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Biological and chemical properties of Zingiber zerumbet
Smith: a review
C. B. Singh •Kh. Nongalleima •
S. Brojendrosingh •Swapana Ningombam •
N. Lokendrajit •L. W. Singh
Received: 29 October 2011 / Accepted: 31 October 2011 / Published online: 1 December 2011
ÓSpringer Science+Business Media B.V. 2011
Abstract Numerous researches have been carried
out in Zingiber zerumbet Smith. Since 1944 till date.
Z.zerumbet is a monocotyledonous perennial medic-
inal plant belonging to Zingiberaceae family. It is
commonly known as shampoo ginger. It has many
different local names depending on their area of
collection and vegetation. It is called as ‘Singkha’ in
Manipuri. Various compounds have been reported to
be isolated from Z.zerumbet and they serve a very
potent and reliable drug candidate for the various
diseases. They have been investigated for its prospects
of effectiveness against number of activities in in vitro
as well as in vivo and mechanisms that may be
involved in chemo preventive measures and various
pharmaceutical studies.
Keywords Anti-cancer Anti-inflammation Anti
HIV Anti-AD (Alzheimer’s disease) Multipotential
bioactivities
Introduction
The rhizomes of Zingiberacea family are vegetables
widely used in many Asian countries, and their
medicinal functions have been broadly discussed and
accepted in many traditional recipes (Chen et al. 2008).
Members of Zingiberaceae are usually aromatic in all
or most parts or at least one of the plant parts and many
species are known to be rich in terpenoids (Christine
2007). Zingiber zerumbet is a wild ginger that grows in
wide ranges around Southeast Asia (Jang et al. 2004).
It is called as Narkachur (Bokyung et al. 2008). The
main compound of volatile oil was found to be
zerumbone 56.48% (Hossain et al. 2005). Z.zerumbet
has been used traditionally for the treatment of
stomach ache, toothache, fever, sprain and indigestion
(Huang et al. 2005a,b). Besides, it is also used as the
spice ginger and a novel factor for mitigating exper-
imental ulcerative colitis (Sharifah et al. 2007).
Compounds of Zingiber zerumbet
As many as 70% of all the drugs approved by the US
Food and Drug Administration in the past 25 years
have been based on natural products (Supachai et al.
2009). The chemistry of volatile components of
Z.zerumbet has been studied by various authors since
1944 (Varier 1944; Duve 1980; Oliveros and Cantoria
1982; Thebpatiphat 1984; Dung et al. 1993; Srivastava
et al. 2000; Malek et al. 2005). Z.Zerumbet was steam
distilled and purified Zerumbone from essential oil of
C. B. Singh (&)Kh. Nongalleima S. Brojendrosingh
Institute of Bioresources and Sustainable Development,
Imphal 795001, India
e-mail: Kishore.ibsd@nic.in
S. Ningombam
S Kula Women College, Nambol, Manipur 795134, India
N. Lokendrajit L. W. Singh
Department of Chemistry, Manipur University, Canchipur
795003, India
123
Phytochem Rev (2012) 11:113–125
DOI 10.1007/s11101-011-9222-4
the rhizomes (Fukuoka et al. 2004). The content of
zerumbone, the major constituent of the rhizome oil of
Z.zerumbet, varied in the range 12.6–73.1% in these
studies from various geographical locations (Varier
1944; Duve 1980; Chane-Ming et al. 2003; Damod-
aran and Dev 1965; Damodaran and Dev 1968a,b,c;
Dev 2006; Kitayama et al. 1999). Zerumbone and a-
caryophyllene have been reported as major constitu-
ents in oils as well as in almost all the leaves and
rhizome oil of the world (Nigam and Levi 1963a).
Ahmad et al. (1994) extracted rhizomes of Z.zerumbet,
they placed a silica column in-line to obtain an
extraction of non polar components. Rana et al. (2008)
identified 13 constituents in Z.zerumbet rhizome oil.
Zerumbone, the anticancer marker from different
parts of Z.zerumbet, was determined by Soxhlet
extraction with chloroform and developed with EtAc-
hexane (15:85) mobile phase (Sherma 2010). The rf
value was 0.9997 in the 60–260 ng range; LOD and
LOQ were 20 and 60 ng, respectively; instrumental
precision and repeatability were 0.8 and 1.1%,
respectively; and recovery ranged from 97.8 to
100%. The maximum amount (1.8%) was found in
the rhizome (Rout et al. 2009). There is report on the
isolation of aromatic compounds and Kaemferol
derivatives from the chloroform soluble fraction of
the methanol extract of the rhizomes of Z.zerumbet
(Jang et al. 2004). Jang and Seo (2005) reported
potentially bioactive two new natural sesquiterpenoids
(6-methoxy-2E, 9E-humuladiene-8-one Stigmast-4-
en-3-one) from the rhizome of Z.zerumbet. The
structure, previously assigned to zerumbone, has been
found to be untenable. The ketone has been shown to
be monocyclic containing three ethylenic linkages,
and has been further correlated with humulene.
Results from ozonolysis, and base-catalysed cleavage
allowed the compound to be formulated as 2,6,9,9-
tetramethyl-2,6,10-cyclo-undecatrien-1-one (Dev
1960). A complete analysis of the essential oil from
the rhizomes of Z.zerumbet Smith.was given and the
isolation of several new humulene-based sesquiterp-
enoidswas described (Damodaran and Dev 1968a).
(?)-Humulenol-II, a minor component of the volatile
oil from the rhizomes of Z.zerumbet, was shown to
possess the absolute stereostructure I and had been
directly correlated with (-)-humulene epoxide-II. The
preparation of (?)-humulenol-I was also described
(Damodaran and Dev 1968b). Two new oxygenated
derivatives of humulene, viz., humulene monoxide (II)
and humulene dioxide (VIII) have been isolated from
the sesquiterpene fractions of wild ginger oil (Z.ze-
rumbet, Smith). The structures of these two epoxides
have been determined by degradative and synthetic
studies (Ramaswami and Bhattacharyya 1962). Evi-
dence leading to the assignment of absolute stereo-
structures I and II to (-)-humulene epoxide-I and (-)-
humulene epoxide-II respectively, was presented.
Partial synthesis of (±)-humulene epoxide-I and -II
by epoxidation of humulene, adsorbed on SiO2 gel–
AgNO3, with one mole of per acid was described
(Damodaran and Dev 2006c). Three new acetylated
and one known kaempferol glycosides have been
isolated from the rhizomes of Zingiber zerumbet and
their structures determined to be the 3-O-(2-O-acetyl-
a-l-rhamnopyranoside), 3-O-(3-O-acetyl-a-l-rhamno-
pyranoside), 3-O-(4-O-acetyl-a-l-rhamnopyranoside)
and 3-O-a-l-rhamnopyranoside on the basis of spec-
troscopic methods (Masuda et al. 1991).
It might be supposed that a high amount of 4-O-
Caffeoylquinic acid was obtained by isomerization
among chlorogenic acid isomers, because it previously
happened to find that isomerization of some plant
components occurred during the extraction with protic
solvent (Nakatani et al. 1991). Compounds that have
been shown to have physiological activities against
cancer cells were used for assaying inhibitory effects
on the proliferation of VSMCs-Vascular Smoothe
Muscle Cells (Fukuoka et al. 2004). Volatile oil
components in Zingiber zerumbet smith rhizomes was
studied by gas chromatography (Supinya et al. 1997).
Response surface methodology (RSM) was applied
to optimize the variables affecting the SuperCritical-
Carbon dioxide (SC–CO
2
) extraction of non-polar
compounds from Z.zerumbet using the Box-Behnken
design (BBD) (Norulaini et al. 2009). Hongliang et al.
(2005) did metabolic profiling and phylogenetic
analysis of medicinal Zingiber species, Tools for
authentication of ginger (Zingiber officinale Rosc.)
including Z.zerumbet. Other applications of super-
critical fluids may be of interest to the analytical
chemist (Table 1; Fig. 1).
Multipotential bioactivities of Zingiber zerumbet
and its compounds
Many researchers reported on different potential
bioactivities of different extracts of Zingiber zerumbet
114 Phytochem Rev (2012) 11:113–125
123
Table 1 The Biological activities of the extracts are listed as follows
Extract Source Bioactivity References
Methanol Rhizome Biological activities Kitayama et al. (1999), Kitayama et al.
(2001)
Methanol Rhizome Anti-inflammatory property Murakami et al. (2003)
Methanol Rhizome Antiflatulant and anti-inflammatory agent Wutthithamavet (1997)
Methanol Rhizome Anti-inflammatory activity Chaungab et al. (2008), Dambisiya and
Lee (1995)
Methanol Rhizome Chemopreventiive, anti-inflammatory, free radical scavenging
activities and activating properties
Abdul et al. (2008)
Methanol Rhizome Potential drug for the treatment of several cancers as well as
leukemia
Kirana et al. (2003), Murakami et al.
(2004), Sharifah et al. (2007), Xian
et al. (2007)
Methanol Rhizome Anti-tumour activity Kinghorn et al. (1997), Rasmos et al.
(2005)
Hexane Rhizome Inhibit the proliferation of human colonic adenocarcinoma cell
lines in a dose dependent manner, while the growth of normal
human dormal and colon fibroblast was less affected
Nakamura et al. (2004,)
Methanol Rhizome Anti-tumour promoting effect Koshimizu et al. (1988), Nishino et al.
(1988)
Methanol Rhizome Prevent colon and skin cancer Tanaka et al. (2001)
Methanol Rhizome Redox regulated mechanism may account for zerumbone’s
ability to suppress cancer cell proliferation
Ohigashi and Murakami (2002)
Aqueous Rhizome Anti-tumour/anti-apoptotic activity Abdel Wahab et al. (2009), Hamid et al.
(2007) and Chung et al. (2007)
Methanol Rhizome Antinociceptic activity Sulaiman et al. (2009), Helen et al. (2009)
Ethanol Rhizome The effective activity of Zingiber zerumbet against
Staphylococcus aureus
Voravuthikunchai et al. (2006)
Aqueous
and
Methanol
Rhizome Elicitate moderate to marked antipyretic activities which was
dose dependent
Somchit and Shukriyah (2005)
Methanol Rhizome Against normal mouse fibroblast Murakami et al. (2002)
Methanol Rhizome Suppress free radicals (superoxide anion) generation from
NADPH oxidase xanthine oxidase
Murakami et al. (2002)
Methanol Rhizome Curative effect of zerumbone in a dose dependent manner on
the osteoarthritic knee joints, and reported that oral
administration
Al-Saffar et al. (2010)
Aqueous Rhizome Development of anti-AD (Alzheimer’s disease) treatment Bustamam et al.(2008)
Methanol Rhizome Chemopreventive activity Taha et al. (2010)
Methanol Rhizome Hepatoprotective activity Nakamura et al. (2004)
Methanol Rhizome Immune-modultory activity Keong et al. (2010)
Methanol Rhizome Anti-edema activity when assessed using the carrageenan-
induced paw edema test and the cotton-pellet induced
granuloma test
Zakaria et al. (2010)
Methanol Rhizome Antipancreatic activity Szabolcs et al. (2007)
Purchased The various beneficial effects of b-eudesmol isolated Fengnian et al. (2008)
Treating epileptic seizures Chiou et al. (1997)
Methanol Rhizome Angiogenic diseases Kimura (2005)
Pentane Rhizome Dementia Obara (2006)
Ethanol Rhizome HIV inhibitory and other cytotoxic activities Dai et al. (1997)
Phytochem Rev (2012) 11:113–125 115
123
Zerumbone
α-humulene
Zederone
6-methoxy-2E, 9E- humuladien-8-one
Vanillin
Kaemferol-3, 4′, 7-O-trimethylether Kaemferol-3 -O-methylether Caryophyllene
Kaemferol-3, 4
′
-O-dimethylether 4″-O-acetylafzelin
Kaemferol-3 -O-(4-O-acetyl-α-1-rhamnopyranoside) 2 ″, 4″ - O - diacetylafzelin
Kaemferol-3 -O-(2, 4-O-diacetyl-
α
-1-rhamnopyranoside) 3 ″, 4″-O- diacetylafzelin
P-hydroxybenzaldehyde
Fig. 1 Compounds isolated
from Z.zerumbet Smith
116 Phytochem Rev (2012) 11:113–125
123
against different ailments and diseases. The a,
b-unsaturated carbonyl group at C8 of the 11-mem-
bered ring zerumbone is the moiety responsible for its
biological activities (Kitayama et al. 1999,2001).
Chane-Ming et al. (2003) reported that oils from
leaves and flowers of Z.zerumbet differed especially
from rhizomes of Z.zerumbet.Z.zerumbet showed a
versatile pharmacological properties such as anti-
atherosclerosis (Eguchi et al. 2007), anti-inflamma-
tory, insulin-like grow factor-1 and induced Waf-1
gene expression, glutathione S-transferase activity and
heat shock protein. Zerumbone was also found to exert
induction of differentiation and cytoprotective activity
(Rodriguez et al. 1997).
Anti-inflammatory activity
Zerumbone which is used as anti-inflammatory folk
medicine in Indonesia was a distinct potent inhibitor of
12-O-tetradeconyl-13-acetate-induced Epstein Barr
Virus (Murakami et al. 1999; Vimala et al. 1999).
Elliot and Brimacombe (1987) reported that zerum-
bone also possessed an anti-inflammatory property
especially in treating ulcerative colitis, which is an
inflammatory bowel disease (Murakami et al. 2003).
Chaungab et al. (2008) reported the anti-inflammatory
potential, especially in asthmatic patients and the
capacity of water extract of Z.zerumbet in protecting
the lungs by inhibiting the release of inflammatory
mediators during short-term treatment and modulating
cytokine gene expression during long term treatment.
Murakami et al. (2003), Abdul et al. (2008) reported
the chemopreventive, anti-inflammatory, free radical
scavenging activities and activating properties of
Z.zerumbet towards phase II drug metabolizing
enzymes. Z.zerumbet Smith is a medicinal ginger
containing zerumbone which has been shown to have
anti-inflammatory properties and inhibitory activities
against Epstein Barr virus which can cause many
cancers (Idris et al. 2009). The association between
inflammation and nociception has previously been
reported (Roosterman et al. 2006). Examined effect of
zerumbone on the expression of pro-inflammatory
genes in human colon adenocarcinoma cell lines,
Caco-2, Colo320DM, and HT-29, using reverse tran-
scription-polymerase chain reaction (RT-PCR) assays,
and reported that zerumbone markedly induced the
expression of interleukin (IL)-1a, IL-1b, IL-6, and
tumor necrosis factor (TNF)-ain each cell line in
concentration- and time-dependent manners and
implied that zerumbone increases the production of
pro-inflammatory cytokines in cancerous tissues in the
colon. Z.zerumbet was reported as anti-flatulent and
anti-inflammatory agent (Wutthithamavet 1997). The
acetic acid-induced writhing reaction in mice, a
standard model for inflammatory pain, has long been
used as a screening tool for assessment of analgesic or
anti-inflammatory properties of new agents (Hunskaar
and Hole 1987). EtOH and water extracts from the
rhizomes of five selected Zingiberaceous plants used
for treatment of inflammation in Thai traditional
medicine, including Curcuma mangga,Kaempferia
galanga,Kaempferia parviflora,Z.officinale and
Z.zerumbet were investigated for their anti-inflam-
matory activities using RAW264.7 cell line (Supinya
and Sanan 2007). Z.zerumbet inhibited inflammation
induced by prostaglandin rat paws (Dambisiya and
Lee 1995).
Anti-cancer and anti-apoptogenic activity
Recent research on Z.zerumbet has demonstrated that
zerumbone is a potential drug for the treatment of
several cancers as well as leukemia (Kirana et al.
2003; Murakami et al. 2004; Sharifah et al. 2007; Xian
et al. 2007). Kaemferol derivatives components of
Z.zerumbet is a scaffold for developing agents that
reverse P-gp-mediated Multi Drug Resistant (MDR) in
human cancer chemotherapy (Han et al. 2005).
Hossain et al. (2005) reported 2,6,9,9-tetramethyl
from Z.zerumbet. Further reported that the extract
decreased the release of tumour necrosis factor-alpha
and interleukin-4 (IL-4) in vitro and effectively
suppressed LTC4 release from lung tissue in vivo.
Zerumbone has been found able to exert anti-tumour
activity (Kinghorn et al. 1997; Koshimizu et al. 2002).
Zerumbone suppressed the activation of NF-KB and
NF-KB regulated gene expression induced by carcin-
ogens, and reported that this inhibition may provide
molecular basis for the prevention and treatment of
cancer (Takada et al. (2005). Mechanisms of inducing
apoptosis in the hepatocarcinoma cells by zerumbone
was carried out in vitro using a well differentiated
transformed cell line HepG2 cells which have been
widely used and considered to be a good model for
liver cancer research (Rasmos et al. 2005). It is
identified that the inhibition of Epstein Barr Virus
(EBV) early antigen (EA) activation which was
Phytochem Rev (2012) 11:113–125 117
123
induced by tumour-promoters in vitro correlated well
with the zerumbone anti-tumour promoting effects in
vivo (Koshimizu et al. 1988; Nishino et al. 1988).
Bokyung et al. (2008) reported that zerumbone
component of Z.zerumbet down regulated the expres-
sion of CXCR4 and HER2-overexpressing breast
cancer cells in a dose and time dependent manner.
The compound was shown to inhibit the proliferation
of human colonic adenocarcinoma cell lines in a dose
dependent manner, while the growth of normal human
dormal and colon fibroblast was less affected (Na-
kamura et al. 2004). Tanaka et al. (2001) demonstrated
the inhibition ability of zerumbone on both azoxyme-
thane induced rat aberrant crypt foci and phorbol ester
induced papilloma formation in mouse skin a further
indication of its efficiency to prevent colon and skin
cancer. The cytotoxic effect of zerumbone on leuke-
mia cells was found to be mediated through the
induction of Fas receptors (Xian et al. 2007). Mura-
kami et al. (2004) did histological examination and
revealed that pretreatment(s) with zerumbone sup-
pressed leukocyte infiltration and reduced proliferat-
ing cell nuclear antigen-labeling indices, further
suggested that zerumbone is a promising and rational
agent for the prevention of skin cancers, whereas its
oral activity to prevent skin cancers and issues of
metabolism and absorption remain to be addressed.
Huang et al. (2005a,b) observed the cell cycle of
HL-60 cells after treatment with zerumbone, which
induced G (2)/M cell cycle arrest in HL-60 cells in a
time- and concentration-dependent manner, and
decreased the cyclin B1/cdk 1 protein level and
suggested that zerumbone is an active principal of
Z.zerumbet and is potentially a lead compound for the
development of anticancer drugs. Zerumbone Down-
regulates Chemokine Receptor CXCR4 Expression
Leading to Inhibition of CXCL 12-Induced INVA-
SION of Breast and Pancreatic Tumor Cells (Nigam
and Levi 1963b). Ohigashi and Murakami (2002)
suggested that redox regulated mechanism may
account for zerumbone’s ability to suppress cancer
cell proliferation, further suggested additional exper-
iments like (1) Measurement of the intracellular
[GSSG]/[GSH] of some normal and cancer cell lines
which are treated,or not treated, with ZER. (2)
Exploration of the relationships among the Evalues,
phosphorylation states of RB protein and cell growth
rates. (3) Confirmation of the production of an
intracellular GSH–ZER adducts. Kirana et al. (2003)
reported that zerumbone inhibited the growth of
human leukemia cell lines (HL-60 cell) and human
colon cancer (HT-29) in vitro. In 2005, Takada and his
groups found that zerumbone suppressed the activa-
tion NF-kB and NF-kappa bregulated gene expression
induced by carcinogenesis, and reported that this
inhibition may provide molecular basis for the
prevention and treatment of cancer. Abdul et al.
(2008) demonstrated the MTT assay and reported the
effective inhibition of zerumbone on cell proliferation
of human cervical cancer cells (HeLa) in a dose
dependent manner. Hoffman et al. (2002) proposed
redox model of cell proliferation which stresses the
importance of intracellular redox potential E in the
control of proliferation of normal and cancer cells.
Further they pointed to the a,b-unsaturated carbonyl
group in Zerumbone as the likely source of the effect.
They called the finding ‘intriguing’. The stimulation of
neoplastic cell death by Zerumbone was reported to be
through the mitochondrial pathway of apoptosis
(Abdel Wahab et al. 2009). Zerumbone has also been
reported having the capacity to induce apoptosis and
morphological changes in different types of leukemic
cells (Hamid et al. 2007). Chung et al. (2007) reported
histone deacetylase inhibitors from the rhizomes of
Z.zerumbet. Histone deacetylase (HDAC) inhibitors
that inhibit proliferation and induce differentiation
and/or apoptosis of tumor cells in culture and in animal
models have been identified. A number of structurally
diverse histone deacetylase inhibitors have shown
potent antitumor efficacy with little toxicity in vivo in
animal models. The histone deacetylase (HDAC)
activities of compounds 1 and 2 were determined in
vitro against HDAC enzyme assay and showed
potential inhibitory activity in histone deacetylase
(HDAC) enzyme assay (GI50 =1.25 lM). It also
exhibited growth inhibitory activity on five human
tumor cell lines and more sensitive inhibitory activity
on the MDA-MB-231 breast tumor cell line
(IC50 =1.45 lM).
Antinociceptive activity
The Methanol Extract of Z.zerumbet exhibit signif-
icant antinociceptive activity when assessed by the
writhing, hot plate and formaline tests. Sulaiman et al.
(2009) investigated the antinociceptive activity of
zerumbone, a natural cyclicsesquiterpene isolated
from Z.zerumbet Smith, in acetic acid-induced
118 Phytochem Rev (2012) 11:113–125
123
abdominal writhing test and hot plate test in mice. The
antinociceptive effect of zerumbone in the hot plate
test was reversed by the non-selective opioid receptor
antagonist naloxone, suggesting that the opioid system
was involved in its analgesic mechanism of action.
Zerumbone was obtained from repetitive recrystalli-
zation from the crude hydrodistillate. They provided
convincing evidence indicating that zerumbone
isolated from Z.zerumbet possessed significant
peripheral and central antinociceptive effects in lab-
oratory animals at the doses investigated.
Antimicrobial activity
Kader et al. (2010) isolated sesquiterpene, zederone
from the crude ethanolic extract of the rhizomes of
Z.zerumbet (L.) Smith. The antibacterial activity of
this compound was determined against a number of
multi-drug resistant and methicillin-resistant Staphy-
lococcus aureus strains (SA1199B, ATCC25923,
XU212, RN4220 and EMRSA15) and minimum
inhibitory concentration (MIC) values were found to
be in the range of 64–128 lg/ml. The Z.zerumbet oil
showed significant inhibitory activity against the
bacteria, Staphylococcus aureus (1.2 cm), Lactococ-
cus lactis (0.8 cm), and the fungus Aspergillus
awomori (1.5 cm), Fusarium oxysporum (1.0 cm),
Aspergillus accularatus (0.9 cm), Candida albicans
(0.8 cm), Tricoderma viridae (0.8 cm), Rhodotorula
sps. (0.8 cm) and Aspergillus niger (0.6 cm) Helen
et al. (2009). No inhibitory activity was observed
against the bacteria, Bacillus cereus and E.coli.
Voravuthikunchai et al. (2006) reported the effective
activity of Zingiber zerumbet against Staphylococcus
aureus, MIC (Minimum Inhibitory Concentration)
values and MBC (Minimmum Bactericidal Concen-
tration) values reported were 0.79 mg/ml and
[12.5 mg/ml, respectively. Zerumbone ring-opening
derivative, 4 (10E/10Z =3/2), inhibited autophos-
phorylation of the essential histidine–kinase YycG
existing in Bacillus subtilis constituting a two-com-
ponent system (TCS). However, it did not inhibit drug-
resistant bacterium such as MRSA and VRE. Kiat and
Richard (2006) screened selected zingiberaceae
extracts for dengue-2 virus protease inhibitory activ-
ities and the results show that the methanol fractions of
Curcuma longa and Zingiber zerumbet, and both the
methanol and hexane fractions of CM were most
potent against Den2 virus NS2B/NS3 protease activity
and may provide potential leads towards the develop-
ment of anti-viral agents. The percentage inhibition of
Den2 virus NS2B/NS3 protease cleavage of the
substrate showed linear dose-dependent increment
for all the samples tested.
Antiplatelet aggregation activity
Twelve compounds isolated from Alpinia mutica
Roxb., Kaempferia rotunda Linn., Curcuma xanthorh-
iza Roxb., Curcuma aromaticaValeton and Zingiber
zerumbet. Smith and three synthesized derivatives of
xanthorrhizol were evaluated for their ability to inhibit
arachidonic acid—(AA), collagen- and ADP-induced
platelet aggregation in human whole blood (Jantan
et al. 2005), further they reported that methanol
extracts of the fruit of A.muticam and the rhizomes of
K.rotunda,C.xanthorrhiza,C.domestica and Z.ze-
rumbet showed strong antiplatelet aggregation activity
at 100 mg/ml in human whole blood in vitro, with all
extracts exhibiting 100% inhibition. Jantan et al.
(2005) investigated forty-nine methanol extracts of 37
species of Malaysian medicinal plants were for their
inhibitory effects on platelet-activating factor (PAF)
binding to rabbit platelets, using 3H-PAF as a ligand,
where Z.zerumbet was one of the compounds,
however it was not found to be PAF antagonistic.
Antipyretic and cytotoxic activity
The ethanol and aqueous extract of Z. zerumbet
elicitate moderate to marked antipyretic activities
which was dose dependent (Somchit and Shukriyah
2005). Further added that the ethanol extract revealed
dose dependent analgesic property which was signif-
icantly different than control. The aqueous extract was
devoid of any analgesic effects 50 and 100 mg/kg. The
analgesic activity of 10 mg/kg Z. zerumbet ethanol
extract was similar to 0.8 mg/kg morphine. Zerum-
bone has been found to exhibit cytotoxic activities on
Hepatoma Tissue Culture (HTC), a neoplastic rat liver
strain cultured in vitro and was found to be selective
against normal mouse fibroblast (Murakami et al.
2002). Murakami et al. (2004) reported similar
findings that the carbonyl group at the 8-position in
zerumbone is the important structural element for its
chemopreventive potential. Combination of both Cis-
platin and toxol induce apoptosis in epithelial ovarian
cancer (Havrilesky et al. 1995; Ormerod et al. 1996).
Phytochem Rev (2012) 11:113–125 119
123
The mechanism underlying the activity of Z.zerumbet
for its anti-pyretic and analgesic is still unknown.
Antihyperglycaemic activity
Reported screening of aqueous extract of Phyllantus
niruri (PL), Z.zerumbet (ZGr), Eurycoma longifolia
(TA-a and TA-b) and Andrographis paniculata (AP)
to determine their blood glucose lowering effect were
conducted in normoglycaemic and Streptozotocin-
induced hyperglycaemic rats. Treatment using aque-
ous extract of TA-a, TA-b, PLr and ZGr at dosages of
50 and 100 mg/kg BW did not show many significant
reduction in blood glucose levels in hyperglycaemic
rats (data not shown) but at the dosage of 150 mg/kg
BW, blood glucose level decreased at 37.88, 46.80,
13.94 and 22.19% when treated with TA-a, TA-b, PLr
and ZGr, respectively, in hyperglycaemic rats
(P\0.05, P\0.001) showed that no antihypergly-
caemic activity was observed in both raw and freeze–
dried aqueous extract of PL and ZG at all concentra-
tion used.
LPS (lipopolysaccharide)-induced NO production
Jang et al. (2005) reported the isolation of a novel
humulene derivative, 5-hydroxyzerumbone, from
Z.zerumbet and its inhibitory activity on lipopolysac-
charide (LPS)-induced nitric oxide (NO) production in
RAW 264.7 mouse macrophage cells. Treatment with
5-hydroxyzerumbone also induced the expression of
heme oxygenase-1 (HO-1) in macrophage cells. In
addition, 5-hydroxyzerumbone inhibited LPS-induced
transcriptional activation of NF-jB, indicating that
regulation of NF-jB activity might be involved in the
inhibition of NO production by 5-hydroxyzerumbone.
5-Hydroxyzerumbone, however, did not affect the
degradation of IjB-aand the activation of p38 and
ERK in LPS-treated cells. They summarized the study
and suggested that 5-hydroxyzerumbone inhibits LPS-
induced NO productionin macrophage cells through
down-regulating iNOS protein and mRNA
expressions.
Anti-oxidant activity
Murakami et al. (2002) reported that zerumbone was
able to suppress free radicals (superoxide anion)
generation from NADPH oxidase xanthine oxidase,
expression of iNOS (inducible nitric oxide synthase)
and COX (cyclo-oxygenase)-2 as well as release of
TNF-a. Ibrahim et al. (2009) reported the preventive
effect of zerumbone in cisplatin-induced liver dys-
function and organ damage in rats via prevention of
lipid peroxidation and preservation of anti-oxidant
glutathione. Further reported that morphological fea-
tures of liver from zerumbone injected animals is
similarly near to the morphology with normal hepa-
tocytes, Kupffer cells and sinusoids.
Chondroprotective activity
Al-Saffar et al. (2010) revealed curative effect of
zerumbone in a dose dependent manner on the
osteoarthritic knee joints, reported that oral adminis-
tration of zerumbone in a dose of 2 ml/kg b. wt. of
0.4% w/v diluted with corn oil for a period of 4 weeks
had some chondroprotective effects on the knee
osteoarthritis of the Sprague–Dawley rats. Z.zerumbet
is used in herbal medicinal practice for the treatment
of rheumatological conditions and muscular discom-
fort (Bordia et al. 1997; Langner et al. 1988).
Anti-AD (Alzheimer’s disease)
Bustamam et al. (2008), had done a study where the
inhibitory effect of ZER towards acetyl cholinesterase
was evaluated using thin layer chromatography (TLC)
bioautography and compared concurrently to tacrine,
as positive control. The results obtained showed that
ZER had an enzymolytic effect towards AChE (Acetyl
Cholinesterase). It could be suggested that ZER might
be a potential candidate for the development of anti-
AD (Alzheimer’s disease) treatment.
Chemopreventive activity
Taha et al. (2010) reported potential chemopreventive
activity of zerumbone from the rhizomes of the
subtropical ginger (Z.zerumbet) against diethylnitro-
samine-initiated and 2-acetylaminofluorene-promoted
hepatocarcinogenesis.
Hepatoprotective activity
The hepatoprotective activity of ZER may be through
the enhancement of drug-metabolising enzyme activ-
ity (Nakamura et al. 2004). It is postulated that in the
120 Phytochem Rev (2012) 11:113–125
123
hepatocytes, the antioxidant effect of ZER is through
the neutralisation of lipid peroxidation.
Immuno-modulatory activity
Keong et al. (2010) reported the immunomodulatory
effects of zerumbone towards the lymphocytes prolif-
eration (mice thymocytes, micesplenocytes and
human peripheral blood mononuclear cells, PBMC),
cell cycle progression and cytokine (intraleukin 2 and
12) induction.
Anti-edema
Zakaria et al. (2010) reported methanol extract of
Z.zerumbet (MEZZ) showed significant anti-edema
activity when assessed using the carrageenan-induced
paw edema test and the cotton-pellet induced granu-
loma test. Z.zerumbet has been shown to inhibit
prostaglandin induced paw edema, a commonly used
acute inflammatory reaction and the efficacy is
equivalent to the non sterouidal anti-inflammmatory
drug, mefanamic acid.
Antipancreatitic activity
Szabolcs et al. (2007) reported zerumbone to be
supressor of Cholecystokinin octapeptide induce acute
pancreatitis in rats and increases in survival of p388
bearing CDF-1 mice. Zerumbone ameliorated the
changes of several parameters of acute pancreatitis
probably by interfering with I-jB degradation, but in
the applied dose, it failed to influence the histology of
the disease.
Antiallergic activity
Ethanolic and water extracts, together with volatile
oils from the rhizomes of six selected Zingiberaceous
plants, including Curcuma mangga,Kaempferia
galanga,Kaempferia parviflora,Zingiber cassumun-
ar,Zingiber officinale and Z.zerumbet were investi-
gated for their antiallergic activities using a RBL-2H3
cell line (Supinya and Sanan 2007).
Anti-oomycete activity
In molecular docking studies, a linear polymeric
molecule of (1,3)-B-D-glucan, a major constituent of
the oomycete cell wall fitted favourably into the
surface cleft of ZzPR5 (Z.zerumbet Pathogenesis
Related Protein 5) and interacted with acidic amino
acid known to be involved in glucanhydrolysis,
suggesting a potential anti-oomycete activity for
ZzPR5 protein. Elucidation of the molecular mecha-
nism of ZzPR5 may provide important insight towards
engineering soft rot resistance into the obligatory
asexual ginger (Aswati Nair et al. 2010).
Antiepileptic seizures and angiogenic activity
Fengnian et al. (2008a,b) reported the various
beneficial effects of b-eudesmol on human health
and was considered to be a lead compound for treating
epileptic seizures (Chiou et al. 1997), angiogenic
diseases (Kimura 2005) and dementia (Obara 2006).
Micronucleus formation
The chromosomal aberrations (CA) assay and micro-
nucleus (MN) test were employed to investigate the
effect in vitro of zerumbone (ZER) on human chro-
mosomes. The results of chromosomal aberrations
assay showed that ZER was not clastogenic, when
compared to untreated control, meanwhile MN test
results showed a dose-dependent increase in MN
formation (Al-zubairi et al. 2007).
Enzyme activation activity
Zerumbone also activated phase two drug metabolizing
enzymes, such as GST (Glutathione S-transferase),
epoxide hydrolase and hemeoxygenase via the tran-
scription factor Nrf2-dependent pathway (Nakamura
et al. 2004) and was able to inhibit HIV (Dai et al. 1997).
Harada et al. (2009)reportedthatwhenthea-humulene
synthase (ZSS1) gene of shampoo ginger was expressed
in the transformant, the resultant E.coli produced
958 lg/ml culture of a-humulene with a lithium aceto-
acetate (LAA) supplement, which was 13.6-fold
increase compared with a control E.coli strain express-
ing only ZSS1. Fengnian et al. (2010)reported
Z.zerumbet CYP71BA2 catalyses the conversion of
a-humulene to 8-hydroxy-a-humulane in zerumbone
biosynthesis. Further reported co-expression of a gene
cluster encoding four enzymes of the mevalonate
pathway with CYP71BA1 and ZSS1 in E.coli leads to
the production of 8-hydroxy-a-humulene in the presence
Phytochem Rev (2012) 11:113–125 121
123
of mevalonate, suggesting the possibility of microbial
production of this zerumbone intermediate from a
relatively simple carbon source by metabolic engi-
neering. Zerumbone is known to be a potent suppres-
sant of cyclo-oxygenase (COX) and inducible nitric
oxide synthesis expression (Murakami et al. 2003).
Fengnian et al. (2008b) isolated a terpenecyclise gene
(ZSS1) from shampoo ginger Zingiber zerumbet Smith
and identified ZSS1 as the a-humulene synthase gene
that mediates the conversion from FPP to a-humulene
(a-caryophyllene).
Anti-HIV
Dai et al. 1997 reported that Zerumbone displayed
HIV inhibitory and other cytotoxic activities. Zerum-
bone was found to exert anti-HIV effects (Ozaki et al.
1991; Kirana et al. 2003; Xian et al. 2007).
Other activities
In southeast Asia, Z.zerrumbet is used for the treatment
of fever, constipation, and to relieve pain (Peri 1980).
Z.zerumbet is commonly used to treat cases of
diarrhoea in Thai Traditional medicine (Farnsworth
and Bunyapraphatsara 1992). Zerumbone found in
some edible parts, including young stems and inflo-
rescence, are used in traditional cooking. Bensch and
Akesson (2005) reported the amplified fragment length
polymorphism (AFLP) as an ideal marker technique
for genetic diversity studies of poorly characterized
plant species like Z.zerumbet.Z.zerumbet and
Kaemferia galangal were found to express Epstein-
Barr virus early antigen (EBV-EA) activation inhibi-
tory activity in Raji cells (Vimala et al. 1999). Huang
et al. (2005a,b) identified that zerumbone inhibited the
growth of p-388 D cells and induced DNA fragmen-
tation in culture and significantly prolonged the life of
p-388 D (1) bearing CDF (1) mice. The sesquiterpene
zerumbone isolated from Z.zerumbet, inhibited Gli1-
and Gli2-transcription with IC50 values of 7.1 and
0.91 lM, respectively, showing sevenfold selectivity
for Gli2 over Gli1 (Neeraj et al. 2009).
Conclusion
The study of Z.zerumbet and its compounds offers
many oppurtunities to investigate the various functions
and prospects in various pharmaceutical studies.
Zerumbone gained certain significances as pharma-
ceutical compounds. It become more evident about its
potential from the bioactivities reviewed above based
on the work of various researchers. Developed
analytical tools and the effective action on various in
vitro and in vivo studies may bring numerous oppor-
tunities to further unravel the potential bioactivies. As
compounds of Z.zerumbet are effective against many
types of cancer and because cancer is one of the
dreaded disease prevalent in the world and even it was
found effective against HIV, it is worthwhile studying
the accumulation of zerumbone and other different
compounds in different parts of the Z.zerumbet.
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