- Access to this full-text is provided by Hindawi.
- Learn more
Download available
Content available from Evidence-based Complementary and Alternative Medicine
This content is subject to copyright. Terms and conditions apply.
Review Article
Propolis: A Complex Natural Product with
a Plethora of Biological Activities That Can Be
Explored for Drug Development
Ricardo Silva-Carvalho,1,2 Fátima Baltazar,1,2 and Cristina Almeida-Aguiar3
1Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal
2ICVS/3B’s, PT Government Associate Laboratory, Guimar ˜
aes, 4710-057 Braga, Portugal
3Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), Biology Department,
University of Minho, 4710-057 Braga, Portugal
Correspondence should be addressed to Cristina Almeida-Aguiar; cristina.aguiar@bio.uminho.pt
Received February ; Revised May ; Accepted May
Academic Editor: Jairo Kennup Bastos
Copyright © Ricardo Silva-Carvalho et al. is is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
e health industry has always used natural products as a rich, promising, and alternative source of drugs that are used in the health
system. Propolis, a natural resinous product known for centuries, is a complex product obtained by honey bees from substances
collected from parts of dierent plants, buds, and exudates in dierent geographic areas. Propolis has been attracting scientic
attention since it has many biological and pharmacological properties, which are related to its chemical composition. Several in
vitro and in vivo studies have been performed to characterize and understand the diverse bioactivities of propolis and its isolated
compounds, as well as to evaluate and validate its potential. Yet, there is a lack of information concerning clinical eectiveness. e
goal of this review is to discuss the potential of propolis for the development of new drugs by presenting published data concerning
the chemical composition and the biological properties of this natural compound from dierent geographic origins.
1. Introduction
Over the years, nature is continually surprising with diver-
sied natural compounds that can be promising sources for
the discovery of new drugs important in medicine []. In
fact, approximately half of the currently available drugs were
obtained from natural compounds or related []. e use of
naturalproductsasanessentialroutetonewpharmaceutical
leadsiscontinuallygrowingandisaresearcheldofenor-
mous interest because the dierent structural range of natural
compounds can provide lead compounds for therapeutic
improvement based on rationalized molecular modications
[,]. It is well known that scientists have curiosity in herbs
and other natural plant products for research; however only
in the last years the interest in modied plant products
by animals, which normally have been largely ignored and
wasted, has been increased [,].
Propolis, a complex mixture of compounds also called
bee glue, is a natural resinous product that honeybees collect
from several plants and mix it with beeswax and salivary
enzymes (𝛽-glucosidase) [–]. As inferred for the meaning
of the Greek word propolis—pro-, for or in defence, and
polis,thecity[]—bees use propolis on their hives as
protection against predators and microorganisms, to repair
damage, as a thermal isolator, and to build aseptic locals
to prevent microbial infection of larvae [,,,]. Since
ancient times, propolis has been used by humans to meet
the needs of health and food preservation []; but only in
the last years the interest in this complex natural product
hasincreasedduetoitsbroadspectrumofbiologicaland
pharmacological properties [–]. Propolis is a lipophilic
material that is hard and breakable when cold but so,
exible, and very sticky when warm; it possesses an enjoyable
aromatic smell and dierent coloration, including brown,
Hindawi Publishing Corporation
Evidence-Based Complementary and Alternative Medicine
Volume 2015, Article ID 206439, 29 pages
http://dx.doi.org/10.1155/2015/206439
Evidence-Based Complementary and Alternative Medicine
green, and red, among others [,,]. In terms of chemical
composition, it is generally composed of % resin, %
wax, % essential oils, % pollen, and % other substances
which include minerals and organic compounds like phenolic
acids (cinnamic and caeic acid) or their esters, avonoids
(avones, avanones, avonols, and dihydroavonols chal-
cones), terpenes, aromatic aldehydes and alcohols, fatty acids,
stilbenes, and 𝛽-steroids [,]. Analysis of dierent samples
revealed that propolis chemical composition is dicult to
standardize because it depends on dierent phytogeographic
characteristics like vegetation, season, and environmental
conditions of the site of collection, as bees select dierent
plants in dierent habitats for propolis production [,,].
Several in vitro and in vivo studies have been describing
the plethora of biological activities and chemical proles
of propolis from dierent geographic origins. is review
highlights published data about such works focusing on the
antimicrobial, anti-inammatory, antioxidant, immunomod-
ulatory, and antitumor activities of dierent propolis types, in
order to unravel the potential of this natural compound for
the development of new drugs.
2. Use of Propolis in Ancient
and Current Times
Propolis is not a new discovery. Since bee’s domestication,
men explore its products to their own benet and propolis,
one of the most important chemical weapons of bees, is no
exception, having been employed extensively since almost
immemorial times [,,–]. It is stated that propolis use
dates back to ancient times, at least to BC, where it was
used in folk medicine and other activities in many parts of
the world []. It was familiar to the Egyptians, in particular
by the priests who controlled medicine and chemistry and
knew very well propolis antiputrefactive properties. ey
learned from the bees the embalming capacity of propolis as
this natural product is used to perform the mummication
of corpses and prevent spread of infections. e Greek
andtheRomanphysiciansalsoacknowledgedthepotential
of propolis by employing it in wound treatment, as an
antiseptic and cicatrizing agent, and as mouth disinfectant.
e Persians described propolis as a drug capable of acting
against eczemas, myalgia, and rheumatism. Populations of
the new world, like Incas, also used propolis as an antipyretic
agent.
Between the th and th century, this natural product
becameverypopularinEurope.In,intheformerUnion
of Soviet Socialist Republics (USSR), the use of propolis was
accepted in human and veterinary medicine, with several
applications including the treatment of tuberculosis, where
the regression of lung problems and recovery of appetite
wereobserved.Also,itwasbelievedtocuresomediseasesin
folk Georgian medicine. During World War II (–),
doctorsusedpropolistotreatwounds[–], but only in
, in Japan, propolis was considered as very promising in
pharmacology. Before that, propolis was considered a prod-
uct without market value, especially because its production
islowandaectshoneyproduction.Nowadays,propolis
is an important product in alternative medicine in Japan,
being widely imported from Brazil []. In the th century,
the Italian Antonio Stradivari who is considered the most
signicant and the greatest craer of string instruments, like
violins, used propolis as an ingredient in the varnish of his
instruments. Curiously, such as in the th century, propolis
is currently used in rosin for stringed instruments and in the
repair of accordions [].
Propolis is one of the few natural products that main-
tainedpopularityforalongtime,althoughitisnotconsidered
a therapeutic agent in conventional medicine. Actually, it is
widely used as a component in pharmaceutical and cosmetic
products such as antiacne creams, facial and body creams,
ointments and lotions, and several formulations for oral
hygiene [,]. It is also used in some foods and beverages,
or simply as food supplement or healthy drinks. is name
was attributed to the drinks because it is thought that propolis
improves human health and prevents diseases such as heart
disease or diabetes, among others [].
3. Origin and Composition of Propolis
Propolis knowledge has registered an important evolution
over time, due to exhaustive studies regarding its chem-
ical composition and biological activities. In the s, it
was thought that, despite its complexity, propolis chemical
composition was more or less constant. Nevertheless, in
the following years, analysis of a large number of samples
from dierent geographic origins revealed that chemical
composition of propolis is highly variable and also dicult
to standardize because it depends on factors such as the
vegetation, season, and environmental conditions of the site
of collection [,,]. Marcucci []andBankovaetal.[]
registered more than substances in propolis and recent
reports showed the presence of compounds never mentioned
before [,,,].
Generally, the main constituents of propolis are resin and
volatiles, which are substances obtained from a variety of
botanical processes in dierent parts of plants, and beeswax,
secreted by the bees []. Typical compounds are summarized
in Table . As can be seen, plant sources vary among the
dierent parts of the globe, leading to panoply of compounds.
In a review on propolis standardization, dierent resin types
were proposed: poplar propolis, birch, green, red, “Pacic,”
and “Canarian” [,]. Samples of poplar propolis (e.g.,
from Europe, North America, New Zealand, and temperate
zones of Asia) are mainly composed of avonoids, phenolic
acids, and their esters [,,], clearly dierent from
other propolis types (Tab le ). Portuguese propolis, despite
similar to the ones found in European samples, also contains
new methylated, esteried, and hydroxylated derivatives of
avonoids and pinocembrin/pinobanksin derivatives con-
taining a phenylpropanoic acid derivative moiety in their
structure [,]. Our group recently showed that propolis
from Pereiro (district of Guarda, Beira Alta) (Figure )hasa
high concentration of phenolic components [].
Poplar-type propolis is undoubtedly the most studied one
but there are many other propolis types. Recent studies have
revealed a new type of European propolis: Mediterranean
propolis. is type of propolis is distinguished by the high
Evidence-Based Complementary and Alternative Medicine
F : Crude sample of propolis from Pereiro, obtained in the
central region of Portugal (Guarda). e sample was kindly supplied
by Engineer Pedro Fernandes (Mel do Abel).
concentration of diterpenoids and is found in many regions
like Greece [,], Switzerland [], Malta [], Turkey [–
], or Algeria [,].
Propolis from tropic regions, like Brazil, Cuba, Venezuela,
and Chile, has been attracting much attention in the
last years due to its particular chemical proles. Preny-
lated phenylpropanoids, prenylated p-coumaric acids, ace-
tophenones, diterpenic acids, and caeoylquinic acids were
showntobeverycommonandabundantinpropolisfrom
Brazil, mainly from the south-eastern region [,,].
e avonoids kaempferide and isosakuranetin and some
amounts of kaempferol were also found in Brazilian samples
[]. Additionally, red propolis from the northeast regions
of Brazil presents high concentrations of phenolic acids and
the avonoids formononetin, isoliquiritigenin, liquiritigenin,
medicarpin, and biochanin A [–]. Cuban propolis has
a peculiar enrichment in polyisoprenylated benzophenones,
more specically nemorosone, and a minor content of a
mixture of xanthochymol and guttiferone E [,]making
this type of sample chemically distinct from both European
and Brazilian propolis. Propolis from Venezuela is also
composed of polyisoprenylated benzophenones in addition
to the usual constituents found in samples of tropical regions
[,,].
Information about the chemical composition of Aus-
tralian propolis is very limited despite the great biodiversity
of the island. Propolis from Kangaroo Island is mainly
composed of stilbenes, some of them being prenylated. Ad-
ditionally, it has also some prenylated cinnamic acids and
avonoids [], like ,,-trimethoxychalcone, -hy-
droxy-,-dimethoxychalcone, ,-dihydroxy--metho-
xychalcone, ,-dihydroxy-,-dihydroavonol -acetate (pi-
nobanksin -acetate), and ,-dihydroxy--methoxy-,-
dihydroavonol -acetate []. Western Australian propolis
is composed of Xanthorrhoeol, pterostilbene, sakuranetin,
and pinostrobin []. Propolis of Australian stingless bees
(Tetragonula carbonaria) is composed of C-methylated
avanones [].
“Pacic” propolis (e.g., Okinawa, Taiwan, Hawaii, Indo-
nesia, and Myanmar) is another particular type of propolis.
A new family of compounds, the prenylavonoids, more
specically isonymphaeol-B, was identied in Okinawa
propolis although three already known compounds—nym-
phaeol-A, nymphaeol-B, and nymphaeol-C—have also
been isolated in three samples []. As Okinawan propolis,
Hawaiian propolis is also composed of nine prenylavonoids
[]. Taiwanese propolis is composed of eight prenyla-
vanones, nymphaeol-A, nymphaeol-B, and nymphaeol-C,
propolins A, B, and E, isonymphaeol B, and -geranyl-
naringenin []. In another sample of the Pacic region,
the Indonesian propolis, an inseparable mixture of four
alk(en)ylresorcinols (-pentadecylresorcinol, -(Z,Z-
heptadecadienyl)-resorcinol, -(Z-heptadecenyl)-resor-
cinol, and -heptadecylresorcinol), along with four prenyla-
vanones, propolins D, C, F, and G, and three cycloartane-
type triterpenes, mangiferolic acid, isomangiferolic acid,
and -hydroxyisomangiferolic acid, was identied [].
Additionally, fractioning of propolis extracts from Myanmar
led to the isolation of two new cycloartane-type triterpenes,
together with cycloartanes and four known prenylated
avanones []. ailand propolis, which might be
possibly obtained from Styrax trees, comprises not only
the typical compounds of temperate regions but also the
two new phenylallylavanones (S)--[-(-hydroxy--
methoxyphenyl)prop--en--yl]-(S)-pinocembrin and (E)-
cinnamyl-(E)-cinnamylidenate []. In propolis from Canary
Islands, a dierent phenolic prole was found, furofuran
lignans being the main compounds. Six furofuran lignans
were isolated and characterized as sesamin, episesamin,
methyl xanthoxylol, aschantin, sesartenin, and yangambin.
Propolis also contains sugars and sugar alcohols [,].
Many studies with African propolis from dierent regions,
like Kenya, Cameroon, Congo, Oman, and Ethiopia, showed
that triterpenoids are major chemical components [–].
Southern Nigeria propolis is uncommon since it presents
prenylated isoavonoids, like Brazilian red propolis, and a
high abundance of stilbenoid compounds [].
Propolis additionally contains minerals such as mag-
nesium, calcium, iodine, potassium, sodium, copper, zinc,
manganese, and iron; some vitamins like B, B, B, C,
E,andD,aswellasprovitaminA;afewfattyacids;and
also some enzymes derived from bee glandular secretion or
possibly from pollen like succinic dehydrogenase, adenosine
triphosphatase, glucose--phosphatase, acid phosphatase,
𝛼-amylase, 𝛽-amylase, 𝛼-lactamase, 𝛽-lactamase, maltase,
esterase, and transhydrogenase [,]. Polysaccharides like
starch and the di- and monosaccharaides glucose, fructose,
ribose, rhamnose, talose, gulose, and saccharose are com-
monly present in propolis too [].
4. Biological Properties and Therapeutic
Activity of Propolis
Despite propolis popularity over time, it is not consid-
ered as a therapeutic agent in conventional medicine as
the standardization of chemical composition and biological
activity is lacking. Such standardization is indispensable
for acceptance in the health system. us, characterization
of dierent types of propolis according to its plant origin
and corresponding chemical prole is mandatory. Studies
about propolis bioactivity must start with chemical proling
of the extracts since that information is essential to have
detailed and consistent comparative data between each type
Evidence-Based Complementary and Alternative Medicine
T : Characteristic compounds of propolis from dierent geographic origins and respective plant source.
Geographic origin Plant source Typical constituents (main components) References
Europe, North America, New Zealand, and
temperate zones of Asia
Populus spp., more predominantly P.
nigra
Pinocembrin, pinobanksin, chrysin, galangin, caeic acid, ferulic acid, cinnamic acid, and their
esters [,,]
Brazil
Green propolis Baccharis spp., predominantly B.
dracunculifolia
Prenylated phenylpropanoids, phenolic acids, prenylated p-coumaric acids, acetophenones,
diterpenic acids, caeoylquinic acids, kaempferide, isosakuranetin, and kaempferol [,,,]
Red propolis Dalbergia ecastaphyllum Formononetin, isoliquiritigenin, liquiritigenin, medicarpin, and biochanin A [,,]
Russia
Betula spp., more specically B.
verrucosa, B. pendula,andB.
pubescens
Cinnamic acids, phenylpropanoid sesquiterpenols, acacetin, apigenin, ermanin, rhamnocitrin,
kaempferide, 𝛼-acetoxybetulenol [,]
Cuba, Venezuela Clusia spp., more specically C. rosea
and C. minor Polyisoprenylated benzophenones, more specically nemorosone, xanthochymol, and guttiferone E [,]
Mediterranean
Greece Probably Conifer spp. Flavonoids, diterpenic acids such as isocupressic, pimaric, and communic acids, isoagatholal,
agathadiol, ferruginol, -elemene, and totarol [,]
Switzerland P. t r e m u l a Benzyl p-coumarate, benzyl ferulate, and phenolic glycerides like dicoumaroyl acetyl glycerol,
diferuloyl acetyl glycerol, feruloyl coumaroyl acetyl glycerol, and caeoyl coumaroyl acetyl glycerol []
Malta Ferula spp., most probably Ferula
communis
Diterpenic acids such as isocupressic, communic, pimaric, and imbricatoloic acid, together with
totarol and -epitorulosal []
Turke y Populus spp., Eucalyptus spp.,and
Castanea sativa
Pinocembrin, pinobanksin and its acetate, prenyl esters of caeic acid, ferulic acids, diterpenic acids
like pimaric, isopimaric, abietic, dihydroabietic acids, cinnamyl cinnamate, and ethyl oleate,
aromatic acid esters such as benzyl cinnamate, benzenedicarboxylic acid and avanols such as
benzopyran and chrysin
[–]
Algeria Populus spp.
Cistus spp.
Pinocembrin, pinobanksin and its acetate, chrysin, apigenin, pectolinarigenin, pilosin, ladanein,
galangin, naringenin, tectochrysin, methoxychrysin, prenyl esters of caeic acids, ferulic acids,
diterpenic acids like hydroxyditerpenic acid, labdane, and clerodane
[,]
Australia
Apis mellifera Acacia paradoxa Xanthorrhoeol, pterostilbene, sakuranetin, pinostrobin, stilbenes, prenylated tetrahydroxystilbenes,
prenylated cinnamic acids, avanones, avonols, chalcones [–,]
Stingless bee Tetragonula carbonaria C. torelliana trees (fruit resins)
Africa
Nigeria
Probably M. schweinfurthii
Isoavonoids, prenylated isoavonoids, and stilbenoids []
Kenya Triterpenes, arylnaphtalene lignans such as tetrahydrojusticidin B and -methoxydiphyllin, geranyl
stilbenes, and geranylavon macarangin []
Cameroon
Congo Triterpenes, derivatives of amyrin and lupeol and diprenyl avonoids []
Oman Azadirachta indica, Acacia spp.,and
Mangifera indica
Triterpenes, prenylated avanones such as -O-methyl--prenylnaringenin, ,-diprenylnaringenin,
and -prenyl-,-dihydroxy--(-hydroxy--methylbutyl)--methoxyavanone, chalcones,
cardanol, cardols, and anacardic acids
[]
Ethiopia Probably Acacia spp.Triterpenoids such as 𝛼-and𝛽-amyrins, 𝛼-and𝛽-amyryl acetates, lupeol, and 𝛼-and𝛽-lupeyl
acetates []
ailand Styrax trees Phenylallylavanone, (E)-cinnamyl-(E)-cinnamylidenate []
e Pacic region
Okinawa, Hawaii, and Taiwan Macaranga tanarius Prenylavonoids, more specically isonymphaeol-B, nymphaeol-A, nymphaeol-B, nymphaeol-C,
propolins, -geranyl-naringenin [–]
Indonesia, Myanmar Mangifera indica Alk(en)ylresorcinols, cycloartane-type triterpenes, cycloartanes, and prenylated avanones [,]
Canary Islands Unknown Furofuran lignans [,]
Evidence-Based Complementary and Alternative Medicine
of biological activity and chemical data. is information
allows extrapolating the possible activity and mechanism of
action of new propolis under study and provides substantial
clues for the development of new drug candidates [,].
In the last decades, several studies have demonstrated the
biological and pharmacological actions of dierent world-
wide propolis samples. e following sections summarize the
recent published information about antibacterial and anti-
fungal [,,–], antiviral [,,], anti-inammatory
[], antioxidant [–], immunomodulatory [,,],
and antitumor activities [,,,,,], revealing the
interest of researchers in this bee product and its potential
for the development of new drugs as well.
4.1. Antioxidant Activity. Itiswellknownthatanendogenous
stimuli, like cellular metabolism, and exogenous agents like
UV, toxins, and drugs, among others, generate reactive
oxygen species (ROS), such as hydrogen peroxide (H2O2), the
superoxide anion (O2−), and hydroxyl ion (HO−), as well as
reactive nitrogen species (RNS), especially nitric oxide (NO).
Carbohydrates, proteins, lipids, and nucleic acids, among
other biomolecules, when exposed to the reactive species,
suer oxidative modications that modify the cell and lead
to its death [–]. Oxidative stress is responsible for the
occurrence of a wide variety of human diseases, such as
neurodegenerative []orcardiovasculardiseases[,],
cancer [,], diabetes [], and atherosclerosis [].
Inthelastyears,severalstudieshavebeenperformed
to evaluate the antioxidant capacity of natural products.
Propolis extracts, composed of dierent polyphenols, have
been reported to possess a potent antioxidant activity [,
,]. Additionally, the chemical varieties in dierent
propolis samples from dierent regions have an inuence
on the antioxidant activity. Recently, Fabris et al. showed
that a sample of Italian and Russian propolis ethanol extract
(PEE), which have a similar polyphenolic composition, have
a similar antioxidant activity, while Brazilian PEE, which
have low polyphenolic composition, have a weak antioxidant
activity []. Another study also showed, using dierent
samples of Transylvania PEE, a positive correlation between
high polyphenolic composition and high antioxidant activity
[]. Phenolic acids and avonoids are characterized by
a powerful antioxidant activity, which is closely related to
the chemical structure of the compounds []. Briey, the
antioxidant activity is exerted by inhibiting the activity of
some enzymes (e.g., xanthine oxidase, protein kinase C,
ascorbic acid oxidase, cyclooxygenase, lipoxygenase, Na+/K+
ATPase, and cAMP phosphodiesterase) which inhibit the
production of ROS species; by scavenging, interrupting the
reactions that lead to the lipid peroxidation; by chelating
metal ions, mainly iron and copper, that are involved in the
process of free radical creation; or by potentiating the action
of other antioxidants []. Table summarizes some of the
studies addressing the antioxidant activity of propolis.
Moreira et al. []andMigueletal.[]proposedthat
Portuguese propolis, an important source of total phenols,
avones, and avonols, could be benecial for human health
due to its antioxidant properties. Portuguese propolis also
protects human erythrocytes from free radicals damaging
by decreasing lipid peroxidation []. ese studies suggest
that Portuguese propolis is a powerful antioxidant agent
that can be used against oxidative stress, thus maintaining
the structural and functional integrity of the cells. Cuesta-
Rubio et al. [] demonstrated that nemorosone, the most
abundant polyisoprenylated benzophenone present in Cuban
propolis, exhibits antioxidant capacity. However, when this
compound suers methylation, a process that facilitates the
separation of the compound from the propolis sample, the
antioxidant property is abolished. Ethyl acetate extract of
Kangaroo Island propolis, which is rich in stilbenes, showed
a stronger scavenging activity []. Yang et al. showed that
ethyl acetate of propolis collected in Anhui, China, has
strong scavenging activity and ferric reducing activity, those
activities being inuenced by caeic acid, phenethyl caeate,
cinnamyl caeate, and benzyl caeate []. Another study
showed that samples of methanolic extracts of Algerian
propolis that contains high amounts of caeic acid esters
and avanones, kaempferol, and galangin possess strong
scavenging activity and ferric reducing activity []. Uruguay
propolis with high polyphenolic composition inhibits low-
density lipoprotein (LDL) peroxidation and protein nitra-
tion in vitro. Moreover, it induces the expression of nitric
oxide synthase (eNOS) and inhibits NADPH oxidase in
bovine aortic endothelial cells []. In another study, the
topical administration of Romanian PEE in mouse, either
prior to or aer UVB exposure, signicantly attenuated the
malondialdehyde (MDA) formation and restored glutathione
peroxidase (GSH-Px) activity []. Talas et al. []showed
that Turkish PEE has antioxidant properties in the liver
tissue of NOS inhibited rats. In fact, NOS inhibition caused
an increase in CAT activity and MDA levels, eect that
was signicantly decreased when the rats were treated with
PEE. It is well known that propolis composition is variable;
nevertheless, one of its major components, CAPE (caeic acid
phenethyl ester), plays an important role in the antioxidant
activity [–].
Antioxidant activity is one of the most studied and
important activities of propolis, though there are no studies
with data on the safe dose to be used in humans. us, clinical
studies using propolis and its active compounds are needed.
4.2. Anti-Inammatory Activity. Inammation is an event
that normally occurs in response to the constant exposure
to environmental and endogenous stimuli as well as to
accidental damage []. A complex cascade of chemical
signals initiates aer tissue injury and maintains a host
response to repair the injured tissue. ere are two stages
of inammation: acute and chronic. Acute inammation is
mediated through the activation of the immune system cells,
which migrate to the site of damage and release growth
factors, cytokines, and ROS/RNS species. Chronic inamma-
tion occurs when the acute inammation is not successfully
resolved. is inammatory condition plays a critical role in
the pathogenesis of many diseases including atherosclerosis,
cancer, asthma, Alzheimer’s, and Parkinsonism [,].
Several studies have associated dierent types of propolis
and its various constituents with anti-inammatory activ-
ity [,–]. Tab l e summarizes the anti-inammatory
Evidence-Based Complementary and Alternative Medicine
T : Antioxidant activity of propolis and its chemical constituents.
Origin Propolis type/plant source Type of extract/isolated
compound(s) Species/cells Eect References
Portugal (Serra de
Bornes and Fund˜
ao)
European propolis/Populus
nigra Methanolic extract Human erythrocytes Decrease in lipid peroxidation [];
Free radical scavenging []
Brazil
Propolis from the stingless bee
Melipona orbignyi/
probablypoplar tree
PEE Human erythrocytes Free radical scavenging; inhibition of hemolysis and lipid
peroxidation []
Portugal (Central
Algarve)
European propolis/Populus
nigra
PEE, PWE, and methanolic
extracts Free radicals scavenging , chelation of metal ions []
Cuba Red propolis/C. rosea Methanolic extract
Nemorosone Free radicals scavenging []
Slovenia European propolis/Populus
nigra PEE Strong reducing power and ability to scavenge free radicals
and metal ions []
Romania European propolis/Populus
nigra PEE Female Swiss mice (UVB
exposure)
Decrease in malondialdehyde levels, restoration of glutathione
peroxidase activity []
Kangaroo Island Australian pro polis/Acacia
paradoxa Ethyl acetate extract; stilbenes Free radical scavenging []
China European propolis/Populus
nigra Ethyl acetate extract Free radical scavenging and ferric reducing activity []
Algeria
Mediterranean
propolis/Populus spp.
and Cistus spp.
Methanolic extract Free radical scavenging and ferric reducing activity []
Uruguay
European and green
propolis/Populus nigra and B.
dracunculifolia
PEE Bovine aortic endothelial cells Inhibition of low-density lipoprotein peroxidation and
NADPH oxidase and increase in nitric oxide synthase []
Brazil Green propolis/B.
dracunculifolia PEE
CBL/ mice (acute lung
inammation caused by
cigarette smoke)
Normalization of nitrite, myeloperoxidase levels, superoxide
dismutase, catalase, and glutathione peroxidase activity and
reduction of glutathione/oxidized glutathione ratio and
malondialdehyde levels
[]
Turke y
Mediterranean
propolis/Populus spp.,
Eucalyptus spp., and Castanea
sativa
PEE
Fibroblast cells Decrease of DNA damage induced by HO[]
Male Wistar rats DecreaseinCATactivityandMDAlevelsinNOSinhibited
rats []
Carps (Cyprinus carpio)
Decrease in malondialdehyde levels, superoxide dismutase
activity and increase of catalase and glutathione peroxidase
activity
[]
Purchased from Sigma
Aldrich Co.
Characteristic of European
type propolis CAPE
Free radical scavenging, inhibition of xanthine oxidase activity
and lipid peroxidation []
Male Wistar albino rats
Maintenance of superoxide dismutase activity, decrease of
xanthine oxidase activity and malondialdehyde and nitric
oxidase levels
[]
Peripheral blood mononuclear
cells from cyclists
Reduction of hyperthermia-induced survival inhibition,
necrosis, superoxide production, glutathione depletion, and
intracellular superoxide
[]
Evidence-Based Complementary and Alternative Medicine
T : Anti-inammatory mechanisms investigated with propolis.
Origin Propolis type/plant source Type of extract/isolated
compound(s) Species/cells Eect References
Purchased: Sigma
Aldrich Co.
Synthesized
Characteristic of European, Brazilian,
and Mediterranean propolis
Caeic acid, quercetin,
naringenin;
CAPE
Peritoneal macrophages
Suppression of lipoxygenase pathway of arachidonic acid
metabolism
CAPE being the most potent modulator of the arachidonic
acid cascade
[]
Croatia European propolis/Populus nigra Water-soluble derivatives Swiss albino mice Reduction of DNA damage in peripheral lymphocytes []
PEE Male Swiss albino mice Suppression of functional activity of macrophages []
Purchased: Sigma
Aldrich Co.
J macrophages, Male
Wistar rats
In vitro and in vivo inhibition of cyclooxygenase and
cyclooxygenase activity [,];
Male Wistar albino rats Decrease of polymorphonuclear neutrophilic leukocyte
inltration in the lungs tissues [];
Characteristic of European type
propolis CAPE
Gastric epithelial cell line
(AGS), H. pylori (strain NCTC
)
Inhibition of H. pylori-induced NF-kB and activator protein
-DNA-binding activity; prevention of IkB𝛼degradation in
AGS; and suppression of TNF-𝛼and interleukin production
[];
Purchased: Wako Pure
Chemical Industries,
Ltd.
RAW. macrophages
Decrease of the production of interleukin-𝛽,monocyte
chemoattractant protein , and the production and expression
of tumor necrosis factor 𝛼(TNF-𝛼)
[];
Male Swiss inbred strain mice
Decrease of cyclooxygenase expression, NF-𝜅Bactivity,
c-Jun-N-terminal kinase, inhibitor of NF-𝜅B kinase (IKK),
and inhibitor of NF-𝜅B (IkB) phosphorylation
[]
Brazil Green propolis/B. dracunculifolia PEE
RAW. macrophages Downregulation of NF-𝜅B, p mitogen-activated protein
kinase, and c-Jun-N-terminal kinase []
Purchased: Acros
Organics
Characteristic of European, Brazilian,
and Mediterranean propolis Caeic acid
Brazil Green propolis/B. dracunculifolia PEE Sprague-Dawley rats
Inhibition of carrageenan-induced rat hind paws edema and
the chemotaxis of human polymorphonuclear leukocytes
(PMNs)
[]
Synthesized Characteristic of European type
propolis CAPE Polymor phonuclear leuko cytes
obtained from Human blood
Inhibition of -lipoxygenase activity and arachidonic acid
release []
Chile European propolis/poplar trees PEE Male CF- mice Inhibition of NO release by the macrophages []
China European propolis/Populus nigra PEE and PWE Male ICR mice and male
Wistar rats
Inhibition of the activation and dierentiation of mononuclear
macrophages; decrease prostaglandin-E (PGE ) and nitric
oxide (NO) levels
[]
Brazil Green propolis/B. dracunculifolia PWE Swiss and BALB/c mice
Decrease in the number of macrophages and neutrophils;
inhibition of proinammatory cytokines and increase of
anti-inammatory cytokines
[]
Red propolis/Dalbergia
ecastaphyllum PEE Male Wistar rats Decrease in renal macrophage inltration in rats with chronic
kidney disease []
Nepal
Nepalese propolis/probably Shorea
robusta, Dalbergia sissoo, Acacia
catechu, and Bombax cieba
PEE, ,-dihydroxy--
methoxydalbergione,
-ethoxydalbergion, cearoin,
and chrysin
Bone marrow-derived mast
cells (BMMC) from CBL/
mice
Inhibiting IL-, TNF-𝛼, and IL- gene expression in BMMC
and also inhibiting the activation of IKK leading to NF-𝜅B
inactivation
[]
Evidence-Based Complementary and Alternative Medicine
mechanisms investigated with propolis and its chemical
constituents. Recently, the role of the avonoids quercetin,
avonols, and avones in modulating inammatory cell
function was studied []. Funakoshi-Tago et al. []inves-
tigated the anti-inammatory eects of avonoids isolated
from Nepalese PEE on the IL- signaling pathway. e
isolated avonoids ,-dihydroxy--methoxydalbergione,
-methoxydalbergion, cearoin, and chrysin inhibited the
expression of inammatory genes including IL-, TNF-𝛼,
and IL- in bone marrow-derived mast cells (BMMC) and
also inhibited the activation of IKK, which leads to the
degradation of I𝜅B𝛼and inhibits the activation of nuclear
factor 𝜅B(NF-𝜅B).
e release and oxygenation of arachidonic acid are a
critical event in inammation. Mirzoeva and Calder []
demonstrated that propolis components such as CAPE, caf-
feic acid, quercetin, and naringenin, among others, inhibit the
production of eicosanoids. In fact, these components signif-
icantly suppressed the lipoxygenase pathway of arachidonic
acid metabolism, CAPE being the most potent modulator.
Another study indicated that CAPE treatment improves
hepatic steatosis induced by high-fat diet in a mouse model.
is eect was attributed to the reduction of c-Jun-N-
terminal kinase (JNK/) and NF-𝜅Bactivationwithdecrease
in COX- expression []. Recently, it was reported that
CAPE exhibits inhibitory eects on the production of proin-
ammatory cytokines (interleukin-𝛽(IL-𝛽)), tumor necro-
sis factor-𝛼(TNF-𝛼), and monocyte chemoattractant pro-
tein (MCP-) from lipopolysaccharide- (LPS-) stimulated
RAW. macrophages []. Machado et al. []showed
that Brazilian green propolis water extracts (PWE) modulate
an anti-inammatory cellular response in the model of LPS-
induced pulmonary inammation by decreasing the number
of macrophages and neutrophils. Additionally, it induced a
reduction in the secretion of IL- and TNF-𝛼andanincrease
in TGF-𝛽and IL-. Another study showed that Brazilian
red PEE promotes a signicant decrease in renal macrophage
inltration in rats with chronic kidney disease []. B´
ufalo
et al. [] demonstrated that Brazilian PEE and caeic
acid inhibited LPS-induced NO production by RAW.
macrophages, acting at the transcriptional level and sug-
gesting that their anti-inammatory eects were mediated
by downregulating NF-𝜅B, p MAP kinase, and JNK/.
According to Naito et al. [], topical application of Brazilian
PEE is eective in inhibiting carrageenan-induced rat hind
paw edema. is sample appears to inhibit the chemotaxis of
human polymorphonuclear leukocytes (PMNs), which also
contributes to its anti-inammatory eects. Another study
showed the topical anti-inammatory activity of propolis
from Chile in mice ear with induced-edema. In fact, PEE
from Buin, Chile, was the most active against the inamma-
tion induced by -O-tetradeca-noylphorbol--acetate and
arachidonic acid and also inhibits signicantly NO release
by the macrophages []. More recently, Boudreau et al.
[] indicated that CAPE is a potent leukotriene biosynthesis
inhibitor in PMNs that blocks -lipoxygenase (-LO) activity
and arachidonic acid release. A Croatian PEE may improve
psoriatic-like skin lesions, which were induced in the study by
irritant agents like n-hexyl salicylate or di-n-propyl disulde,
by reducing the lipid peroxidation in the skin and total
number of inammatory cells in the skin and peritoneal
cavity, more specially by suppressing functional activity of
macrophages [].
4.3. Immunomodulatory Activity. Natural substances are
considered alternative adjuvant therapies in the treatment of
dierent diseases due to their immunomodulatory eects.
Information about this type of activity was scarce for propolis
until the s; but published work in the last years has pro-
vided information about the inuence of dierent propolis
samples on the immune system [,–](Tabl e ).
In a study using Brazilian green propolis, it was seen
that the administration for days of a PEE to male BALB/c
mice modulated the activation of the initial steps of the
immune response by upregulating toll-like receptor- (TLR-)
and toll-like receptor- expression and proinammatory
cytokines (IL- and IL-) production by macrophages and
spleen cells []. Another study demonstrated that Brazilian
greenPEEupregulatesTLR-andCDexpressioninhuman
monocytes as well as TNF-𝛼and IL- production []. It
was also shown that caeic acid stimulates the activity of
monocytes against C. albicans but it inhibits TLR- and HLA-
DR expression as well as TNF-𝛼and IL- production [].
Additionally, Missima et al. []showedthatBrazilian
green PEE administered to stressed mice reduces the proin-
ammatory cytokines IL-𝛽and IL-. When administered to
melanoma-bearing mice submitted or not to chronic stress,
it induces high levels of IL-𝛽and IL- and also stimu-
lates cytokines production, indicating the activation of
antitumour cell-mediated immunity. Bachiega et al. []
investigated the immunomodulatory eect of propolis and
cinnamic and coumaric acids on cytokines IL-𝛽, IL-, and
IL- production. Peritoneal macrophages from BALB/c mice
were incubated with dierent concentrations of propolis
(, , and mg/well) and coumaric and cinnamic acid
( and mg/well). Propolis and the acids stimulated IL-
𝛽production and signicantly inhibited IL- production.
en, aer LPS incubation, the inhibitory concentrations of
cinnamic and coumaric acids prevented eciently its eects
on IL- production, whereas propolis inhibited LPS eects
both before and aer its addition. Additionally, propolis and
coumaric and cinnamic acids inhibited IL- production. A
study which evaluated the eect of Brazilian green propolis
on macrophage activation by H2O2and NO metabolite
determination [] showed that propolis increased H2O2
generation and decreased NO generation, which favours
the microbicidal activity. Recently, the immunomodulatory
eect of propolis collected in Brazil was evaluated in Leish-
mania (Viannia) braziliensis experimental infection. Data
shows that macrophages incubated with propolis showed a
signicant increase in interiorization and further killing of
parasites. Also, an increased TNF-𝛼production was seen in
propolis-pretreated mice, whereas IL- was downregulated
during the infection [].
e immunomodulatory action of propolis does not
occur only at the macrophage level. In fact, some studies
show that this action has also an eect on lymphocyte pro-
liferation [,]. S´
a-Nunes et al. []showedinhibitory
Evidence-Based Complementary and Alternative Medicine
T : Immunomodulatory activity of propolis and its chemical constituents.
Origin Propolis type/plant source Type of extract/isolated
compound(s) Species/cells Eect References
Brazil Green propolis/B. dracunculifolia PEE
Male BALB/c mice
Upregulation of toll-like receptor- and receptor- expression and
increases in interleukin- and interleukin- production []
Upregulation of toll-like receptor- and receptor- mRNA expression []
Male CBL/ mice, BF cell
line
Stimulation of the expression and production of interleukin- and
interleukin- and cytokine (interleukin- and IFN-𝛾)production []
Male BALB/c mice Inhibition of cells generation; reduction of the frequency of
IFN-𝛾-producing CD+T cells under -polarizing conditions []
Male BALB/c mice Increase of HOgeneration and decreases in the NO generation in
peritoneal macrophages []
Male BALB/c mice
Increase in the interiorization and killing of the parasites Leishmania
(Viannia) braziliensis by macrophages; increase in TNF-𝛼production
and decrease in interleukin- production
[]
Monocytes from human blood TLR- and CD expression in human monocytes as well as TNF- 𝛼
and IL- production []
Melanoma cells (BF); male
CBL/ mice
Reduction of IL-𝛽and IL- in LPS-stressed mice; induction of IL-𝛽
and IL- and cytokines in melanoma-bearing mice submitted or
not to chronic stress
[]
Brazil
Purchased: Acros Organics
Green propolis/B. dracunculifolia
Characteristic of European, Brazilian,
Russian, Mediterranean, and Australian
type propolis
PEE,
cinnamic and coumaric acids Male BALB/c mi ce Stimulation of interleukin-𝛽production and inhibition of
interleukin- and interleukin- productions []
Purchased: Acros Organics Characteristic of European, Brazilian, and
Mediterranean propolis Caeic acid Monocytes from human blood
Stimulation of monocytes activity against C. albicans;downregulation
of TLR- and HLA-DR expression and inhibition of cytokine
production
[]
Purchased: Acros Organics Characteristic of European, Brazilian,
Russian, Mediterranean, and Australian
type propolis
Cinnamic acid Monocytes from human blood
Downregulation of toll-like receptor-, HLA-DR molecules from
human antigen-presenting cells, and CD; upregulation of toll-like
receptor-, inhibition of TNF-𝛼and interleukin- production
[]
Purchased: Sigma Aldrich Co. Cinnamic acid Female IRC mice Increase of lymphocyte proliferation and release of cytokines
interleukin- and interleukin- []
Brazil Green propolis/Baccharis dracunculifolia Hydroalcoholic (HPE) solution
Male BALB/c mice Increase of HOgenerationanddecreaseofNOgeneration []
Male BALB/c mice Decrease of splenocyte proliferation and increase of IFN-𝛾production
by spleen cells []
Indonesia e Pacic region propolis/Macaranga
tanarius and M. indica HPE Male BALB/c mice Increase of IgG generation and macrophage phagocytosis activity and
capacity []
Tur k e y Mediterranean propolis/Populus spp.,
Eucalyptus spp.,andCastanea sativa PEE Peripheral blood mononuclear cells
from healthy humans
Suppression of neopterin release and tryptophan degradation,
downregulation of the enzyme indoleamine ,-dioxygenase (IDO) and
decrease of IFN-𝛾and TNF-𝛼levels
[]
Purchased: Sigma Aldrich Co. Characteristic of European type propolis CAPE
Human m ono cyte-der ive d
dendritic cells (MoDCs) generated
from peripheral monocytes
Inhibition of IL- p, IL- p, IL-, IFN-𝛾-inducible protein- (IP-)
levels; inhibition of I𝜅B𝛼phosphorylation and NF-𝜅Bactivation []
Female BALB/c mice
Increase of IgM antibody production, T lymphocyte proliferation,
interleukin- and interleukin- production by splenocytes, and IFN-𝛾
production
[]
Human peripheral blood
mononuclear cells, jurkat cells
Inhibition of transcription factors NF-𝜅BandNFAT;inhibitionof
interleukin- gene transcription, interleukin- receptor expression, and
proliferation of human T cells
[]
Evidence-Based Complementary and Alternative Medicine
eects of Brazilian green propolis on splenocyte proliferation,
eect that was attributed to avonoids, and enhancement
eects on interferon- (IFN-) 𝛾production by spleen cells.
CAPE displays inhibitory eects on transcription factors NF-
𝜅B and NFAT and, as a consequence, inhibits IL- gene
transcription, IL- receptor expression, and proliferation of
human T cells []. is provides new information into the
molecular mechanisms involved in the anti-inammatory
and immunomodulatory activities of propolis. CAPE has
various biological activities but its eect on the immunomod-
ulatoryactivityremainslittlestudied.AccordingtoWang
et al. [], CAPE can be useful in the treatment of asthma
and other allergic diseases because it can inhibit cytokines
and chemokines production by human monocyte-derived
dendritic cells (MoDCs), which might be related to the
NF-𝜅B signalling pathway. Another study demonstrated for
the rst time that Brazilian propolis signicantly inhibited
the generation of cells. Furthermore, the eects of
propolis were investigated on ,,-trinitrobenzene sulfonic
acid- (TNBS-) induced colitis in a mouse model. Propolis
reduced the frequency of IFN-𝛾-producing CD T cells
in a dose-dependent way under -polarizing conditions.
e inhibitory eect of propolis on dierentiation was
demonstrated in vivo too, and the severity of colitis in
propolis-fed mice was signicantly lower than that of mice
fed with the control diet [].
4.4. Antiviral Activity. Propolis comprises a complexity of
compounds which play a role in antiviral protection. Despite
the few data available regarding this activity, it was shown that
propolis from dierent geographic regions has considerable
antiviral activity by acting at dierent levels and interfering
with the replication of some viruses [], like herpes simplex
types and , adenovirus type , inuenza virus, or human
immunodeciency virus (HIV), among others [,,–
]. Tab l e summarizes the antiviral activity of propolis and
its chemical constituents.
Schnitzler et al. [] analysed the antiviral eect of
PWEandPEEfromCzechRepublicaswellasthatof
the constituents caeic acid, p-coumaric acid, benzoic acid,
galangin, pinocembrin, and chrysin, against herpes simplex
virus type (HSV-) in cell culture. Both extracts exhibited
high anti-HSV- activity when cells were treated prior to
viral infection, galangin and chrysin being the main bioac-
tive compounds. Amoros et al. [] showed the antiviral
activity of the major avonoids of propolis, more specically
avonols and avones, the rst being more active against
HSV-. Additionally, they analysed the eect of propolis on
several DNA and RNA viruses (HSV-, HSV-, adenovirus
type , vesicular stomatitis virus (VSV), and poliovirus type
). Propolis at a concentration of 𝜇g/mL reduced the
titer of herpes virus; however, vesicular stomatitis virus
and adenovirus were less susceptible. In addition, propo-
lis appears to exert a virucidal action on the enveloped
viruses HSV and VSV []. Recently, it was shown that
hydromethanolic extract of geopropolis from the stingless
bee Scaptotrigona postica (Brazil) inhibits the HSV replication
and also the entry of the virus into cells, eect that was
attributed to the C-glycosyl avones, catechin--O-gallate,
and ,-dicaeoylquinic acid []. According to Tait et
al. [], natural and synthetic avonoids might interfere
with picornavirus replication preventing the decapsidation
of viral particles and RNA release within cells or blocking
viral RNA synthesis. ese authors also showed that dier-
ent homoisoavonoids have good antiviral activity against
the coxsackie viruses B, B, and A and echovirus .
Shvarzbeyn and Huleihel [] tried to determine which
step of Tax oncoprotein-induced NF-𝜅Bactivationisblocked
by propolis and CAPE and showed that both substantially
inhibited the activation of NF-𝜅B-dependent promoter by
Tax. A l s o, the y s trong l y p reve n t e d bot h Ta x bind i n g to I𝜅B𝛼
and its induced degradation by Tax. Ma et al. []showed
that nanometer propolis avones could signicantly inhibit
in vitro porcine parvovirus (PPV) infecting PK- cells and
in vivo they restrain the PPV copy in lung, gonad, and blood,
decrease the impact of PPV on weight of guinea pigs, and
increase hemagglutination inhibition of PPV in serum as well
as improving the contents of IL-, IL-, and 𝛾-IFN.
Over recent years, therapeutic benets of propolis and/or
its isolated compounds have been described in HIV treat-
ment. Ito et al. [] tested the anti-HIV activity in H
lymphocytes of triterpenoids melliferone, moronic acid,
anwuweizonic acid, and betulonic acid and four known
aromatic compounds isolated from Brazilian propolis and
showed that moronic acid had signicant anti-HIV activity.
Gekker et al. [] assessed the anti-HIV- activity of propolis
in CD+lymphocytes and microglial cell cultures, observ-
ing the inhibition of viral expression in a concentration-
dependent way. e possible mechanism of propolis antiviral
property was suggested to involve inhibition of viral entry.
4.5. Antimicrobial Activity. Antimicrobial activity, one of
the most studied propolis biological properties, is very well
documented. is bioactivity has been largely investigated
in the last years due to the need of new treatments against
infectious diseases, especially with the increase of resistant
pathogens to current antibiotics. Tables and summarise
the antibacterial and antifungal activities found in propolis
from dierent geographic origin and/or its chemical con-
stituents.
4.5.1. Antibacterial Activity. Propolis eect against several
bacterial strains has evaluated [,–,]andsupported
the fact that propolis is more active against Gram-positive
bacteria than Gram-negative bacteria [,]. Briey, data
from dierent studies showed that propolis inhibits bac-
terial motility and enzyme activity, exhibits bacteriostatic
activity against dierent bacterial genera, can be bactericidal
in high concentrations, and aects cytoplasmic membrane
[].
Mirzoeva et al. [] investigated the eect of PEE
on the physiology of Bacillus subtilis, Escherichia coli,and
Rhodobacter sphaeroides,proposingthatpropolisandsome
of its components, like cinnamic acid and avonoids, aect
the ion permeability of the inner bacterial membrane causing
thedissipationofthemembranepotentialandinhibiting
bacterial motility. A recent study []providedvaluable
information for understanding the potential anti-H. pylori
Evidence-Based Complementary and Alternative Medicine
T : Antiviral activity of propolis and its chemical constituents.
Origin Propolis type/plant source Type of extract/isolated
compound(s) Species/cells/viruses Eect References
Purchased: Sigma Aldrich
Co.
Characteristic of European type
propolis
Caeic acid, p-coumaric acid,
benzoic acid, galangin,
pinocembrin, and chrysin
RC- cells, herpes simplex virus type (HSV-)
strain KOS
High anti-HSV- activity for both extracts when cells were treated prior
to viral infection []
Czech Republic European propolis/Populus nigra PEE and PWE RC- cells, herpes simplex virus type (HSV-) High antiherpetic activity for both extracts when viruses were
pretreated prior to infection []
Brazil
Brown propolis/B. dracunculifolia HPE HSV- strain propagated in Vero cells, female BALB/c
mice
Eective against HSV- infection and in reducing extravaginal lesions
by acting on inammatory and oxidative processes; reducing reactive
species, tyrosine nitration, ascorbic acid levels, and myeloperoxidase
activity and protecting against inhibition of catalase activity
[]
Characteristic of Brazilian propolis Isopentyl ferulate (isolated from
an PEE)
Inuenza viruses A/PR// (HN),
A/Krasnodar// (HN), and A/Hong Kong//
(HN)
Suppression of inuenza virus A/Hong Kong reproduction in vitro []
Green propolis/B. dracunculifolia,
B. erioclada, Myrceugenia euosma PEE
Inuenza A/PR// (HN) virus propagated
Madin-Darby canine kidney (MDCK) cells, female
DBA/ Cr mice
Reductionofbodyweightlossofinfectedmiceandvirusyieldsinthe
bronchoalveolar lavage uids of lungs []
France European propolis/Populus nigra PEE
RC- cells, HSV- strain HS, acyclovir resistant
mutant HSV-R strain HR, HSV-, adenovirus type
, poliovirus type , and vesicular stomatitis virus
(VSV)
Reduction of titre of herpes virus, being vesicular stomatitis virus and
adenovirus less susceptible; virucidal action on the enveloped viruses
HSV and VSV
[]
Brazil Geopropolis from the stingless bee
Scaptotrigona postica Hydrom eth anol ic extract African green monkey kidney cells (ATCC CCL-);
herpes simplex virus strain (McIntyre) Inhibition of HSV replication and entry into cells []
Synthesized Characteristic of Brazilian red and
green propolis
Homoisoavonoids, spe cially
-benzyl--chromones
BGM (Bualo Green Monkey) cells, coxsackie viruses
B,B,andAandechovirus
Good antiviral activity against the coxsackie viruses B, B, and A and
echovirus []
Canada European prop olis/P. trichocarpa
and P. tr e m u l o i d e s PEE
HSV- and HSV- virus replicated in MDBK
(monolayer cultures of Madin-Darby bovine kidney)
cells
Impairingtheabilityofthevirustoadsorbortopenetratethehostcells []
Brazil
Green propolis/Baccharis
dracunculifolia Wa ter e x t r a c t s
Female BALB/c mice, Inuenza A virus strain
A/WSN/ (HN)
Extension of the lifetime of mice. ,-dicaeoylquinicacid which
increases mRNA levels of tumor necrosis factor-related
apoptosis-inducing and decreases HN hemagglutinin mRNA
[]
Characteristic of Brazilian green
propolis
,-dicaeoylquinic acid
(Isolated from Brazilian
propolis)
Brazil Characteristic of Brazilian green
propolis
Mellif erone, moroni c acid,
anwuweizonic acid, and
betulonic acid (isolated from
Brazilian propolis)
H lymphocytes, HIV- Moronic acid inhibiting anti-HIV replication []
Israel
Mediterranean propolis/Populus
spp., Eucalyptus spp.,andCastanea
sativa
PWE Jurkat, uninfected human T-cell lines, and MT
(HTLV- infected human T cells) cells
Inhibition of the ac tivation of NF-𝜅B-dependent promoter by Tax and
prevention of Tax binding to I𝜅B𝛼and its degradation []
Purchased: Sigma Aldrich
Co. Characteristic of European propolis CAPE
Provided by Binzhou
Animal
Science and Veterinary
Medicine Academy of
Shandong
Province
Nanometer propolis Flavone
Kidney cells (PK-)
Porcine parvovirus (PPV)
Britain White guinea pigs
Inhibition of PPV infecting porcine kidney- (PK-) cells
Restraining of PPV copy in lung, gonad, and blood, decrease of the
impact of PPV on weight of guinea pigs, and increase of
hemagglutination inhibition of PPV in serum as well as improving the
contents of IL-, IL-, and 𝛾-IFN
[]
USA and China European propolis/Populu s nigra
PEE
Peripheral blood mononuclear cells obtained from
blood of healthy donors, microglial cells isolated f rom
human fetal brain tissue, HIV-AT,HIV-
SF
Inhibition of HIV- variants expression []
Brazil Green propolis/Baccharis
dracunculifolia
Evidence-Based Complementary and Alternative Medicine
T : Antibacterial activity of propolis and its chemical constituents.
Origin Propolis type/plant source Type of extract/isolated
compound(s) Species Eect References
Purchased: Bee Health Ltd.
(Scarborough, Yorkshire,
UK);
European propoli s/Populu s nigra; PEE
B. subtilis SG, E. coli,andR. sphaeroides
Inuencing the ion permeability of the inner bacterial
membrane;
Inhibition of bacterial motility
[]
Purchased: Sigma
Chemical Co. (Poole,
Dorset, UK)
Characteristic of European, Brazilian,
and Mediterranean propolis
Caeic acid, CAPE,
quercetin, and naringenin
Greece Mediter ranean propo lis/probab ly Conifer
spp.
Terpenes (isolated from
Cretan propolis)
S. aureus (ATCC ), S. epidermidis (ATCC ), E. coli
(ATCC ), E. cloacae (ATCC), K. pneumoniae
(ATCC ), and P. aeruginosa (ATCC )
Inuencing the Gram-positive and Gram-negative bacteria
viability []
France European propolis/Populus nigra Dichloromethane extract
Gram-negative: Acinetobacter baumannii (RCH, SAN, ,
AYE, CIP, , and ), Escherichia coli (ATCC
and a clinical isolate), Pseudomonas aeruginosa (ATCC
and two clinical isolates), and clinical isolates of
Enterobacter cloacae,E. aerogenes,Klebsiella oxytoca,and
Salmonella enteritidis (phage type )
Gram-negative: Staphylococcus aureus (ATCC , six
methicillin-susceptible clinical isolates, and six
methicillin-resistant clinical isolates), clinical isolates of S.
epidermidis (methiS and methiR), clinical isolates of
Enterococcus faecalis and E. faecium,andclinicalisolateof
Corynebacterium striatum
Inuencing the Gram-positive bacteria viability specially S.
aureus and several of its methicillin-resistant and
methicillin-susceptible
[]
Bulgaria Mediterranean propolis
PEE S. aureus 209; E. coli WF+, Decrease of S. aureus growthandweakorlackofactivity
against E. coli []
Greece Populus spp.
Tur k e y Conifer spp.
Algeria
Populus spp., Eucalyptus spp.,and
Castanea sativa Populus spp.
Cistus spp.
Australia
Australian propolis f rom stingless bee
Tetragonula carbonaria/C. torelliana trees
(fruit resins)
PEE S. aureus (ATCC );
P. aeruginosa (ATCC ) Inhibition of S. aureus growth []
Cameroon and Congo African propolis/probably M.
schweinfurthii PEE
S. aureus (ATCC ), S. epidermis (ATCC ), E. coli
(ATCC ), Klebsiella pneumonia (ATCC ), and P.
aeruginosa (ATCC )
Inhibition of S. aureus growth []
Brazil Green propolis/B. dracunculifolia PEE S. aureus and S. aureus isolated from mastitic cows,
S. aureus (ATCC )
Decrease of S. aureus growth in complex media and killing of
S. aureus cells resuspended in milk; promotion of changes in
morphology and cell size
[]
Czech Republic European propolis/Populus nigra Dimethylsulfoxide extract
S. aureus (CAPM ), E. faecalis (CAPM (EBF//)),
E. coli (CAMP T(U /)), and L. monocytogenes (CCM
)
Dierent concentrations aectthe growth of the tested bacteria []
Italy Mediterr ane an pro pol is/Crupessus spp.PEE
Staphylococcus spp. strains ( S. aureus,S. epidermidis,S.
hominis,S. haemolyticus,S. warneri,S. capitis,andS.
auricularis)andStreptococcus spp. strains ( S. faecalis,S.
viridans,S. 𝛽-haemolyticus,andS. pneumoniae)
Complete suppression of the factor coagulase, reduction of
lipase and prevention of biolm formation of Staphylococcus;
increase of the eect of ampicillin, gentamycin, and
streptomycin and moderating the action of chloramphenicol,
ceriaxone, and vancomycin
[]
Brazil Red propolis/D. ecastophyllum; Green
propolis/B. dracunculifolia PEE S. aureus (ATCC )
NanoHA matrix with red and green propolis which reduces
bacterial growth and biolm formation, the nanoHA with red
propolis being the most ecient
[]
Evidence-Based Complementary and Alternative Medicine
T : C o n t i n u ed.
Origin Propolis type/plant source Type of extract/isolated
compound(s) Species Eect References
Poland
European propoli s/Populu s nigra and
some species of Betula alba, Alus
glutinosa, Aesculus hippocastanum, Fagus
sylvatica
Coagulase-positive S. aureus strains isolated from blood
clinical samples, S. aureus (ATCC ), S. aureus (ATCC
), methicillin-sensitive and resistant S. aureus
Inhibition of S. aureus growth and bactericidal activity;
potentiation of antistaphylococcal drugs action; eective
against twelve S. aureus strains, with MIC values within . to
. mg/mL and MB C within . to . mg/mL
[]
Brazil;
Bulgaria
Green propolis/B. dracunculifolia;
Mediterrane an prop olis/Populus spp.;
PEE
S. typhi ()
Brazilian propolis having bacteriostatic activity; Bulgarian
propolis having bactericidal activity; both having similar
synergetic eect when in combination with amoxicillin,
ampicillin, and cephalexin
[]
S. typhimurium
Male BALB/c mice Increase of bactericidal activity of macrophages []
S. typhimurium Both samples having antibacterial activity but no synergistic
eects with ciprooxacin, noroxacin, and cotrimoxazole []
Tur k e y Mediterranean propolis/Populus spp.,
Eucalyptus spp.andCastaneasativa
PWE M. tuberculosis (HRv), male guinea-pig
Inhibition of tuberc ulosis infection in guinea-pigs since it
promotes a decrease in necrosis formation and increase in
granuloma formation
[]
PEE
E. coli (ATCC ),K.pneumoniae(ATCC ),P.
aeruginosa (ATCC ), Morganella morganii (clinical
isolate), S. aureus (ATCC ),B.subtilis(ATCC ),and
Proteus vulgaris
Inhibition of Gram-negative bacteria growth []
Purchased from Sigma
Aldrich Co. Characteristic of European propolis CAPE H. pylori Competitive inhibitor against H. pylori peptide deformylase,
blocking substrate entrance []
Evidence-Based Complementary and Alternative Medicine
T : Antifungal activity of propolis and its chemical constituents.
Origin Propolis type/plant source Type of extract/isolated
compound(s) Species/cells Eect/stimulus References
Brazil
Green propolis/B. dracunculifolia PEE
C. albicans, C. tropicalis, C. krusei, and C.
guilliermondii; adult volunteer patients showing
symptoms of stomatitis
Inhibition of cell growth, C. albicans being the most sensitive and C.
guilliermondii the most resistant; reduction of the number of Candida
yeasts in the saliva
[]
Green propolis/B. dracunculifolia; red
propolis/D. ecastaphyllum PEE T.rubrum,T.tonsurans,T.mentagrophytes,and T.
mentagrophytes (ATCC ) (control)
Both samples which decrease cell growth, red PEE being more ecient
than the green one []
Green propolis/B. dracunculifolia
PEE, PWE, matricial
microparticles, and soluble dry
extract
C. albicans strains SC (wild type), CAI, and
A (wild type), female BALB/c mice
PEEbeingthemostpotentininhibitingcellgrowthfollowedby
propolis soluble dry extract, propolis matricial microparticles, and PWE
Dierent gel formulations of propolis: propolis based Carbopol gel
(CP%), propolis based poloxamer gel with Carbopol (PP%),
propolis alginate with pectin (AlP%), and propolis based chitosan gel
with Natrosol (ChP%); CP% and chitosan gels being the most
pseudoplastic ones; propolis based gels presenting antifungal action
similar to clotrimazole cream
[]
Green propolis/B. dracunculifolia PEE, gels, and cream obtained
from the extract
C. albicans strains used were SC, CAI,
BWP, DAY, A, and L (wild type),
female BALB/c mice (murine model of
vulvovaginal candidiasis)
Induction of cel l death in C. albicans mediated via metacaspase and
RAS pathway
Inhibition of all three C. albicans morphogenetic types, several mutants
in genes involved either in the morphological transitions or in the
maintenanceofaspecicmorphotypewhicharemoresensitiveto
propolis
Propolis based gels and cream which were partially able to control
vulvovaginal candidiasis
[]
Green propolis/B. dracunculifolia PEE C. albicans (ATCC ), C. albicans isolates
from patients with vulvovaginal candidiasis
Inhibiting biolm for mation by C. albicans from vulvovaginal
candidiasis []
Red propolis/D. ecastaphyllum n-Hexane extract
C. parapsilosis (RL, RL, RL, RL, and
RL), C. glabrata (RL, RL, RL, RL, and
RL), C. tropicalis A, and C. krusei (ATCC
)
ActiveagainstuconazoleresistantCandida spp.[]
France European propolis/Populu s nigra PEE, PWE, methanolic extract,
and dichloromethane extract
C. albicans (ATCC ),C.glabrata(LMA
–), and A. fumigates (CBS )
Antifungal activity against C. albicans and C. glabrata butonlyhavinga
weak activity towards A. fumigates []
Brazil Green propolis/B. dracunculifolia PEE P. b r a s i l i e n s i s , peritoneal macrophages obtained
from male BALB/c mice Increase of fungicidal activity of macrophages against P. b ra s i l i e n s i s []
Bulgaria Mediterranean propolis/Po pulus spp.
Czech Republic European propolis/Populus nigra Dimethyl sulfoxide extract C. albicans,A. fumigatus,M. gypseum,andM.
canis
Aecting the growth of the tested bacteria in dierent ways by dierent
concentrations []
Portugal (Braganc¸a and
Leiria) European prop olis/ Populus nigra PEE C.albicans,T.rubrum,and A. fumigatus Plant extracts not exhibiting relevant antifungal activity, but in general
both propolis samples aecting the fungal growth []
Poland
European propoli s/Populu s nigra and
some species of Betula alba, Alnus
glutinosa, Aesculus hippocastanum,
and Fagus s ylvat ica
PEE isolated C. albicans, isolated C. glabrata, and
C. krusei Inhibition of fungal growth []
Iran European propol is/Poplar spp.,
Ferul a ovina PEE
C. albicans, C. tropicalis, C. kefyr, C. krusei, M.
globosa, M. slooae, and M. pachydermatis,all
obtained from patients with clinical features of
onychomycosis
Decrease of Candida and Malassezia strains growth, isolated from
onychomycosis, even in the uconazole-resistant strains []
Evidence-Based Complementary and Alternative Medicine
T : C o n t i n u ed.
Origin Propolis type/plant source Type of extract/isolated
compound(s) Species/cells Eect/stimulus References
Brazil Green propolis/B. dracunculifolia PEE and propolis microparticl es
yeast strains from vaginal exudates of the
vulvovaginal candidiasis patients: C. albicans
and C. glabrata,C. tropicalis,C.
guilliermondii,andC. parapsilosis
Inhibition of all ye asts growth by ethanol extract and propolis
microparticles,withsmallvariation,independentofthespeciesofyeast [ ]
Argentina
Tropical region propolis/Salix
humboldtiana, Pinus spp., Eucalyptus
spp., and Populus spp.
PEE
Xyloph ag ous (G. applanatum, L. elegans, P.
sanguineus, and S. commune)and
phytopathogenic (A. niger, Fusarium sp.,
Macroph omina sp.,P. n o t a t u m , and Rhodotorula
spp.)
Inhibition of fungal growth []
Spain (Basque Country) European propolis/Populus nigra PEE and propylene glycol
extracts
C. albicans (CECT ), S. cerevisiae (CECT
) Inhibition of fungal growth []
Evidence-Based Complementary and Alternative Medicine
mechanism of CAPE. H. pylori,amajorfactorforgas-
trointestinal illnesses, contains the enzyme H. pylori peptide
deformylase that catalyses the removal of formyl group from
the N-terminus of nascent polypeptide chains. Since the
action of this enzyme is essential for H. pylori survival, it is
considered a promising therapeutic drug target. Results from
absorption spectra and crystal structural characterization
showed that CAPE is a competitive inhibitor of peptide
deformylase, blocking the substrate entrance and preventing
substrate from approaching the active site [].
It has been suggested that the combination of propolis
with other antibiotics would allow dose reduction of selected
antibiotics, thus potentiating their eect. e antibacterial
activity of Italian PEE in some clinically isolated Gram-
positive strains, as well as the synergetic eect with some
antibiotics, was assessed by Scazzocchio et al. []. Ital-
ian PEE drastically increased the eect of ampicillin, gen-
tamycin, and streptomycin and moderated the action of
chloramphenicol, ceriaxone, and vancomycin. No eect
wasobservedwhenusedsimultaneouslywitherythromycin.
Wojty c zka e t a l. [ ]evaluatedthein vitro antimicrobial
activity of a Polish PEE against methicillin-sensitive S. aureus
(MSSA) and methicillin-resistant S. aureus (MRSA) clinical
isolates and also the combined eect of propolis with ten
selected antistaphylococcal drugs. PEE displayed varying
eectiveness against twelve S. aureus strains and potentiated
the antimicrobial eect of eight antistaphylococcal against
all tested strains. No synergism was observed in the case
of ciprooxacin and chloramphenicol. In another study, the
eect of dichloromethane extract of French propolis against
dierent human pathogenic bacterial strains was also tested.
Although Gram-negative bacteria were not susceptible to
the extract, a signicant antibacterial activity against both
methicillin-resistant and methicillin-susceptible S. aureus
strains was observed []. e same was conrmed by
Veli k ova e t a l. [] using dierent PEE from Bulgaria,
Greece, Turkey, and Algeria. All the samples showed a
good antibacterial activity against S. aureus but a week or
lacking eect against E. coli.AustralianPEEfromstingless
bee Tetragonula carbonaria also inhibited the growth of S.
aureus. Nevertheless, it was less active against P. a e r u g i n o s a
[]. e same was observed by Papachroni et al. []
using PEE from Cameroon and Congo.Contrary to these
studies, Katircio˘
glu and Mercan []showedthatTurkish
PEE was eective against Gram-negative bacteria like E. coli.
Orsi et al. [] investigated the possible synergism between
Brazilian and Bulgarian propolis and antibiotics acting on
DNA (ciprooxacin and noroxacin) and on metabolism
(cotrimoxazole) in Salmonella typhi.Bothsampleshad
antibacterial activity, but no synergistic eect was detected.
Recently, the suitability of nanohydroxyapatite- (nano-
HA-) based surfaces containing two Brazilian PEE (green
and red ones) to prevent S. aureus bacterial growth and
biolm was studied. e nanoHA impregnated with the
two highest concentrations ( and 𝜇g/mL) of red PEE
showed a remarkable reduction of % in the number of
viable bacteria, while nanoHA with green PEE at same
concentrations showed a reduction of and %. Moreover,
the nanoHA impregnated with the highest concentration of
red PEE was able to inhibit % of the staphylococcal biolm
formation [].
Diverse studies show that as the composition of propolis
varies from region to region, the antibacterial activity also
displays some variations []. Susceptibility of dierent
Gram-positive bacteria to PEE varies with the place of
propolis collection []. e antibacterial eect was shown
to be higher for samples from a wet-tropical rain forest-
type climate. Other studies revealed the inuence of propolis
geographical origin on its antibacterial properties [,,,
]. Propolis from the north and centre of Portugal has a
great activity against S. aureus [,].
4.5.2. Antifungal Activity. Antifungal activity is also inu-
enced by the chemical variation of propolis []. Several
studieshaveshowntheeectofpropolisfromdierent
geographic origin against dierent fungi, particularly of
clinical interest [–]. Quiroga et al. [] demonstrated
the antifungal activity of propolis from the northwest of
Argentina, focusing their study on the environment and
the development of agrochemicals with reduced economic
costs, possibly containing propolis extracts and its isolated
compounds, such as pinocembrin and galangin, as active
principles.
Recently, Falc˜
ao et al. []screenedtheantifungal
activity of Portuguese propolis and its potential oral sources
Populus x Canadensis and Cistus ladanifer against Candida
albicans,Trichophyton rubrum,andAspergillus fumigatus.
Plant extracts did not exhibit relevant antifungal activity, with
exception of T. ru b r um, but both propolis samples revealed
similar antifungal activity, the highest being obtained against
T. rubr u m and the lowest against A. fumigatus.Asampleof
PEEfromPolandshowedahighfungicidalactivityagainst
C. albicans,C. glabrata,andC. krusei []. Recently, it was
shown that dierent organic extracts of French propolis (PEE,
PWE, methanolic extract, and dichloromethane extract) were
eective against C. albicans and C. glabrata but only have a
weak activity towards A. fumigates [].
Brazilian PEE was proved to be active against several
Candida strains (C. albicans,C. tropicalis,C. krusei,and
C. guilliermondii), C. albicans being the most sensitive and
C. guilliermondii the most resistant []. Brazilian green
and red propolis display activity against dierent fungal
species of Tr ichophy t o n , which cause dermatophytosis, red
PEE being more ecient than the green one []. Also, it
was shown that n-hexane extract of Brazilian red propolis
did not induce resistance in Candida spp. In fact it was
active against Candida spp. resistant to antifungal agents,
like uconazole []. Dota et al. []evaluatedthein vitro
antifungal activity of PEE and propolis microparticles (PMs)
obtained from a sample from Argentina against clinical yeast
isolates of importance in the vulvovaginal candidiasis. C.
albicans and non-C. albicans were inhibited by PEE and PMs,
with small variation. Additionally, it was shown that Brazilian
green PEE has the ability to inhibit growth and biolm
formation by C. albicans from vulvovaginal candidiasis [].
Another study showed fungicide action of propolis (PEE,
PWE, propolis matricial microparticles (PMM), and propolis
soluble dry extract aer –-hour treatment against all three
Evidence-Based Complementary and Alternative Medicine
C. albicans morphotypes (yeast, pseudohyphae, and hyphae),
PEE being the most potent followed by PSDE, PM, and
PWE []. Brazilian propolis induces C. albicans cell death
mediated via metacaspase, since the metacaspase mutant in
C. albicans showed reduced sensitivity to propolis, and by
the Ras pathway. Using C. albicans deletion libraries, it was
possible to screen several mutants in genes involved either
in the morphological transitions or in the maintenance of a
specic morphotype that are more sensitive to propolis. To
conclude the study, the authors also showed that propolis
based gels and cream were partially able to control vulvo-
vaginal candidiasis in a mouse model []. ese studies
[]stronglyindicatethatpropolishasagreatpotentialto
control vulvovaginal candidiasis, representing a promising
alternative therapeutic strategy.
4.6. Antitumour Activity. Recognition of the hallmarks of
cancer aects the search and development of new meth-
ods and therapeutic agents with a suciently large thera-
peutic window to kill tumour cells while sparing normal
cells. In the last years, the natural product propolis has
attracted a growing interest by a large number of researchers
since it contains a variety of phytochemical compounds
that may act through multiple pathways to reduce the
development and other malignant characteristics of cancer
cells.
Recently, several in vitro studies have demonstrated a
cytotoxic action of propolis from dierent geographic origin
andofsomeofitsisolatedcompoundsonvarioustumour
cells. In vivo studies also show a potential in the development
of new antitumor agents, since propolis administration to
mammals (e.g., rats) does not lead to detectable side eects
[]. Briey, this natural product can block specic oncogene
signalling pathways, which in turn lead to a decrease in cell
proliferation and growth and can also act by decreasing the
cancer stem cell population, increasing apoptosis, exerting
antiangiogenic eects, and modulating the tumour microen-
vironment [,,]. Table summarizes the antitumour
activity of propolis from dierent geographic origin and its
chemical constituents.
Some researchers showed the eect of dierent types of
propolis and its constituents on cancer cell growth, prolifera-
tion, and apoptosis. e hexane extract of propolis from ai-
land, collected by the stingless bee Trigon a l a e v i c e ps,which
has a dierent behavior in propolis collection compared to
the honey bees, exerts antiproliferative activity against ve
tested cancer cell lines (Chago, KATO-III, SW, BT,
and Hep-G) but not against the normal cell lines tested
(HS broblast and CH-liver) []. A sample of PEE from
Poland inhibited human malignant melanoma (Me) and
colorectal cancer (HCT ) cells growth, as well as reduced
cell size []. Other studies reported the antitumor activity of
Brazilian PEE [–] which regulate the protein expression
of cyclin D, B and cyclin dependent kinase (CDK) as well
as p in human prostate cancer cells, signicantly aecting
proliferation [].
Although propolis containing CAPE is dierent from
thosewithartepillinC,itispossibletoobtainasimilar
inhibitory eect from both types. e eect of CAPE on
dierent cancer cell lines was analysed and many of its
eectshavebeenshowntobemediatedthroughinhibition
of NF-𝜅B[,]. CAPE can inhibit the proliferation of the
colorectal cell line SW by decreasing the 𝛽-catenin, c-
myc, and cyclin D protein expression []. Chuu et al. []
observed that CAPE suppressed the proliferation of LNCaP,
DU-, and PC- human prostate cancer cells in a dose-
dependent manner and also inhibited the tumour growth
of LNCaP xenogras in nude mice. It was suggested that it
acted through inhibition of pSK (an intermediary of the
PIK/AKT pathway responsible for the protein synthesis) and
some Akt signalling networks. Wu et al. [] demonstrated
that CAPE inhibits in vitro and in vivo MCF- and MDA-MB-
tumourgrowthwithoutmucheectonnormalmammary
cells by reducing the expression of growth and transcription
factors, including NF-𝜅B. Recently, it was demonstrated that
CAPE eect on genes that are associated with tumour cell
growth and survival is related in part to its role as a histone
deacetylase inhibitor [].
As previously said, propolis can also act by decreasing
thecancerstemcellpopulation.UsingtheputativeCD
(+)/CD (−/low) breast cancer stem cells able to generate
mammospheres from single cells, Omene et al. []showed
that CAPE caused a dose-dependent inhibition of cancer
stem cells self-renewal, progenitor formation, and clonal
growth.
Concerning cell death, some in vitro studies showed
dierent sensitivities of tumour cells to propolis extracts.
PWE from Iraq inhibits the proliferation of HL- cells
and leads to downregulation of Bcl- and activation of Bax
[]. Alizadeh et al. [] investigated the protective eects
of Iranian PEE on N-methyl-N-nitro-N-nitrosoguanidine-
(MNNG-) initiated gastric cancer in rats. Results showed
that tumour incidence, the number of lesions, structural
abnormalities, and beta-catenin of the animals group treated
with PEE signicantly declined compared with the control.
PEE also induced the expression of proapoptotic Bax and
reduced antiapoptotic Bcl- expression. Propolis inhibits
colony formation potential and promotes necrotic changes in
HCT- cells and decreases mitotic cells and increases p
and Ki- expression in HCT- tumor-bearing mice [].
Szliszka’s group have performed many studies to analyze the
antitumour eect of dierent propolis and its constituents
on prostate cancer cells (LNCaP and DU) [–].
Brazilian green PEE sensitized these cells to TRAIL-induced
death, enhanced the expression of TRAIL-R, and decreased
the activity of NF-𝜅BinLNCaPcells[]. Cotreatment of
TRAIL with artepillin C induced the signicant activation of
caspase- and caspase-, as well as a signicant disruption of
the mitochondrial membrane potential []. Many studies
have been conducted to understand the pathways involved
in the apoptotic eect of CAPE. CAPE induces cell cycle
arrest and apoptosis and reduces expression of NF-𝜅Bin
MDA-MB- and MCF- human breast cancer cells [].
In PC prostate cancer cells, CAPE induced apoptosis in a
dose-dependent manner that was associated with the loss of
expression of the inhibitors of apoptosis: cIAP-, cIAP-, and
XIAP []. Cavaliere et al. []showedthatCAPEtreatment
Evidence-Based Complementary and Alternative Medicine
T : Antitumoral activity of propolis and its chemical constituents.
Origin Propolis type/plant
source
Type of extract/isolated
compound(s) Species/cells Eect References
ailand
Propolis from
stingless bee Tr igo na
laeviceps
Hexane ex trac t
Colon (SW), breast (BT), hepatic
(Hep-G), lung (Chago), and stomach (Kato-III)
cells
Normal cell lines: liver (CH-liver) and broblast
(HS-)
High antiproliferative activity against the ve cancer cell lines and low
cytotoxic activity on the normal cell lines []
Poland
European
propolis/Populus
nigra and some
species of Betula
alba, Alnus
glutinosa, Aesculus
hippocastanum, and
Fagus sylvatica
PEE Human malignant melanoma cell line Me;
colorectal cancer cell line HCT Inhibition of cell growth and reduction of cell size of the tested cancer cells []
Synthesized
Characteristic of
propolis from the
Pacic region,
ailand, Africa,
Australia, and Brazil
Prenylated avanones Prostate cancer cell lines PC- and DU-
Human hepatoma cell line Hep-B
Induction of a more potent cytotoxicity against the PC- cell line than
-urouracil; induction of apoptosis []
Characteristic of
European propoli s CAPE
C cell line established from a glioma generated
by intravenous exposure of male Wistar rats to
N-nitrosomethylurea BALB/c-nu mice
Inhibition of C glioma cells growth; increase in the percentage of cells in the
G/G phase, and decrease in the protein level of hyperphosphorylated pRb;
increase in cyclin dependent kinase inhibitors p, p, and p; decrease in
tumor growth in xenogras, reduction of the number of mitotic cells and
proliferating cell nuclear antigen- (PCNA-) positive cells in C glioma
[]
HL- cell line Induction of apoptosis by activation of caspas e-, downregulation of Bcl-, and
upregulation of Bax []
Brazil
Characteristic of
Brazilian propolis
Drupanin, baccharin
((E)--prenyl--(,-
dihydrocinnamoyloxy)
cinnamic acid) and
artepillin C (isolated from
PEEs of propolis)
Human leukemia cell line HL-, colon cancer
cell line SW
Inhibition of cells growth; promotion of mor phological changes and
nucleosomal DNA fragmentation (artepillin C >baccharin >drupanin) []
Red propolis/D.
ecastaphyllum Methanolic extract Human pancreatic cancer cells (PANC-) Killing% of PANC- cells in the nutrient-deprived condition []
Green propolis/B.
dracunculifolia PEE
DU and PC- cell lines,
telomerase-immortalized primary human
prostate cancer-derived cell (RC-T/h/SA),
and primary human prostate epithelial cells
(PrEC)
Inhibition of human prostate cancer cells proliferat ion by regu lating the
protein expression of cyclin D, B and cyclin dependent kinase (CDK), p []
Green propolis/B.
dracunculifolia
Baccharin, beturetol,
kaempferide,
isosakuranetin, and
drupanin (isolated from
PEE)
Human e mbr yon ic kidney (HE K) ce ll,
HCT cell line
Inhibition of HIF-𝛼, glucose transporter , hexokinase , and vascular
endothelial growth factor A (VEGF-A) expression; exhibiting anti-angiogenic
eects in the chick chorioallantoic membrane
[]
Green propolis/B.
dracunculifolia PEE HUVECs cells Induction of apoptosis in tube-forming endothelial cells through the
inactivation of the survival signal ERK/ and by the activation of caspase- []
Green propolis/B.
dracunculifolia PWE Female Wistar rats Inhibition of angiogenesis in N-butyl-(- -hydroxybutyl) nitrosamine- (BBN-)
induced rat bladder cancer []
Red propolis/D.
ecastaphyllum PEE
Human immortalized endothelial-like cell line
EA.hy, renal cell carcinoma cell line RCC,
and mouse embryonic stem cell line CGR
Reduction of migration and sprouting of endothelial cells and attenuation of
new blood vessels formation; decrease in the dierentiation of embryonic stem
cells into CD positive cells; decrease in HIF-𝛼proteinaccumulationwhich
attenuates VEGF gene expression, increases the von Hippel-Lindau- (pVHL-)
dependent proteasomal degradation of HIF-𝛼, and downregulates Cdc
protein expression
[]
Evidence-Based Complementary and Alternative Medicine
T : C o n t i n u ed.
Origin Propolis type/plant
source
Type of extract/isolated
compound(s) Species/cells Eect References
Brazil Green propolis/B.
dracunculifolia PEE Human umbilical vein endothelial cells
(HUVECs), NF-decient MPNST (S-), and
NF-decient schwannoma (HEI-) cell lines
Female nu/nu mice
Blocking PAK signaling selectively, without aecting AKT; suppressing almost
completely the growth of human neurobromatosis tumor xenogras in mice []
Synthesized
Characteristic of
Brazilian
propolis
Artepillin C
Brazil Green propolis/B.
dracunculifolia PEE
HUVECs
Female ICR mice
Reduction of the number of newly formed vessels in vivo
Suppression of HUVECs proliferation and inhibition of tube formation []
Purchased: Wako Pure
Chemicals Industries
(Osaka, Japan)
Characteristic of
Brazilian propolis Artepillin C
Brazil Green propolis/B.
dracunculifolia PEE
LNCaP cell line
Sensitizing TRAIL-resistant LNCaP cells to TRAIL-induced apoptosis
Induction of a signicant disruption of
ΔΨm
Enhancing the expression of TRAIL-R and decreasing the activity of NF-𝜅B
Artepillin C, quercetin, kaempferol, and p-coumaric acid strongly cooperating
with TRAIL to induce apoptosis
[]
Purchased: Alexis
Biochemicals (San Diego,
CA, USA) Characteristic of
Brazilian propolis
Quercetin, kaempferol, and
p-coumaric acid
Purchased: Wako Pure
Chemicals (Osaka, Japan) Artepillin C
Brazil Red propolis/D.
ecastaphyllum PEE
MCF- cell line
Reducing cell viability through induction of mitochondrial dysfunction,
caspase- activity, and DNA fragmentation and increase in expression of
CCAAT/enhancer-binding protein homologous protein (CHOP) []
Purchased: Api Co. Ltd.,
Gifu, Japan
Characteristic of
European propoli s CAPE
Purchased: Sigma Aldrich
Co.
Characteristic of
European propoli s CAPE
LNCaP -S, DU-, and PC- cell lines
Male BALB/c mice
Suppressing the growth of LNCaP, DU-, and PC- and inhibiting the tumor
growth of LNCaP xenogras, possible inhibition of pSK and some Akt
signaling networks
[]
PC- cell line
Suppressing proliferation, colony formation, and cell cycle progression,
decrease in protein expression of cyclin D, cyclin E, SKP, c-Myc, Akt, Akt,
Akt, total Akt, mTOR, and Bcl-, Rb, as well as phosphorylation of Rb,
ERK/, Akt, mTOR, GSKa, GSKb, and PDK, and increase in KLF and
pCip protein expression
[]
Breast cell lines MDA-MB-, MCF-, MCF-A,
and MCF-A Bovine capillary endothelial (BCE)
cells
Female (Ncr-nu-nu) mice
Inhibition of in vitro and in vivo MCF- and MDA-MB- tumor growth
without much eect on normal mammary cells; induction of cell cycle arrest
and apoptosis by downregulation of Bcl- proteins; reduction of NF-𝜅Band
mdr- gene expression and suppression of VEGF production by MDA- cells
and formation of capillar y-like tubes by endothelial cells