24.77%), insulin (35.03%)
vidanga (E. ribes) as one of the components for liver disorder and leptin (43.39%) levels. In addition, it significantly
treatments are available on the market (such as Livomyn, San- decreased the hepatic thiobarbituric acid-reactive substance
jivani vati, Kumariasava, Liv-52 and Livosin), there are very (TBARS) levels, while increasing superoxide dismutase
few investigations into the heparoprotective activity of embe- (SOD), catalase (CAT) and GSH levels in obese rats. Thus,
lin alone. Poojari et al. [53] demonstrated significant hepato- embelin could be useful as a new drug therapeutic to prevent
protection in rats orally treated with embelin (100 mg/kg) obesity, hyperlipidaemia and oxidative stress.
for 5 weeks, including 1 week of pre-treatment prior to car- The anti-diabetic effect of embelin in the management of
bon tetrachloride (CCl4, 0.7 ml/kg i.p. once weekly for diabetes and severe hyperglycaemia has been established.
4 weeks)-induced hepatotoxicity. Embelin treatment signifi- Wu et al. [59] have shown replication deficient adenoviral
cantly attenuated the elevated enzyme activities of transami- vector-encoding human XIAP transduced normal rat insuli-
nases, alkaline phosphatase, lipids and enhanced the fall in noma cells and human islets on embelin treatment immensely
protein and albumin levels caused by CCl4, as well as decreased the XIAP activity by blocking protein synthesis and
markedly reduced the swelling of hepatic cords and inflamma- decreased the cell viability and insulin production under
tory response and minimised mononuclear cell infiltration, inflammatory cytokines. It reversed the protective effect of
thus indicating the effectiveness of the hepatoprotectant XIAP in these cells against cytokines, thus suggesting the
drug. Embelin protected the structural integrity of hepatocyte important role of XIAP expression in graft viability and func-
cell membranes or stimulated hepatic regeneration. Previ- tion in a post-transplantation (STZ, 40 mg/kg i.p. for 5 days,
ously, the hepatic natural antioxidant potential of embelin induced diabetic NOD-SCID mice, human islets transplanta-
(25 mg/kg) taken orally for 15 days against CCl4 (1 ml/kg tion) model. In another study, embelin (15, 25 and 30 mg/kg)
i.p. once/week for 15 days)-induced liver damage in rats was treatment for 21 days caused a significant decrease in blood
evaluated [54]. Peroxidative damage was measured to minimise glucose, serum nitric oxide, total cholesterol and triglyceride
the deleterious effects of free radicals including the peroxy levels and an increase in low-density lipoprotein cholesterol
radicals and the inhibition of lipid peroxidation (LPO) by levels in STZ (50 mg/kg i.p. once weekly)-induced diabetic
embelin reflected the liver recovery from CCl4 toxic effects rats. Further, embelin increased the pancreatic antioxidant
towards normal liver cell functioning. defence enzyme status (SOD, CAT, GSH, glutathione perox-
idase [GPx], glutathione S-transferase [GST] and ascorbic
acid), and decreased TBARS levels against the reactive oxygen
3.4Antihyperlipidaemic and antihyperglycemic species (ROS) produced under hyperglycaemic conditions.
activity The protective action of embelin could be due to the stimula-
Embelin possesses lipogenic properties [55]. The lipid levels of tion of pancreatic regeneration through improved synthesis of
total cholesterol, phospholipids, triglycerides and free fatty proteins and/or its accelerated detoxification, reduction of

Embelin
deleterious effects of free radicals (including peroxynitrate) and in vitro (10 µM) and in vivo (5 mg/kg, i.p. for 3 days in
its antioxidant activity. Histologically, degenerated pancreas mice) which is useful in the muscle differentiation process.
on embelin treatment significantly regenerated islet cells, This PCAF KAT activity inhibition in turn inhibited the acet-
thereby protecting the pancreatic b-cells against loss and exhib- ylation of MyoD, which blocks the differentiation of myo-
ited anti-diabetic properties [60-62]. A recent study [63] revealed blasts into myotubes. Microarray analysis of embelin-treated
embelin’s potential to regulate insulin resistance, alter b-cell differentiated C2C12 cells revealed many altered gene expres-
dysfunction and modulate key markers involved in insulin sen- sion levels which are useful to explore the neuro-muscular
sitivity and glucose transport using high-fat diet fed STZ gene regulatory network. In breakthrough research evi-
(40 mg/kg)-induced type 2 diabetic mellitus rats. Embelin dence [68], embelin treatment (low-dose 10 mg/kg or high-
(50 mg/kg oral) administration for 30 days exhibited an dose 40 mg/kg s.c.) for 3 days significantly exacerbated the
insulin-sensitising effect through adipose tissue-specific partial stroke-induced injury in female mice but had no effect in
agonism of peroxisome proliferator-activator receptor gamma male mice, demonstrating XIAP regulation as a major
(PPARg) and activated glucose transport through the translo- contributor to sex differences after stroke. MicroRNA,
cation and activation of glucose transporter protein miR-23a, directly bound the 3¢ UTR of XIAP and miR-23a
(GLUT4) expression mediated by the insulin-dependent inhibition led to an increase in XIAP mRNA. Cerebral ischae-
PI3K/p-Akt signalling pathway in epididymal adipose tissue. mia induced a significant decrease in the miR-23a expression
Embelin also protected the b-cells from scavenging free radi- levels in males, whereas it significantly increased after stroke
cals and alleviated dyslipidaemia in the insulin-resistant animal in females. Embelin eliminated the stroke-induced decrease
model. This drug can be useful in the prevention and treat- of XIAP and Smac/DIABLO protein expression, whereas the
ment of obesity-related type 2 diabetic mellitus. The molecular decrease was still evident in males. Females were more sensi-
docking of embelin into PPARg, PI3K, p-Akt and GLUT4 tive to manipulation of XIAP signalling than males. An
active sites promoting insulin sensitisation and glucose uptake increased XIAP--caspase-3 interaction was observed in males
is a significant finding. Sun et al. [64] demonstrated embelin to after stroke, but this interaction was decreased in females.
be a potential agent for the prevention and treatment of dia- This decrease led to enhanced caspase activity after embelin
betic retinopathy, wherein, Muller cell alterations induced by treatment which in turn led to an exacerbation of infarct in
high-glucose conditions were counteracted by the XIAP females. Hill et al. [69] reported that inhibition of XIAP prior
inhibitor embelin. to hypoxia-ischaemia (HI) caused significant increase in the
behavioural deficits and anatomical abnormalities (ventricular
3.5 Neurodegenerative disorders enlargement) in embelin-treated (20 mg/kg s.c.) neonatal HI
In the indigenous systems of medicine, vidanga fruits have injured female rodents in comparison to vehicle-treated HI
been used for the treatment of mental disorders, dyspnoea, females. XIAP protected female brains from deleterious effects
central nervous system (CNS) disorders and as brain tonic [1,4]. of early HI injury, while elimination of this protection via
The effect of an oral dose of embelin (25 and 50 mg/kg) for XIAP inhibitor embelin exacerbated both damage and behav-
4 days on transient global ischaemia/reperfusion-induced neu- ioural deficits, with no effect on HI males. This reflected the
ronal damage in rats significantly increased the locomotor sex-dependent differences in the behavioural and anatomical
activity and hanging latency time and decreased beam walking outcome following HI, as well as in the underlying apoptotic
latency in comparison to ischaemic rats. It also significantly mechanisms which is very exciting. Hence, the potential use
reduced the LPO and increased the total thiol content and of embelin as a sex-specific neuroprotectant in clinical practice
GST activity in brain homogenates. Decreased cerebral infarc- remains warranted.
tion area and histopathological alterations, such as normal
glial density, decreased oedema, absence of lymphocytes, con- 3.6 Anti-cancer activity and the molecular targets
gestion of blood vessels and necrosis in embelin-treated Embelin is the only known class of non-peptide, cell-perme-
groups suggested that embelin as a potent neuroprotective able, small-molecule inhibitor that binds to the XIAP
agent and would be useful in the adjunct for cerebral stroke BIR3 domain -- a promising cancer therapeutic target. Embe-
treatment [65]. In another study [66], embelin (2.5, 5 and lin inhibited cell growth (IC50 3.7 µM), induced apoptosis
10 mg/kg, i.p.) administration showed significant inhibition (25 µM with 30% [3-fold] and 50 µM with 75% [9-fold]
of seizures induced by electroshock and pentylenetetrazole in increase) and activated caspase-9 (20 µM with 33.0%
a dose-dependent manner and the activity was comparable [10-fold] and 40 µM with 62.1% [20-fold] increase) in pros-
to phenytoin and diazepam. A significant decrease in locomo- tate cancer cells with high XIAP levels in comparison to con-
tion revealed its CNS-depressant activity. Thus, embelin pos- trol cells. In stable XIAP-transfected Jurkat cells, embelin
sesses anticonvulsant activity against both grand mal and petit (50 µM) effectively overcomes the protective effect of XIAP
mal epilepsy. Recently, embelin has been identified by to apoptosis and enhanced etoposide (10 µM)-induced apo-
Modak et al. [67] as a novel p300/CBP-associated factor ptosis with minimal effect in control vector-transfected Jurkat
(PCAF, KAT 2B)-specific non-competitive inhibitor which cells [11]. Chen et al. [12] synthesised new XIAP inhibitors with
inhibits the lysine acetyltransferase (KAT) activity of PCAF better binding affinities than embelin by modifying its

R. Poojari
hydrophobic tail. An embelin derivative [2,5-dihydroxy- significant tumour regression and prolonged survival time is
3-{2-[4-(2-m-tolyl-ethyl)-phenyl]-ethyl}-[1,4] benzoquinone] significant, in addition to retardation of cell multiplication
(embelin 6 g) had a twofold better binding affinity (Ki value having high chemotherapeutic potential. Embelin has been
0.18 µM) to XIAP BIR3 compared to embelin (Ki value reported to scavenge 1,1-diphenyl-2-picrylhydrazyl radicals
0.40 µM) with potent anti-proliferative effects in human and inhibit hydroxyl radical-induced deoxyribose degrada-
breast (IC50 5 µM) and prostate cancer (IC50 5.5 µM) cells. tion. It also inhibited LPO, reduced Fe(III) and restored
In addition, embelin 6 g (5 µM, p < 0.01) was more potent impaired Mn-SOD in rat liver mitochondria. The kinetics
than embelin (5 µM, p < 0.05) in repressing XIAP gene and mechanism of reactions of embelin with hydroxyl, one-
expression at mRNA levels and protein levels by ELISA, by electron oxidising, organo-haloperoxyl and thiyl radicals
almost twice that of embelin. However, embelin and embelin have been studied using a nanosecond pulse radiolysis tech-
6 g exhibited a similar ability to inhibit prostate cancer cell nique. Its redox potential has been evaluated with cyclic vol-
growth. Embelin (5 µM) and embelin 6 g (5 µM) also tammetry. Further, its free radical scavenging activity was
decreased androgen receptor (AR) and prostate-specific anti- better than a-tocopherol. These studies suggest that embelin
gen expression by > 50% of the mRNA transcriptional activ- acts as a competitive antioxidant in physiological condi-
ity levels in comparison to control in LNCaP and C4-2 cells. tions [75,76]. Anti-tumour activity of such quinonic com-
Embelin prevented AR nuclear translocation from the cyto- pounds is known to be, in part, due to their redox reactions
plasm to the nucleus in C4-2 cells. A concentration-dependent and formation of semiquinone radicals [77]. Allensworth et al.
effect of AR Ser81 phosphorylation post-embelin treatment [78] identified SOD overexpression and decreased induction of
(5/10 µM) strongly suggested that embelin suppressed ROS-mediated apoptosis in inflammatory breast cancer (IBC)
androgen-mediated AR phosphorylation. Anti-androgen ((S)- cells with acquired therapeutic resistance in XIAP overexpres-
N-(4-cyano-3-(trifluoromethyl) phenyl)-3-((4-cyanophenyl) sion models. XIAP inhibition by embelin (12.5 -- 50 µM) in
(methyl)amino)-2-hydroxy-2-methylpropanamide)) (CBDIV17, combination with TNF-related apoptosis-inducing ligand
25 µM) and embelin (5 µM) combination was more potent in (TRAIL,50 ng/ml) caused a synergistic decrease in cell viabil-
inhibiting cell growth and inducing apoptosis in advanced ity. Embelin treatment resulted in activation of ERK1/2 and
prostate cancer in comparison to control or monotherapy. ROS accumulation, which correlated with downregulation
The percentage of cells in the sub-G1 phase for combination of antioxidant protein SOD and consumption of redox mod-
therapy was 40-fold, 28-fold and 2-fold greater in comparison ulator reduced GSH in XIAP-overexpressed cells. Simulta-
to control, embelin and CBDIV17, respectively. This superior neous treatment with a SOD mimic, which protects against
effect signified their supra-additive anti-proliferative and apo- ROS accumulation, reversed the decrease in cell viability
ptotic effects [70]. The protein--protein interactions in the caused by embelin (50 µM) + TRAIL (50 ng/ml) treatment.
Smac--DIABLO-XIAP and Smac--DIABLO-Survivin com- Embelin primed IBC cells for TRAIL-mediated apoptosis by
plexes to design Smac/DIABLO peptidomimetics, which was its direct action on the anti-caspase activity of XIAP and by
investigated by Obiol-Pardo et al. [71], suggested the binding shifting the cellular redox balance towards oxidative stress-
mode of embelin and its two derivatives using molecular dock- mediated apoptosis. Thus, ROS modulators, such as embelin,
ing and molecular dynamics simulations to analyse the ligand represent a novel approach for enhancing the efficacy of
and receptor flexibility. This approach could be utilised to TRAIL-based treatments in IBC.
find innovative therapeutic agents for the treatment of malig- Studies have shown novel insights into the molecular net-
nant cancers. work of apoptosis resulting from embelin treatment on a panel
Natural products, their derivatives and the synthetic com- of tumour cancer cells in vitro. Embelin, which prevents the
pounds derived from natural products are crucial in the man- binding of XIAP to procaspase-9, significantly decreased epi-
agement of pathophysiological conditions of various diseases dermal growth factor receptor-2 (Erb B2) overexpressing IBC
caused by ROS. An example of this is quinones which are cell line SUM190PT cell viability, revealing the inhibitory
used as anti-tumour agents [72]. Chitra and Shyamala effect of XIAP on caspase-dependent cell death. However, it
Devi [73] reported that potent cytotoxicity and antioxidant failed to affect cell viability in combination with trastuzumab
properties were exhibited by embelin (50 and 100 mg/kg as embelin has no direct effect on XIAP translation or stability.
orally for 20 days)-treated fibrosarcoma rats where free radical These data have identified a novel functional link between Erb
scavenging properties (i.e., SOD, CAT, GPx, GST and GSH B2 signalling and the anti-apoptotic pathway mediated by
activities) were significantly enhanced and LPO content was XIAP, which established the feasibility of developing a targeted
restricted sharply in the liver, intestine and kidney tissues in therapy to potentiate apoptosis in combination with Erb
comparison to the control rats. Moreover, an interesting B2-targeted strategies for IBC therapy. Another advancement
report [74] showed the cytotoxic effects of embelin (2.5 -- was the discovery that XIAP downregulation in
20 mM) exhibiting inhibitory effects on the activation of rSUM190 and rSUM149 GW583340 (Lapatinib analogue,
polymorphonuclear leucocytes and a dose-dependent decrease Erb B1/2 inhibitor)-resistant IBC cells by embelin
in [3H]-thymidine uptake, LPO and GSH levels. The antiox- (20/50 µM) prevented XIAP--procaspase-9 interaction with
idant status of this drug on fibrosarcoma-bearing rats with decreased cell viability (40 -- 50%) and increased apoptosis

Embelin
(p < 0.005) [79-81]. Embelin sensitised XIAP-overexpressing variety of gene products involved in tumour cell survival,
malignant human pancreatic cancer AsPC-1 cells (20 µM) in proliferation, carcinogenesis, invasion, angiogenesis and infla-
TRAIL-mediated apoptosis [82] as well as glioblastoma U251, mmation, making this agent potentially useful for cancer ther-
LN229 and NCH89 cells (25/50 µM) via inhibition of apy. Embelin (50 µM) inhibited the expression of COX-2,
cellular-FLICE inhibitory protein (c-FLIP) expression or the MMP-9, cyclin D1, VEGF and ICAM-1. It sequentially
mitochondrial pathway [83,84], as well as non-small-cell lung inhibited the TNF-a-induced activation of the inhibitory
cancer NSCLC H460 cells (25 µM) [85]. It also induced apo- subunit of NF-kBa (IkBa) kinase, IkBa phosphorylation,
ptosis in human myeloid HL-60 leukaemia cells (33.97 µM/l IkBa degradation, p65 phosphorylation and nuclear translo-
or 30 µg/ml) through microtubular disassembly in the G0/G1 cation. Embelin also suppressed the NF-kB-dependent
phase of the cell cycle, and anti-mitotic activity [86-89] and in reporter gene transcription induced by TNF-a, TNF
hepatocellular carcinoma HepG2 and Huh 7 cells receptor-1 (TNFR1), TNFR1-associated death domain pro-
(10 -- 35 µM or 40 -- 120 µg/ml) [90-92] in a dose- and time- tein, TNFR-associated factor-2, NF-kB-inducing kinase and
dependent manner. It has been shown that p53-dependent IkBa kinase, but not that induced by p65. This downregula-
lysosomal destabilisation and cathepsin B activation contrib- tion was associated with enhanced apoptosis from 2 to 58%
uted to the increased sensitivity of p21-deficient colon cancer by cytokines and chemotherapeutic agents [99,100].
cells to embelin with enhanced caspase-9 and -3 activation. Embelin (25, 50, 100 and 200 mg/kg orally for 20 days)
A cathepsin B inhibitor reduced cell death and cytochrome c elicited potent anti-proliferative activity and prolonged the life-
release in embelin-treated cells, thereby indicating that the span of methylcholantherene-induced fibrosarcoma-treated rats
lysosomal pathway is upstream of mitochondrial death signal- with significant tumour regression [26]. XIAP inhibition with
ling [93]. Embelin has been reported to elicit a rapid increase of embelin triggered caspase activation, implicating XIAP in
intracellular free Ca2+ leading to activation of endothelial nitric caspase blockade in pancreatitis. Embelin (20 mg/kg/day s.c.)
oxide synthase and nitric oxide-induced cyclic GMP accumu- for 5 days induced cleavage of receptor-interacting protein
lation in endothelial cells [94]. Embelin (50 µM) also elicited (RIP) through activation of caspases-9, -3, -8, stimulated
suppression of the STAT3 signalling pathway in human mul- apoptosis ~ 3-fold and led to a significant decrease in necrosis
tiple myeloma (U266), prostate carcinoma (DU-145) and with normalisation of pancreatic histoarchitecture in mouse
head and neck squamous carcinoma (SCC4) cells via protein cerulein-induced pancreatitis, representing a therapeutic strat-
tyrosine phosphatase PTEN expression. STAT3 suppression egy for pancreatitis treatment [101]. Moreover, it exhibited che-
was mediated through inhibition of the activation of mopreventive activity against carcinogens NDEA-initiated
JAK2 and c-Src. The results indicated that embelin suppressed (200 mg/kg single i.p.) and PB-promoted (0.05% in drinking
constitutive STAT3 activation and downregulated the expres- water orally for 13 weeks) two-step hepatocarcinogenesis (pre-
sion of cell survival, proliferative and angiogenic gene products neoplastic foci/hyperplastic nodules stage) in Wistar rats.
leading to suppression of proliferation and induction of apo- Embelin treatment (50 mg/kg, oral dose) daily for 14 weeks
ptosis through caspase-3 activation [95]. Embelin-induced prevented induction of neoplastic nodules, increased levels of
XIAP suppression resulted in an increase of apoptosis via phos- hepatic diagnostic markers and LPO, caused hypoproteinemia
phorylation of p38 in BRAF V600E-mutant thyroid cancer and hyperlipidaemia, decreased hepatic glutathione antioxidant
cell lines. Thus, regulation of XIAP activity may be potentially defence and minimised the histological alterations (dysplasia
useful for thyroid cancer treatment [96]. A new death pathway, and atypical cells with abnormal chromatin pattern) induced
demonstrated by Jehan et al. [97] on the treatment of ovarian by NDEA/PB [102,103]. In a similar approach, rats received
cancer cells with embelin, promoted autophagy as evidenced NDEA (1 ppm/g body weight in drinking water) for 6 weeks
by the cell death without caspase-3 activation, induced cellular in a liver preneoplasia model and received embelin (50 and
swelling and cytoplasmic vacuolisation with necrotic cell 100 mg/kg) orally prior, during and after exposure to NDEA
death. Autophagic hallmarks, increased autophagosomes, for 20 weeks. Embelin treatment significantly prevented
punctuated distribution of GFP-LC3, LC3 cleavage and NDEA-induced increase in glutamate pyruvate transaminase,
beclin1 activation depicted the role of embelin as a new che- glutamate oxaloacetate transaminase, alkaline phosphatase,
motherapeutic agent for ovarian cancer treatment. Recent evi- g-glutamyl transpeptidase, GST and LPO as well as causing
dence [98] revealed that embelin significantly inhibited hypoproteinemia, hypoalbuminuria and GSH depletion. This
multiple signalling cascades in the Akt/mTOR/S6K1 pathway was further substantiated by a marked decrease in the incidence
along with downregulation of anti-apoptotic (Bcl-2, Bcl-xL, of preneoplastic foci and inflammatory cells on histopatholog-
Survivin, IAP-1 and IAP-2) and proliferative (cyclin D1) ical and transmission electron microscopic analysis. Embelin
proteins, activation of caspase-3, and cleavage of poly(ADP- proved remarkable in suppressing and/or arresting the degener-
ribose) polymerase in androgen-independent PC-3 prostate ative changes brought about by NDEA, thus suggesting that
cancer cells. embelin is a promising chemopreventive agent [53]. Dai et al.
Being a multifaceted drug, embelin not only induces apo- [104] reported that embelin (30 µM) significantly inhibited
ptosis by inhibiting XIAP but it also potently blocks NF-kB cell proliferation and induced apoptosis in colon cancer
signalling pathways, thereby leading to downregulation of a HCT116 cells. 1,2-dimethylhydrazine dihydrochloride

R. Poojari
(DMH, 20 mg/kg/week s.c.) administration for 15 weeks potency. To counteract this drawback, Lu et al. [109] have
induced colon cancer in PPARg +/+ and PPARg +/- mice. Mice recently developed a formulation based on a hydrophilic poly-
fed with embelin daily (100 mg/kg) for 10 days before DMH mer, polyethylene glycol 5000 (PEG5K)--embelin conjugate,
injection and continued for 30 more weeks suppressed colon which self-assembled to form stable micelles in aqueous solu-
carcinogenesis in PPARg ligands in mice. Reduced expression tion and efficiently encapsulated the hydrophobic drug, pacli-
of PPARg significantly sensitised colonic tissues to the carcino- taxel (PTX). This novel micelle system (20 -- 30 nm) had
genic effects of DMH. PPARg activation inhibited NF-kB sustained release kinetics over 5 days and exhibits potent cyto-
activity. Embelin suppressed the NF-kB target gene expressions toxicity in DU145 and PC-3 androgen-independent human
namely cyclin D1, survivin, Cox-2 and c-Myc with a more prostate cancer and 4T1.2 mouse metastatic breast cancer
efficient anti-cancer effect in PPARg +/+ mice. cells. Total body near-infrared fluorescence imaging depicted
Embelin (20 µM) in combination with ionising radiation that PEG5K--embelin micelles selectively accumulated at a
(IR, 4 Gy) potently suppressed prostate cancer PC-3 cell pro- tumour site with minimal uptake in major organs, including
liferation (72%) and triggered caspase-independent apoptosis the liver and spleen, and also depicted a safety profile with
(14%) when compared with either treatment alone. An oral a maximum tolerated dose of 100 -- 120 mg PTX/kg single
dose of embelin (60 mg/kg on days 1 to 5/week for 3 weeks) intravenous (i.v.) administration in mice which was
significantly improved tumour response to X-ray radiation significantly higher than taxol (15 -- 20 mg PTX/kg). Potent
(2 Gy fraction on days 1 to 5/week for 2 weeks) in a anti-tumour activity at 10 and 20 mg PTX/kg micellar formu-
PC-3 xenograft model. The tumour size in the combination lation i.v. injection in xenograft models of breast (treatment
group was 60% of that in the IR alone group and 18% of days 1, 4, 7, 10 and 13) and prostate cancers (treatment
that in the control group. The combination group also pro- days 1, 3, 7, 10, 13, 24 and 28) were demonstrated over taxol
longed the time to progression by ~ 5- to 6-folds more than formulation. Interestingly, earlier a similar version of the
either treatment alone with minimal systemic toxicity, sug- highly efficient micelle system (20 -- 30 nm) PEG
gesting a significant combinatorial inhibition by radiation 3500--Embelin conjugate exhibited synergism with PTX
therapy on tumour suppression and angiogenesis. This find- with potent anti-tumour activity, representing a dual func-
ing warrants embelin as a novel adjuvant therapeutic candi- tional delivery system [110]. Poly (ethylene glycol)-b-poly
date for hormone refractory prostate cancer treatment (carbonate-co-lactide) micelles (83 -- 90 nm) prepared by a
resistant to radiation therapy [105,106]. In a co-clinical film sonication method at 5% drug loading led to encapsula-
approach, embelin sensitised castration-resistant prostate can- tion efficiency for CBDIV17 at 91.2% and embelin at 38.4%.
cers (CRPCs) to androgen deprivation therapy [107]. In A combination of CBDIV17 (25 µM) and embelin (5 µM)
human prostate cancer cells, dutasteride (10 µM) and/or micelle formulation was more potent than their monotherapy
MDV3100 (10 µM) and/or embelin (5 µM) treatment for in prostate cancer (C4-2) treatment with a 20% decrease in
2 or 4 days caused a marked increase in apoptotic response. cell growth, while combination therapy inhibited about
In genetically induced CRPC mouse models, dual combina- 70% with superior cell migration inhibition. In a C4-2 xeno-
tion of bicalutamide (Casodex, 10 mg/kg) and embelin graft tumour model, intratumoral injection of a combination
(60 mg/kg) orally for 5 days/week for 4 weeks or triple com- of 10 mg/kg CBDIV17 and 10 mg/kg embelin-loaded
bination treatments with bicalutamide (10 mg/kg), embelin micelles administered on days 0, 3 and 7 inhibited tumour
(60 mg/kg) orally for 3 days/week, bicalutamide (10 mg/kg) growth more potently and increased tumour-doubling time
and dutasteride (2 mg/kg) orally for 2 days/week for 4 weeks in comparison to mice treated with void micelles or mono-
led to a significant co-clinical therapeutic approach which was therapy. On day 7, tumour size in the combination group
beneficial to CRPC patients genetically stratified by XAF1, was 50% of that in the CBDIV17 group, 25% of that in
XIAP and SRD5A1. In another study, pre-treatment of embe- the embelin group and 18% of that in the control group
lin (10 and 20 µg/ml) for 60 min inhibited ultraviolet B with minimal toxicity and therefore appears to be a promising
(290 -- 320 nm for 30 min) radiation-induced oxidative dam- therapeutic approach for hormone refractory prostate cancer
age and DNA damage in peripheral blood human lympho- treatment [70]. In another study, an embelin--phospholipid
cytes due to its antioxidant property [108]. The above reports (Phospholipon 90H, a soya phosphatidylcholine) complex
established the potent antioxidant and anti-tumour potentials (0.05 -- 0.5 µM) formulated by a mechanical dispersion
of embelin. method exhibited embelin 92.44% (w/w) content with
improved water solubility of 3 -- 42 µg/ml in the complex.
3.7 Nanomedicines Free embelin showed only 19% drug release, whereas the
Transforming traditional drugs such as embelin into designer complex showed 99.80% release at 120 min of dissolution
drugs using the nanotechnological approach is currently very in distilled water [111]. Li et al. [112] demonstrated that
demanding. Poor oral bioavailability due to the low aqueous embelin-loaded poly(ethylene glycol)-block-poly(2-methyl-
solubility of embelin leads to poor pharmacokinetic- 2-carboxyl-propylene carbonate-graft-dodecanol) (PEG-
pharmacodynamic profiles which in turn restricts its use in PCD) lipopolymeric micelles showed significant inhibition
the treatment of human diseases with low therapeutic (IC50 10 µM) of C4-2 prostate cancer cell proliferation.

Embelin
PEG-PCD lipopolymers with various hydrophobic core toxicity on 10 weeks administration of 10 mg/kg of embelin
lengths showed similar drug release profiles. Poly(ethylene)- to rats also indicated the drug to be free from toxic effects
b-poly(D,L-lactide) polymeric micelles (30 -- 50 nm) fabri- on heart, liver, kidney and bone marrow, thereby having a
cated using a film sonication method to solubilise the hydro- high margin of safety in acute toxicity studies [39]. The rec-
phobic drugs, bicalutamide and embelin, led to 60-fold ommended doses in official Ayurvedic Pharmacopoeia and
increase in drug aqueous solubility. Drug-loading capacity Indian Herbal Pharmacopoeia are 5 -- 10 g of fruit pow-
increased up to 20% for embelin and 10% for bicalutamide. der [117,118] which are considered practically safe without
In LNCaP xenograft mouse models, sequential exposure to side effects. New semi-synthetic derivatives of embelin,
bicalutamide- loaded micelles in intratumoral injection such as diamines and bisquinones, were developed of which
(20 mg/kg) three times a week up to 20 days followed by embelin and its disalt, 2:5-isobutylamine embelin, exhibited
embelin-loaded micelles from day 28 resulted in regression antipyretic, anti-inflammatory, analgesic, tranquilising and
of prostate cancer tumours [113]. Thus, micellar delivery of hypotensive activities in varying degrees. These compounds
anti-androgen and XIAP inhibitors has immense potential in were effective at 5 -- 10 mg/kg i.p. doses in mice, rats, dogs,
the treatment of advanced prostate cancer. cats and rabbits with some side effects [4]. A short-term tox-
Natural polymers are promising candidates for functional icity of 6 weeks of embelin 120 mg/kg oral administration
materials, such as quinones from natural products, and have was observed in female rats including an increase in acid
a number of significant advantages. A biodegradable, biocom- and alkaline phosphatase activities in kidney and adrenal
patible polymer matrix of poly("-caprolactone) (PCL) micro- cells, disintegration, necrotic changes, perinuclear vacuola-
fibre meshes containing embelin were obtained by tion in the liver and kidney, kidney tubular damage and
electrospinning [114]. Thermal properties revealed that the adrenal hypertrophy which were recouped after embelin dis-
crystallinity of embelin was significantly decreased and the continuation [119]. Acute toxicity studies in mice treated
drug almost completely dissolved in the PCL fibres. An with embelin 50 and 100 mg/kg oral dose showed no signif-
important aspect to consider in topical drug applications icant body weight change, mortality or apparent toxic effects,
was drug-loaded fibrous scaffolds which exhibited an 86% signifying its safety profile [53].
increase in the area-to-volume ratio and provided an effective

area per unit mass which was 5.8-fold higher than in drug-
loaded films. For the meshes, 90% embelin release occurred 6. Pharmacokinetics and metabolism
after 12 h of PBS exposure, whereas, for the films, a compara-
ble level of release occurred only after 72 h. This polymeric The pharmacokinetic studies of potassium embelate (20 mg/kg
carrier would allow a better in situ bioavailability of embelin. oral and i.v.) in rats revealed a bi-exponential kinetic pattern.
The above evidence signifies that nano-embelin is a novel, Absorption was complete (bioavailability 97%) and fast with
effective drug delivery system. drug peak plasma at 0.28 h (9 µg/ml). The disposition half-
life was 9.5 h on i.v. and 11 h on oral administration. High
4. Clinical efficacy drug concentrations (8.1 µg/g wet tissue) were found in the
brain between 0.25 h and 2 h in comparison to the liver, heart,
The drug consists of dried ripe fruits of vidanga which gives lung and spleen and slowly decreased. The kidney played a
protection against several diseases. Vidanga has gained partic- major role in drug excretion with 60.9% of the dose found in
ular importance due to the proven efficacy in preclinical set- urine after 24 h [25]. Pharmacokinetics of embelin after oral dos-
tings and clinical trials investigating its contraceptive and ing (75 mg/kg/day) for 30 days in rats depicted the highest lev-
antihelminthic potential. Not many randomised, controlled els in the kidney (249 mg/g), followed by the testis (257 mg/g)
and double-blind clinical trials are available. In ayurvedic sys- and intestine (232 mg/g). Significant levels were observed in the
tems of medicine, it forms a chief ingredient found in the brain (163 mg/g), heart (196 mg/g) and spleen (176 mg/g).
composition of a number of polyherbal formulations available Embelin levels in all of the organs were higher than after
on the market such Livomyn, Liv-52, Sanjivani vati, Abana, 15 days treatment, with mainly the prostrate, heart, kidney,
Koflet, Gasex, Geriforte, Mahamanjisthadi Kwatha, Krumiva- liver and intestine showing tissue accumulation. However, these
kar Kwath, Livosin, and the like (Table 1) [3,115,116]. Efforts to levels slowly declined in all of the organs after 30 days of embe-
enhance embelin’s bioavailability in humans are needed in lin treatment, indicating slow elimination from the body. T1/2
order to take embelin to the next phase, from the bench was 21.86 h; embelin on s.c. dosing for 30 days depicted the
to bedside. highest concentration in the heart (204 mg/g), followed by
the testis (200 mg/g), epididymis (176 mg/g), kidney
5. Safety and tolerability (toxicology) (159 mg/g) and brain (147 mg/g). Low levels were observed
in the spleen (139 mg/g), seminal vesicles (110 mg/g), liver
The LD50 value of embelin from E. ribes was 44 mg/kg by (106 mg/g), intestine (90 mg/g), prostrate (86 mg/g) and lung
i.p. route. Embelin in doses of 10 mg to 3 g/kg given orally (82 mg/g). About 30 days after embelin withdrawal,
to rats and mice did not show any toxic effects. Subacute 20 -- 75 mg/g levels were observed with T1/2 of 16.5 h [120].

R. Poojari
Table 1. Polyherbal vidanga formulations in market and its uses.
Formulations Chief ingredients Indication/uses Dosage
Vidangadi churna Vidanga, yastimadhu, trikatu, Antihelminthic, purgative, alternative, 3 -- 5 g

dantamoola, trivrit, chitraka flatulence, dyspepsia and tapeworms
Kuberakshadi yoga Putikaranja, vidanga, ajwain, jatiphala, Antihelminthic 200 mg
lavangaha, jeeraka
Vidangadi yoga Vidanga, japapushpa, hingu Anti-fertility 100 mg
Eladi grita Ela, ajmoda, harad, baheda, amla, Tuberculosis, anal fistula, dyspepsia 12 g
saurastri, shunthi, kalimirch, pippali, and eye diseases
arishtak, khadir, sala-sara, bijakasara,
bhallataka-suddha, vidanga, ghrta,
tavaksiri, sita, madhu, dalchini, ela,
chitrak, tejpatra, water

Pippalyadi yoga Vidanga, pippali, borax Contraceptive 1g
Madhusnuhi rasayana Shunthi, kalimirch, pippali, harad, Diabetic carbuncle, tumour, goitre, 12 g
baheda, amla, dalchini, ela, tejpatra, anal fissure, gout, leprosy, piles and
jatiphal, agni, laung, dhaniya, saariva, itching
krsna jirak, vidanga, chavya, kusth,
trivtita, pippali, ashwagandha, bhangri,
tejovati-bija, kesara, suddha gandha,
mahisaksa guggul, ghrita, sita, madhu
Vidangsaravaleha Vidanga, pippali, triphala Antihelminthic, fistula, sinus, urinary Not available
diseases, ulcers, leprosy and skin
diseases
Sunder vati Vidanga, kutaj, amla, shunti Skin diseases 180 mg
Krmimudgar rasa Rasa-suddha, gandhaka-suddha, Worm infestations and dyspepsia 250 -- 500 mg
ajmoda, vidanga, visamustika-suddha,
palaash
Vidangarishta Vidanga, pippali, rasna, kutaj, dalchini, Goitre, anal fissure and cystitis 12 -- 24 ml
kutaj phala, patha, elavalukamka,
amla, ksadura, dhatki, dalchini, ela,
tejpatra, priyangu, kanchnaar, lodhra,
shunthi, kalimirch, pippali, water
Vidangadi lauh Vidanga, clove, borax, jatiphala, Vermifuge, dyspepsia, anorexia, piles, 500 mg
lavangaka, shunthi, salt, nutmeg, long anaemia, swelling, fever, asthma and
pepper, black pepper, lauha bhasma cough
Madhukasava Madhuka, vidanga, chitrak, bhallatak, Bile disorders, leprosy, leucoderma, 12 -- 24 ml
manjishtha, madhu, ela, mrnala, blood disorders, dyspepsia and
agaru, chandan, water emaciation
Abhyarista Harad, draksha, vidanga, maduka Piles, urine retention and dyspepsia 12 -- 24 ml
bhasma, guda, gokshurtrivrta, dhaniya,
dhatki, indravaruni, chavya, danti,
madhurika, shunthi, mocarasa, water
Kumariasava Kumari rasa, guda, makshika, parva Dyspepsia, duodenal ulcer, 12 -- 24 ml
loha, shunthi, kalimirch, paippali, regurgitation, dysuria, stones, epistaxis,
laung, dalchini, ela, tejpatra, seminal disorders, dementia, debility,
nagkeshar, chitrak, pippalamool, emaciation, weakness, anorexia and
vidanga, chavya, gajpippali, hapusha, liver disorders
dhaniya, poog, katuka, mustak, harad,
baheda, amla, rasna, devdaru, haldi,
daruharidra, moorva, madhurasa,
danti, dhatki, pushkarmool, bala,
atibala, kapikachu, gokshur,
shatpushpa, hingpatri, akaarkrabh,
utingana, svetapunarnava, punarnava,
lodhra, dhatumakshika
Vidangasava Vidanga, pippalimula, rasna, kutaja, Round worms, thread worms and 2 -- 4 tsp.
indrayava, paripatha, amalaki, shunthi, hook worms
pippali, tamalpatra, bruhatela, tvak
taila

Embelin
7. Regulatory affairs chemopreventive therapeutic agents are justified. Moreover,

prediction of possible embelin-induced toxic effects could be
A number of ayurvedic products are available on the market elucidated by using advanced toxicogenomic analyses rather
containing vidanga as a constituent. A critical issue is that than the conventional techniques. Molecular docking of
ayurvedic medicinal market is poorly regulated by acquiring embelin for diabetes prevention and management is an
illegal licenses and over-the-counter sales. Therefore, this leads important aspect for designing new targets. Embelin bound
to adulteration or substitution of black pepper mixed as spice, to PPARg disclosed stable binding affinities to the active sites
allied Embelia sps. or Myrsine africana fruits due to their close of PI3K, p-Akt and GLUT4. Embelin could improve adipose
resemblance. Hence, to standardise the content, check the sta- tissue insulin sensitivity, enhance glycaemic control, protect
bility and batch-to-batch variation in consistency as well as b-cells from damage and maintain glucose homeostasis. Stud-
preserve its potency, it is necessary to implement stringent ies at the miRNA level would immensely improve under-
quality control standards such as embelin markers and standing of the potential mechanisms of action by which
mandatory registration policies for these formulations. embelin acts against cancer or neurodegenerative disorders.
A crucial finding was that miR-23a inhibition reduces caspase
activation by enhancing XIAP levels and decreasing cell death.
8. Conclusion Therefore, development of miRNA-targeted therapies should
keep in mind the potential for differential sex regulation.
Overall, this review provides updated developments of an Embelin, the natural small molecular inhibitor of XIAP, is
under-explored source, embelin, an antique drug known for a lead molecular target for designing new anti-cancer drugs
its vermifuge and contraceptive properties in ayurvedic medi- to promote apoptosis in cancer cells. It is an NF-kB blocker
cine, moving towards an anti-cancer molecule and nanomedi- and potential suppressor of tumorigenesis, including acute
cine. The current approach tends to focus on the mechanistic leukaemia. Embelin-promoted cell death is more effective
molecular levels of embelin and the issue of poor bioavailabil- in cancer cells with higher levels of XIAP which implicates
ity is challenging. Several approaches, as discussed in this embelin therapy in addressing clinical drug-resistant cancers.
review, would resolve the unanswered questions. A plethora
Embelin inhibits the caspase-inhibitory activity of XIAP by

of preclinical trials of embelin provides a rationale for early binding to its BIR3 region and disrupting caspase 9 and
clinical trials for various diseases. Safety and effectiveness Smac binding to XIAP, indicating an anti-apoptotic activity
need to be firmly established before such clinical practices of XIAP in controlling drug-resistant cancer cells. The
can be endorsed. Embelin acts as a sensitiser and can be embelin + TRAIL-mediated apoptosis pathway is a promis-
used as an adjuvant to current conventional drug treatments ing target for anti-cancer therapy. The role of embelin in a
for enhanced potency with minimal toxicity. The new wave variety of tumour cells through the inhibition of IkBa
of multidisciplinary approaches from diverse disciplines, kinase, XIAP, c-FLIP expression, activation of PPARg,
such as chemistry, systems biology, pharmacology, toxicology, microtubular disassembly, induction of lysosomal destabilisa-
pharmaco-genomics, nanoengineering, absorption-drug tion and antioxidant activity have been discussed above. The
metabolism-excretion dynamics, bioinformatics, quality con- effect of embelin on STAT3 activation, Erb B2 and Akt/
trol and patients clinical data would have striking effect on mTOR/S6K1 established new mechanistic signalling cas-
this investigational, naturally occurring small quinonic cades in cancer cells. It also represents a promising adjuvant
molecule, embelin, and help develop it as powerful chemo- intervention for enhanced radiotherapy treatment in
therapeutic for the prevention and treatment of diverse radiation-resistant hormone refractory prostate cancers. Bear-
malignancies. ing in mind the co-clinical approach of embelin for CRPCs,
it is a significant stride for genetically tailored new anti-
9. Expert opinion cancer therapeutics. Although evidence of embelin as an
effective cancer chemopreventive agent against chemically
Embelin possesses enormous potential for research and the induced cancers in experimental rodents with no side effects
exploitation of new drugs is impressive. Literature since has been established, further research is warranted to
1934 pertaining to the Embelia species showed investigations elucidate the specific mechanisms involved.
mainly regarding its medicinal properties (crude extracts) and Embelin is water insoluble; PEG, polymeric and lipid
ayurvedic formulations. Few attempts had been made to modalities were explored to increase its solubility and
investigate the major active constituent, embelin, isolated enhance its anti-tumour efficacy. Among the new materials,
from the fruits of this plant as a source of drug. Hence, the polymers with quinone functionality and biodegradability,
interest in the development of newer embelin derivatives, such as microfibre meshes containing embelin in PCL matrix
embelin as phytochemical marker for quality control, its with high bioavailability, are unique. More studies on
bioprospection as an analgesic, anti-inflammatory, contracep- structure--activity relationships can be designed using bioin-
tive, anti-infective, antioxidant, anti-diabetic, gastro-hepato- formatics tools for improved new nano-embelin delivery
protective, neuroprotective, radiation-protective and cancer systems.

R. Poojari
Significant strides have been made in understanding the Acknowledgement

molecular aspects of embelin, but the clinical progress remains
slow. Few clinical trials of vidanga fruits or multi-component The author is thankful to A Varma from Advanced Centre for
ayurvedic formulations on skin diseases, antihelminthic, Treatment, Research and Education in Cancer (ACTREC),
gastrointestinal troubles and anti-fertility perspectives are Navi Mumbai, India for critically reviewing the manuscript
available. More in-depth preclinical studies of embelin are and his helpful suggestions.
required. Hence, well-designed clinical trials of embelin for
various therapeutic applications and its marketability exploita-
tion remain warranted. Truly, unravelling the journey of this Declaration of interest
ancient medicine, embelin, from a potent antihelminthic
agent to a novel anti-cancer molecule and nano-embelin in The author states no conflict of interest and has received no
particular is remarkable. payment in preparation of this manuscript.
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Affiliation
Radhika Poojari
Indian Institute of Technology Bombay,
Department of Biosciences and Bioengineering,
Mumbai -- 400076, India
E-mail: drradhikapoojari@gmail.com

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Drug Evaluation

Embelin -- a drug of antiquity:

5. Safety and tolerability

Expert opinion: Embelin is the only known non-peptide small-molecule

Keywords: embelin, ethnomedicinal uses, molecular targets, pharmacotherapeutics, vidanga

Expert Opin. Investig. Drugs (2014) 23(3):427-444

The genus Embelia is a group of shrubs belonging to the Myrsinaceae family, a

Box 1. Drug summary.

428 Expert Opin. Investig. Drugs (2014) 23(3)

mechanism of action has been summarised in this review. An

3.1 Analgesic and anti-inflammatory activity

(10 days) of psoriasis using 12-O-tetradecanoylphorbol-

and TNF-a and the subsequent blockade of leucocyte accu-

Expert Opin. Investig. Drugs (2014) 23(3) 429

Figure 4. Pharmacotherapeutics of embelin are shown.

430 Expert Opin. Investig. Drugs (2014) 23(3)

Cell Antioxidant Immuno- Molecular docking Drug delivery

Figure 5. Molecular targets of embelin are shown.

Expert Opin. Investig. Drugs (2014) 23(3) 431

432 Expert Opin. Investig. Drugs (2014) 23(3)

Expert Opin. Investig. Drugs (2014) 23(3) 433

434 Expert Opin. Investig. Drugs (2014) 23(3)

Expert Opin. Investig. Drugs (2014) 23(3) 435

436 Expert Opin. Investig. Drugs (2014) 23(3)

increase in the area-to-volume ratio and provided an effective

Expert Opin. Investig. Drugs (2014) 23(3) 437

Table 1. Polyherbal vidanga formulations in market and its uses.

Formulations Chief ingredients Indication/uses Dosage

Vidangadi churna Vidanga, yastimadhu, trikatu, Antihelminthic, purgative, alternative, 3 -- 5 g

chitrak, tejpatra, water

438 Expert Opin. Investig. Drugs (2014) 23(3)

7. Regulatory affairs chemopreventive therapeutic agents are justified. Moreover,

Embelin inhibits the caspase-inhibitory activity of XIAP by

Expert Opin. Investig. Drugs (2014) 23(3) 439

Significant strides have been made in understanding the Acknowledgement

1958. p. 597; 672

440 Expert Opin. Investig. Drugs (2014) 23(3)

Wound - healing activity of embelin plant benzoquinone, on male albino rats

Expert Opin. Investig. Drugs (2014) 23(3) 441

442 Expert Opin. Investig. Drugs (2014) 23(3)

93. Joy B, Sivadasan R, Abraham TE, et al.

Expert Opin. Investig. Drugs (2014) 23(3) 443

118. Anonymous. Indian herbal pharmacopoeia.

444 Expert Opin. Investig. Drugs (2014) 23(3)

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