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Received: 22 April 2020 Revised: 20 July 2020 Accepted: 20 August 2020
DOI: 10.1002/ptr.6875

REVIEW

Artepillin C as an outstanding phenolic compound of Brazilian

green propolis for disease treatment: A review on
pharmacological aspects

Fernando Pereira Beserra1,2 | Lucas Fernando Sérgio Gushiken2 |

2 1
Maria Fernanda Hussni | Victor Pena Ribeiro | Flávia Bonamin3 |
4 2
Christopher John Jackson | Cláudia Helena Pellizzon | Jairo Kenupp Bastos1

1
Department of Pharmaceutical Sciences,
School of Pharmaceutical Sciences, University Propolis is a viscous resin consisting of plant material (shoots, flowers, and plant exu-
of S~ao Paulo (USP), Ribeir~ao Preto, SP, Brazil
dates), salivary secretions and waxes produced by Apis mellifera bees. Its popular use
2
Department of Morphology, Institute of
Biosciences, S~ao Paulo State University aroused the interests of scientific research, which proved to be a potential source of
(UNESP), Botucatu, S~ao Paulo, Brazil various bioactive substances. The chemical composition of propolis depends on sev-
3
Avaré Faculty (EDUVALE), Avaré, S~ao Paulo,
eral factors, such as the different types of plant sources collected by bees, geographic
Brazil
4
Kolling Institute of Medical Research, The
origin, and the time of year in which they are produced, but it is known that phenolic
University of Sydney (USYD) at Royal North represent the main bioactive constituents of propolis. Baccharis dracunculifolia DC
Shore Hospital, Sydney, New South Wales,
Australia
(Asteraceae) is the most important botanical source of propolis and a native to south-
eastern Brazil. It is widely known as the green propolis because of its deep green
Correspondence
Fernando Pereira Beserra, Department of
color. One of its major phenolic acids is artepillin C (Art-C), a diprenyl-p-
Pharmaceutical Sciences, School of hydroxycinnamic acid derivative. This review aims to provide a comprehensive sum-
Pharmaceutical Sciences, University of S~ao
Paulo (USP), 14040-903, Ribeir~ao Preto, SP,
mary of the pharmacological effects of Art-C. The limited number of publications on
Brazil. this topic over the past two decades have been collected from databases and sum-
Email: fernando.beserra@unesp.br
marized. Numerous biological activities have been described for the Art-C, such as
Funding information gastroprotective, anti-inflammatory, antimicrobial, antioxidant, antitumor. This article
Fundaç~ao de Amparo à Pesquisa do Estado de
S~ao Paulo, Grant/Award Number: Process
describes aspects of occurrence, synthesis, biological activities and pharmacokinetic
number: 2017/04138-8 approaches.

KEYWORDS

artepillin C, green propolis, pharmacological properties, phenolic compounds

1 | I N T RO DU CT I O N resulting in an adhesive product. In addition to resin, propolis col-

Medicinal plants are important sources of natural compounds that
exhibit various therapeutic activities (Mishra et al., 2018; Salehi
et al., 2018). Since ancient times, various types of plants and their
phytochemicals have been used in both traditional and modern medic-
inal purposes in the world (Prakash et al., 2018; Salehi et al., 2018;
Sharifi-Rad et al., 2018). Propolis is a naturally occurring resinous sub-
stance that can be obtained by bees from different plant species. This
material is transported to the hive where it is mixed with beeswax,
lected contains also essential oils, beeswax, and pollen grains in low
concentrations (Marcucci, 1995). Five different types of propolis have
been identified, all from Brazil: two red propolis from the Northeast,
one type of Southeastern green propolis and two types of brown
propolis from the South. Differences in color and composition can
vary according to geographic origins and the type of local vegetation
(Marcucci, Sawaya, Custódio, Paulino, & Eberlin, 2008).
The Brazilian green propolis is produced by Apis mellifera bees
after collecting resins from the leaves of B. dracunculifolia DC

2274 © 2020 John Wiley & Sons Ltd wileyonlinelibrary.com/journal/ptr Phytotherapy Research. 2021;35:2274–2286.

BESERRA ET AL.
(Asteraceae). Its use in traditional medicine has gained notoriety
due to several interesting biological properties attributed to green
propolis, and many of these activities are related to Artepillin C
(Art-C)—3,5-diprenyl-4-hydroxycinnamic acid—a phytochemical
marker of green propolis (Kumazawa et al., 2003; Nakanishi
et al., 2003). B. dracunculifolia is a plant native to Brazil, popularly
known as “alecrim-do-campo”. It is a weed plant in pasture and was
considered a pest before studies found it was the main botanical
source of green propolis (Budel, Duarte, Santos, Farago, &
Matzenbacher, 2005). Nowadays, this plant has gained importance
not only because of its use in folk medicine as having anti-
inflammatory properties (Ribeiro, Arruda, El-Salam, & Bastos, 2018)
and in the treatment of stomach ulcers (Lemos et al., 2007), but
more recently for being important in the production of green prop-
olis (Hata et al., 2012).
Currently, Brazil is the third largest producer of propolis in the
world and about 80% of the production of green propolis is exported
to Japan (Berretta et al., 2017). Art-C, which is one of the main chemi-
cal markers of green propolis, is undoubtedly one of the main respon-
sible for the success of green propolis. Therefore, studies involving
this molecule are extremely important, because despite the researches
proving its biological properties, there is still a long way until this mol-
ecule is available on the market in the form of a medicine (Berretta
et al., 2017). In addition, the certification of the importance of Art-C is
directly related to the enhancement of its source: B. dracunculifolia
and, consequently, green propolis. The natural production of Art-C
occurs through the implementation of cultivation and preservation
fields of the species B. dracunculifolia, also associated with the produc-
tion of green propolis by the Apis mellifera bees, which may result in
the production of other bee products with importance, like honey,
wax and royal jelly (Pereira, Seixas, & Aquino Neto, 2002). As an
effect, Art-C can really be considered a miracle molecule, as it can act
directly and indirectly in the production of economic, ecological and
health wealth.
Although Art-C is found in large amounts in green propolis and
B. dracunculifolia, it has also been identified in the plant Flourensia
heterolepis (Asteracea) (Bohlmann & Jakupovic, 1979), in the genus
Relhania (Tsichritzis & Jakupovic, 1990), as well in other species of the
genus Baccharis (Matsuda & Almeida-Muradian, 2008). Barth, Freitas,
Matsuda, and Almeida-Muradian (2013) analyzed twenty-one types of
propolis from different Brazilian regions using palynological tech-
niques. The presence of Art-C was identified in samples in which Bac-
charis pollen grains were absent. It is known that Art-C possesses
some pharmacological properties and modulates several signaling
pathways to prevent the development of chronic diseases, including
anti-inflammatory (Szliszka, Mertas, Czuba, & Król, 2013), antioxidant
(Veiga et al., 2017), antimicrobial (Aguiar et al., 2013), immunomodula-
tory (Cheung et al., 2011), gastroprotective (Costa et al., 2018), anti-
obesity (Hata et al., 2012), and antitumor effects (Endo et al., 2018).
This review discusses current research related to the chemical and
pharmacological properties of Art-C in the past decades to show its
therapeutic potential and possible gaps, offering opportunities for fur-
ther drug research and development.
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2275
An extensive search for relevant articles published in the English
language between 2000 and 2020 was conducted, in the following
databases: PubMed, Scopus, ISI web of Cochrane Database of Sys-
tematic Reviews, Science Direct, LILACS, Google Scholar and Medline.
However, some papers published before 2000 were also included for
insight in the introduction and explanation. We have used “Artepillin
C" either alone or combined with “green propolis”, “phenolic com-
pounds”, “chemical aspects and biological activities” as key words for
literature searches. Initially, 121 publications were selected, but only
64 papers about phytochemical studies and pharmacological effects
of Art-C were finally included after reading the titles, abstracts and
whole articles.
2 | NA T U R A L OC C U R R E N C E O F
ARTEPILLIN C
There is a consensus in the literature that Art-C is found exclusively in
Brazilian propolis. Works from authors as Kumazawa, Hamasaka, and
Nakayama (2004) and Ahn et al. (2007) that investigated the chemical
composition of propolis from several regions confirmed this. How-
ever, Zhang et al. (2017) raised an interesting discussion, when they
reported that two authors have identified the presence of Art-C in
Chinese propolis. The authors concluded that in phytochemical stud-
ies by High Performance Liquid Chromatography with Electrospray
Ionization tandem Mass Spectrometry (HPLC-ESI-MS/MS) an interfer-
ing compound can be misidentified as Art-C in Chinese propolis, using
their method of analyzes.
The isolation and purification of compounds from natural origin is
an arduous task, and there are different techniques reported for
obtaining Art-C. Aga, Shibuya, Sugimoto, Kurimoto, and Nakajima
(1994) were the first to report the isolation and identification of this
compound from Brazilian propolis through the Sephadex LH-20 col-
umn. Nafady et al. (2003) used β-cyclodextrin-inclusion as a selective
method for the isolation of phenolic compounds from propolis, includ-
ing Art-C (Figure 1).
Lee, Chen, Yang, Lin, and Chang (2007) investigated the use of
different organic solvents and the application of supercritical carbon
dioxide extraction in the recovery of Art-C in samples of Brazilian
propolis, and observed that the extractions with supercritical carbon
dioxide added with ethyl acetate provided a recovery twice higher
than using organic solvent partitioning techniques. Other authors,
HO O
OH
FIGURE 1 Chemical structure of Artepillin C

2276
such as Paviani et al. (2012) and Machado et al. (Machado
et al., 2016), also applied techniques of extraction with supercritical
carbon dioxide to obtain fractions rich in Art-C.
The development and validation of analytical methods is
extremely important to ensure the quality of natural products (Ribeiro
et al., 2019). Sousa et al. (2009) developed and validated a method by
Reversed Phase High Performance Liquid Chromatographic method
with UV detection (RP-HPLC-UV) to quantify phenolic compounds in
Baccharis and propolis. Zhang et al. (2017) developed a HPLC-ESI-
MS/MS method for identification and quantification of Art-C aiming
to achieve quality control of Brazilian green propolis. The Liquid chro-
matography coupled to mass spectrometry with diode array detector
(LC-DAD-MS) method was developed and validated by Gardana,
Scaglianti, Pietta, and Simonetti (2007) for phenolic analysis of propo-
lis from different regions.
A seasonal study of phenolic compounds in Baccharis cultivars
was carried out by Sousa et al. (2011). The authors verified that out of
ten evaluated cultivars, Art-C was absent in only one individual for a
certain period of the year (May to October). Art-C showed a variation
in concentration between 0 and 1.09%, and from January to April,
showed the highest concentrations. The molecular properties of Art-C
were evaluated by Camuri, Costa, Ito, and Pazin (2018), where differ-
ent molecular rearrangements were identified in aqueous solutions at
different pHs, through optical absorption and fluorescence spectros-
copy. The obtained data can be corroborated with the development
of processes mediated by biological membranes, since they demon-
strated the state of protonation of Art-C.
Organic compounds can undergo chemical transformations
under certain conditions. Arruda et al. (2020a) evaluated the stabil-
ity of the Art-C against factors as sunlight, oxygen and tempera-
ture. It was verified that under the effect of sunlight the Art-C
suffered E-Z isomerization by radical intermediates formation after
five days of exposure and after 20 days of exposure both isomers
underwent total degradation, while under oxygen and high temper-
atures the degradation process resulted in three other compounds
identified as 2-propenoic (E)-3-[2,3-dihydro-2-(1-methylethyl)-
7-prenyl-5-benzofuranyl] acid, 2-propenoic (E)-3-(2,2-dimethyl-
3,4-dihydro-3-hydroxi-8-prenyl-2H-1-benzopyran-6-yl) acid and
3-[2-dimethyl-8-(3-methyl-2-butenyl) benzopiran]-6-propenoic acid.
In a complementary, study Arruda et al. (2020b) evaluated the bio-
logical activities of the Art-C degradation products and observed
that the Z-isomer had more activity against the gastric cancer cell
line, AGP-01, and against the amastigote forms of Leishmania
amazonensis, while the other degradation products were less active.
The Art-C molecule was first synthesized by Uto et al. (2002).
Synthesis was performed by O-diprenylation of p-iodophenol in water
followed by Mizoroki-Heck coupling with methyl acrylate. The
authors demonstrated that O-diprenylation of p-halophenols can be
achieved at room temperature in alkaline solution. More recently,
Yashiro, Hanaya, Shoji, and Sugai (2015) reported a new synthesis
proposal for Art-C using lipase-catalyzed regioselective deacetylation.
Firstly, the authors submitted 4-methoxyphenol (starting product) to
repeated allylation and Claisen rearrangement with 4-methoxy-
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BESERRA ET AL.
2-(2-propenyl)phenol, resulting in 4-methoxy-2,6-di(2-propenyl)phe-
nol with 66% yield. The resulting product suffered dimerization and
olefin cross-metathesis with transformation to 2,6-diprenyl-
1,4-hydroquinone diacetate and reacted with Candida antarctica
lipase, suffering β-catalyzed deacetylation. After triflation, a three-
carbon side chain was included and a final hydrolysis resulted in the
Art-C (Yashiro et al., 2015).
Despite this new technique containing more steps, the pure start
material is more accessible and also furnishes a good yield, presenting
advantages for Art-C synthesis in a preparative scale.
3 | P H A R M A C O L O G I C A L P R O P E R T I E S OF
ARTEPILLIN C
3.1 | Anti-inflammatory activity
Inflammation is a natural response of the innate immune system to
protect the organisms with the cleaning of cellular and extracellular
debris (Zhao, Liang, Clarke, Jackson, & Xue, 2016). Through the dam-
age of pathogens or aggressive agents, leukocytes migrate to the
region and release cytokines and other mediators in order to acti-
vate defense cells and remove the harmful agent (Nathan &
Ding, 2010). After a few days, the inflammatory response naturally
disappears and the tissues get back to the normal state. However,
noxious stimulus can increase inflammatory mediators, leading to
chronic inflammation (Zhao et al., 2016). In prolonged inflammation,
the cells of the region release large amounts of pro-inflammatory
cytokines and chemokines, increasing inflammatory signals such as
pain, erythema and oedema until the loss of function of the tissue
(Nathan & Ding, 2010; Vane & Botting, 1987). There are a variety of
exogenous anti-inflammatory molecules, including steroidal and
nonsteroidal anti-inflammatory drugs. However, the prolonged use
of anti-inflammatory drugs can cause adverse effects, such as peptic
ulcers, adrenal atrophy and osteoporosis. Therefore, researchers and
industry are trying to discover new therapeutic strategies to modu-
late the inflammation, including the use of natural products
(Abdulkhaleq et al., 2018).
As a secondary metabolite derived from propolis, Art-C is a
cinnamic acid derivative with anti-inflammatory potential in several
models in vitro and in vivo (Table 1). Various reports (de Moura
et al., 2011; Ikeda et al., 2011; Paulino et al., 2008; Szliszka
et al., 2013; Tani et al., 2010) have reported the anti-inflammatory
potential of Art-C through: a decrease in the cytokine synthesis (TNF-
α, IL-1β, IL-6, IL-8, IFN-γ, MIP and others) and pro-inflammatory mole-
cules (nitric oxide, histamine, leukotrienes, prostaglandins, prostacy-
clins and thromboxanes); inhibition of vasodilatation; migration of
new immune cells; and prevention of the symptoms of inflammation
such as pain, oedema and erythema. Moreover, inflammation can be
controlled through downregulation of cytoplasmic and nuclear signal-
ing mediators like NF-κB and JNK that controls the signaling pathway
of cytokines and chemokines synthesis, summarized in Table 1 (Ikeda
et al., 2011; Paulino et al., 2008).
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BESERRA ET AL. 2277

TABLE 1 Anti-inflammatory, antioxidant, antimicrobial, and immunomodulatory effects and mechanisms of Artepillin C in in vitro and in vivo
assays

Dose/
concentration
Assay Model of Artepillin C Effect Mechanisms Reference
In vitro 3 T3-L1 adipocytes 25 μM Anti-inflammatory Inhibition of TNF-α-mediated Ikeda et al. (2011)
downregulation of
adiponectin; increase of
PPAR-γ activity; inhibition
of TNF-α-induced JNK
signaling
In vivo Female Swiss mice 500 mg/kg Anti-inflammatory Decrease of inflammatory de Moura et al. (de
cells; modulation in matrix Moura et al., 2011)
remodeling
In vivo Male Swiss mice 0.1 mg/kg Anti-inflammatory Decrease of oedema; Paulino et al. (2008)
1 mg/kg reduction of neutrophils
10 mg/kg number; decrease in
prostaglandin E2 level
In vitro RAW 264.7 cells 3 μM Anti-inflammatory Reduction in nitric oxide Paulino et al. (2008)
10 μM synthesis
100 μM
In vitro HEK 293 cells 3 μM Anti-inflammatory Decrease of the NF-κB levels Paulino et al. (2008)
10 μM
100 μM
In vitro RAW 264.7 cells 25 μM Anti-inflammatory Inhibition of IL-1β, IL-3, IL-4, Szliszka et al. (2013)
50 μM IL-5, IL-9, IL-12p40, IL-13,
100 μM IL-17, TNF-α, G-CSF, GM-
CSF, MCP-1, MIP-1α, MIP-
1β, RANTES, KC and NF-
κB
In vitro Peripheral leukocytes of 3 μg/mL Anti-inflammatory Decrease of cysteinyl- Tani et al. (2010)
human blood 10 μg/mL leukotrienes; inhibition of
30 μg/mL histamine;
100 μg/mL
In vitro Human umbilical vein 3.13 μg/mL Antioxidant Increase in free radical- Ahn et al. (2009)
endothelial cells 12.5 μg/mL scavenging activity by
50 μg/mL DPPH method; increase in
reducing ability with FRAP
method
In vivo HRS/J hairless mice 100 mg/kg Antioxidant Inhibition of UV-mediated Fonseca et al. (2011)
GSH depletion
In vitro RGC-5 cells 20 μM Antioxidant Decrease of lipid Nakajima et al. (2007)
200 μM peroxidation
In vitro RGC-5 cells 0.1 mg/kg Antioxidant Increase of scavenging Nakajima et al. (2009a)
1 mg/kg potential of hydrogen
10 mg/kg peroxide, superoxide and
100 mg/kg hydroxyl radicals
In vitro RGC-5 cells 40 μg/mL Antioxidant Increase in casein-kinase 2 Nakajima et al. (2009b)
expression
In vitro - 3.14 μg/mL Antioxidant Increase in free-radical Seibert et al. (2019)
25.04 μg/mL scavenging potential by
DPPH and ABTS assays
In vitro Caco-2 cells 20 μM Antioxidant Decrease of lipid Shimizu et al. (2004)
HepG2 cells peroxidation; suppression
of oxidative damage to
DNA
In vitro - 52.2% Antioxidant Increase in free-radical Souza et al. (Souza, de
scavenging potential by Souza, Patitucci, &
DPPH Silva, 2007)

(Continues)
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2278 BESERRA ET AL.

TABLE 1 (Continued)

Dose/
concentration
Assay Model of Artepillin C Effect Mechanisms Reference
In vitro Rat liver mitochondria 0.72 μM Antioxidant Inhibition of lipid Uto et al. (Uto
7.81 μM peroxidation et al., 2006)
In vitro - 13.9 μg/mL Antioxidant Increase in free-radical Veiga et al. (Veiga
scavenging potential by et al., 2017)
DPPH
In vitro Fibrobacter succinogenes, 20–80 mg/mL Antibacterial Not evaluated Aguiar et al. (Aguiar
Ruminococcus flavefaciens, activity et al., 2013)
Ruminococcus albus,
Butyrivibrio fibrisolvens,
Prevotella albensis,
Peptostreptococcus sp.,
Clostridium aminophilum
and Streptococcus bovis
In vitro Leishmania braziliensis 1–250 μg/mL Antileishmanial Might be due to macrophage Pontin et al. (Pontin
activity activation et al., 2008)
In vivo Leishmania braziliensis 1.5 mg kg/day Antileishmanial Might be due to macrophage Pontin et al. (Pontin
activity activation et al., 2008)
In vitro Staphylococcus aureus, 50.0 mg/mL Antibacterial Not evaluated Seibert et al. (Seibert
Listeria monocytogenes, activity et al., 2019)
Enterococcus faecalis and
Staphylococcus
saprophyticus
In vitro Staphylococcus aureus 2 μg/mL Antibacterial Not evaluated Souza et al. (Souza
activity et al., 2007)
In vitro Staphylococcus aureus 246.3 μg/mL Antibacterial Not evaluated Veiga et al. (2017)
activity
In vitro Mixed leukocytes 50 mg/mL Immunomodulatory Induce apoptosis in Cheung et al. (2011)
proliferating T cells
In vivo Mice 10 mg/dose Immunomodulatory Increase in antibody titres Fisher et al. (2010)

3.2 | Antioxidant activity
Oxidative and nitrosative stress are conditions of the cellular metab-
olism involving an increase of reactive oxygen species (ROS) and
reactive nitrogen species (RNS), respectively. ROS and RNS are
physiologic products of the cellular metabolism and, in low quanti-
ties, act as signaling mediators (Bhattacharyya, Chattopadhyay,
Mitra, & Crowe, 2014). However, in high concentrations, these mole-
cules can cause oxidative and nitrosative damage in the tissues
which can lead to mutations and cell death (Bedard & Krause, 2007),
being associated with diseases like ageing, chronic inflammation,
dementia and cancer (Aboulkassim, Ongali, Tong, Hamel, &
Nicolakakis, 2007; Baud & Ardaillou, 1993; Bhattacharyya et al.,
2014; Butterfield et al., 2007; Faraci, 2005; Forbes, Coughlan, &
Cooper, 2008; Perry, Cash, & Smith, 2003). Due to the deleterious
effects caused by oxidative and nitrosative stress, organisms have
endogenous antioxidant mechanisms, with activation of superoxide
dismutase (SOD) (Kwon, Kim, Lee, & Kim, 2012), glutathione peroxi-
dase (GP), catalase (CAT), (Schrader & Fahimi, 2006), reduced gluta-
thione (GSH), glutathione reductase (GR) and melatonin (MEL)
(Bhattacharyya et al., 2014; Ferreira & Matsubara, 1997; Reiter, Tan,
Manchester, & El-Sawi, 2002). Moreover, there Considering the del-
eterious effects derived from oxidative and nitrosative stress, scien-
tists and industry are exploring new therapeutic strategies to reduce
the damage of ROS and RNS like the application of natural products
(Gál et al., 2009).
One example of a natural product that has been tested as an anti-
oxidant molecule is Art-C, a diprenyl-p-hydroxycinnamic acid deriva-
tive from propolis. Some studies relate Art-C as a potent exogenous
antioxidant molecule in free radical-scavenging and reducing activities
(Table 1) through DPPH (2,2-difenil-1-picril-hidrazil), FRAP
(Fluorescence recovery after photobleaching) and ABTS (2,2'-
azinobis-[3-ethylbenzthiazoline-6-sulfonic acid) methods (Ahn
et al., 2009; Nakajima, Tsuruma, Shimazawa, Mishima, & Hara, 2009;
Seibert et al., 2019; Souza et al., 2007; Veiga et al., 2017). Moreover,
the exogenous reducing activity of Art-C can be related to the pres-
ence of phenolic hydroxyl moiety in the structure. Another mecha-
nism through Art-C can exert its antioxidant activity is increasing the
potential of endogenous proteins like GSH, GR, MEL, GP, SOD and
CAT, which reduces the pro-oxidative and nitrosative molecules
responsible to cellular damage, as we can see in Table 1 (Fonseca
et al., 2011; Nakajima, Shimazawa, Mishima, & Hara, 2007; Nakajima,

BESERRA ET AL.
Shimazawa, Mishima, & Hara, 2009; Shimizu, Ashida, Matsuura, &
Kanazawa, 2004; Uto et al., 2006). The last antioxidant mechanism in
which Art-C is involved is lipid peroxidation, an oxidative process of
lipids from cell membranes, resulting in membrane disruption and cell
damage. Art-C decreases the lipid peroxidation from cell membranes
in vitro in retinal ganglion cells (RGC-5) (Nakajima et al., 2007), hepatic
cells (HepG2) (Shimizu et al., 2004) and in mitochondrial membranes
of hepatic cells (Uto et al., 2006), preventing cellular damage and cell
death in these cultures. Furthermore, Uto et al. (2006) obtained iso-
prene analogues of Art-C, and investigated the inhibitory activity on
lipid peroxidation of rat liver mitochondria and isoprenomics toxicity.
The authors reported that Art-C isoprene analogues could be potent
lipid peroxidation inhibitors with low mitochondrial toxicity, and that
elongation of the isoprene side chain of Art-C, to increase lipophilicity,
had little influence on the inhibitory activity toward rat liver mito-
chondrial lipid peroxidation.
Therefore, the antioxidant potential of Art-C is related to the
capacity to reduce the oxidative and nitrosative stress, increase free-
radical scavenging, improve the activity of GSH, GP, CAT, SOD and
decrease lipid peroxidation.
3.3 | Antimicrobial activity
Medicinal plants are an important therapeutic source for many disease
treatments, especially in developing nations (Eller, Feitosa, Arruda,
Antunes, & Cat~ao, 2015), whose diseases are often related to poor
sanitation, poor nutrition and poor access to medicines (Michelin
et al., 2005). In these countries, “home medicine” is part of popular
culture, as a raw material for the preparation of herbal medicines
(Eller et al., 2015). Such plants constitute an enormous source of com-
pounds with a wide range of biological activities, but especially in the
treatment of infectious diseases. Therefore, it represents a great con-
tribution to the development of new therapeutic strategies, which can
be used to treat diseases caused by multi-resistant microorganisms
(Porfírio, Melo-Filho, Alvino, Lima, & Santana, 2008). Currently, micro-
organism resistance has been considered as a growing worldwide pub-
lic health problem and a major obstacle to therapeutic success, given
the continued reduction in the number of valid antibiotics available
(Blair, Webber, Baylay, Ogbolu, & Piddock, 2015). Therefore, the use
of naturally occurring antimicrobials becomes a necessary and effec-
tive alternative.
Among the various biological and pharmacological properties pre-
sent in propolis extract, there is antimicrobial activity, which has been
studied in many microbiological fields as an alternative to antibiotics
or chemical additives (Aguiar et al., 2013). However, the activity pro-
files obtained for many microorganisms tested in several studies has
shown very distinct aspects, indicating that the variation of results
was due to the geographical region where the propolis was collected
(Machado et al., 2016) (Table 1). Machado et al. (2016) have evaluated
the antimicrobial activity of propolis extracts obtained by supercritical
extraction (SCO2) and ethanolic extraction (EtOH), and have discov-
ered that the red propolis from the Brazilian Northeast (states of
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2279
Sergipe and Alagoas) showed the higher biological potential (Table 1).
They have also verified that the composition and biological activity of
the Brazilian propolis vary significantly, depending on the type of sam-
ple and geographical area of collection.
Aguiar et al. (2013) evaluated the antimicrobial activity of three
Brazilian propolis extracts against bacterial strains representing major
rumen functional groups, which showed activity against gram-positive
bacteria Staphylococcus aureus and gram-negative Escherichia coli. The
effects were dependent on the origin of the matrix and method of
extraction but in general showed a higher activity against the gram-
positive than against the gram-negative bacteria. The extract con-
taining the lowest number of phenolic compounds showed the lowest
antimicrobial activity against all bacteria (Table 1). From the evaluated
major phenolic compounds identified in the propolis extracts
(naringenin, chrysin, caffeic acid, p-coumaric acid and Art-C), only
naringenin showed an inhibitory effect against all strains.
Veiga et al. (2017) reported that Art-C exhibits greater inhibition
of bacterial growth when it is combined with other propolis extracted
molecules, suggesting that it works synergistically with other propolis
molecules (Veiga et al., 2017). Numerous studies have reported anti-
microbial mechanisms of Art-C, although the mechanism of action is
unclear (Table 1).
3.4 | Immunomodulatory effects
Cytokines are small proteins, glycosylated or not, that send modula-
tory signals to the various immune cells. These molecules may exert
an autocrine function (acting in the producer cell itself), paracrine
function (acting on nearby cells) and/or endocrine function (when it
acts by distance) (Varella & Forte, 2001). Cytokines act in very low
concentrations, and their synthesis usually occurs after antigen stimu-
lation, presenting well established actions helping on the defense
against infections (Varella & Forte, 2001). Disturbances that occur in
the balance of these molecules may contribute to different diseases.
Chan, Cheung, and Sze (2012) have compiled several studies
regarding propolis and Art-C immunomodulatory activity, as shown in
Table 1. Several studies have shown that Art-C can indirectly kill can-
cer cells by increasing T cell-mediated cytotoxicity via an upregulation
of the CD4/CD8 ratio and the total number of T cells in vivo, as well
as by inhibiting NFκB activity in macrophages and neutrophil
mobilization.
In addition to its bactericidal activity, Art-C modulates the
immune system by normalizing TLR4 and IL-4, inhibiting IFN-γ and
IL-6. Art-C affects various immune cells, such as immunosuppression
of T lymphocyte subsets and activation of macrophage function.
Art-C inhibits the exacerbation of carrageenan-induced paw edema in
a mouse model (Chan et al., 2012). Cheung et al. (2011) discovered
that Art-C selectively induces apoptosis in proliferating T cells,
although this effect is reversible (Table 1). Although there exist ample
evidences on the immunomodulatory activity of Art-C, the exact
underlying mechanisms of these actions remain uncertain at this time
(Chan et al., 2012).
 10991573, 2021, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ptr.6875 by UNIVERSIDADE ESTADUAL PAULISTA, Wiley Online Library on [16/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
2280 BESERRA ET AL.

3.5 | Antitumor effects
Art-C exerts potent antitumor activity in various types of cancers
and cancer cells, as can be seen in Table 2. Colon cancer represents
the fourth leading cause of cancer mortality worldwide (Klobučar
et al., 2018). Akao and colleagues showed an inhibitory effect on cell
proliferation of propolis active ingredients in gastrointestinal cancer
cell lines. In this study, when cells were exposed to Art-C at 150 μM
the growth of all cell lines was markedly inhibited, with greater
effectiveness in comparison with other cinnamic acid derivatives,
baccarin and drupanin, present in propolis (Akao et al., 2003).
Another study showed that Art-C isolated from Brazilian propolis
inhibited cell growth in a dose-dependent manner by inducing
G0/G1 arrest. This effect may be due to Cip1/p21 upregulation
after a 12 hr treatment accompanied by the downregulation of the
cyclin D/CDK4 activity (Shimizu et al., 2005). Oral squamous cell
carcinoma (OSCC) is the most common oral cancer and represents
2–4% of cancers worldwide and has a low survival rate
(Markopoulos, 2012). A recent study by Pang, Yee, Saba, and
Chino (2018) showed that Art-C was cytotoxic in a dose- and time-
dependent manner to HSC-3 cells (a human tongue squamous carci-
noma cell line) up to 72 hr.
Melanoma is one of the most aggressive tumors of the skin and
mucosa, and its incidence has been increasing in recent decades
(WHO, 2018). It is known that 85% of the cutaneous melanomas
affect the populations of North America, Oceania and Europe (Pisano
et al., 2019). Art-C showed cytotoxic effects on the B16F10 murine
melanoma cell line, with an IC50 value of 38.9 ± 7.6 μg/mL,
significantly lower than the normal cell line (335.1 ± 10.6 μg/mL)
(de Oliveira et al., 2014).
Prostate cancer is the most prevalent malignancy in men in the
western world, and currently among the leading causes of cancer-
related morbidity and mortality (Santos, Patel, Henrique, &
Félix, 2020). Recent research has indicated the beneficial effects of
the Art-C on autophagy and apoptosis in human prostate cancer cell
lines. Endo et al. (2018) reported that Art-C administration induces
autophagy and apoptosis in prostate cancer cells by DNA fragmenta-
tion and increases cleaved caspase-3 and poly ADP-ribose polymer-
ase. Szliszka, Zydowicz, Mizgala, and Krol (2012) showed the cancer
chemopreventative action of Art-C in LNCaP prostate cancer cells
through the modulation of TRAIL-mediated apoptotic signaling path-
ways, a potent stimulator of apoptosis in cancer cells, and decreased
the activity of NF-κB.
Lung cancer has a high incidence and mortality, especially in men,
according to a global cancer statistical report (Bray et al., 2018). Art-C
is able to block the oncogenic/melanogenic/ageing kinase PAK1, but
due to their COOH moiety, cell-permeability of the Art-C is rather lim-
ited. To increase cell-permeability, Takahashi et al. (Takahashi
et al., 2017) carried out a study showing that esterification of Art-C
with the water-soluble 1,2,3-triazolyl alcohol through Click Chemistry
is able to boost the anti-cancer activity of Art-C by over 400 fold
against the PAK-dependent growth of A549 lung cells. The authors
suggest that the esterification of Art-C significantly improves its phys-
icochemical properties and it is most likely that the potentiation of
this anticancer effect is at least partly due to the increase in its cellular
permeability.

TABLE 2 Antitumor activity of Artepillin C

Cancer type Suppressive effect Cellular processes Function study Reference

Colon cancer Anti-proliferation Cell growth In vitro Akao et al. (2003)
Gastric cancer Anti-proliferation Cell growth In vitro Akao et al. (2003)
Leukemia Anti-proliferation Cell growth In vitro Akao et al. (2003)
Melanoma Anti-proliferation Cell viability In vitro Oliveira et al. (Oliveira,
Lima, & Neto, 2013)
Colon carcinoma Anti-proliferation Cell viability In vitro Oliveira et al. (Oliveira
et al., 2013)
Prostate cancer Autophagy-inducing/anti- Apoptosis, DNA damage, In vitro Endo et al. (2018)
proliferation cell viability
Fibrosarcoma Anti-proliferation/ Cell viability, wound In vitro and Bhargava et al. (2018)
anti-migration healing in vivo
and cell growth
Renal cancer Antioxidant Lipid peroxidation and In vivo Kimoto et al. (2000)
apoptosis
Oral squamous Anti-proliferation Apoptosis In vitro Pang et al. (2018)
carcinoma
Colon cancer Anti-proliferation Cell growth In vitro Shimizu et al. (2005)
Prostate cancer Anti-proliferation Cell viability and apoptosis In vitro Szliszka et al. (2012)
Lung cancer Anti-proliferation Cell viability In vitro Takahashi et al.
(Takahashi
et al., 2017)

BESERRA ET AL.
Malignant renal tumors represent 2% of global cases and it is esti-
mated that its incidence increases each year. In 2018, 63,000 new
cases and 15,000 kidney cancer deaths occurred in the United States
and  350,000 new cases were reported in the rest of the world
(Turajlic, Swanton, & Boshoff, 2018). The antitumor activity of Art-C
has been demonstrated in mouse renal carcinogenesis induced by fer-
ric nitrilotriacetate. Oral administration of Art-C prevented the
increase in lipid peroxides in the kidneys at the early stages. Art-C also
induces apoptosis of tumor cells directly and has inhibitory effects on
cancer growth in mice, and is considered an important antic-
arcinogenic agent (Kimoto et al., 2000).
Additionally, Art-C exerts an anticancer effect in human fibrosar-
coma, a malignant neoplasm of fibroblasts with variable collagen pro-
duction (Bhargava et al., 2018). Although its incidence has declined
substantially in recent decades, it is still considered a major challenge
in the search for new antitumor molecules (Folpe, 2014). Bhargava's
study showed that treatment with Art-C possesses high cytotoxicity
to HT1080 (Fibrosarcoma) cell lines and in vivo suppresses tumors in
nude mice. This effect possibly occurs through activation of p53
tumor suppressor protein by abrogating its complex with the p53
inactivating protein, mortalin (Bhargava et al., 2018).
3.6 | Other activities
Art-C has been evaluated for its gastroprotective effects against HCL-
ethanol-induced ulcer in mice and the histological, histochemical, oxi-
dative and inflammatory parameters were analyzed in the ulcerated
tissue of these animals (Costa et al., 2018). Art-C presented anti-ulcer
effects at 0.3 mg/Kg (p.o) and 0.03 mg/Kg (i.p). Moreover, Art-C nor-
malizes superoxide dismutase, catalase, and glutathione S-transferase
activities and reduces myeloperoxidase activity and TNF. Further-
more, Art-C showed gastric acid antisecretory activities (Costa
et al., 2018).
One of the most serious public health problems in recent times in
the world has been obesity, which continues to increase globally. In
this context, as described by Giralt and Villarroya (2013), mammals
have two types of adipose tissue: white (energy storage as triglycer-
ides) and brown (thermogenesis). According to Nishikawa et al. (2016),
Art-C significantly induces brown-like adipocytes and this significant
induction is due to stabilization of the protein PRDM16, and increas-
ing energy expenditure by darkening the formation of white
adipocytes.
A study by Hata et al. (2012), points out that the Brazilian green
propolis extract has an herb smell and a unique bitter and pungent fla-
vor, which can is likely related to the palatability of propolis. Art-C
activates the human transient receptor potential ankyrin 1 channels
(Hata et al., 2012), non-selective Ca2+ permeable cation channels, that
are co-expressed with potential transient receptor vanilloid 1 in noci-
ceptive neurons.
Neto et al. (2011) showed that the Art-C, on Swiss mice, not only
had no genotoxic effect, but also presented a protective effect against
DNA damage induced by mutagenic substances using the
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2281
micronucleus and comet assays. They showed that Art-C at low con-
centrations was effective in reducing the genotoxicity induced by
MMS in V79 cells (cultures of Chinese hamster lung fibroblasts)
(Oliveira et al., 2013). Resende et al. (2012) showed similar activity of
Art-C in ethyl acetate extracts of Baccharis dracunculifolia leaves (Bd-
EAE), by demonstrating that the antimutagenic activity of Bd-EAE can
be partially attributed to Art-C. The findings by Rodrigues, Plentz, Flo-
res, Dihl, and Lehmann (2017) indicate that the various responses
elicited by Art-C, namely induction of DNA damage, production of
genetic lesions, or activation of DNA repair mechanisms are depen-
dent on Art-C concentration.
Previous study has identified an important role of a Taiwanese
green propolis extract on experimental models of liver fibrosis in vitro
and in vivo (Su et al., 2014). It is known that the pathogenesis of this
condition is a common but complex process that may lead to chronic
liver disease and liver cirrhosis. Su et al. (2014) investigated the
antifibrotic effect of an ethanol extract of Taiwanese green propolis in
experimental models in vitro by using active hepatic stellate cells
(HSCs) and ethanol-induced liver injury in mice. The results showed a
potent antifibrotic effect through the inhibition of TGF-βSmad2/3 sig-
naling, directly or indirectly reducing Smad2/3 formation. In in vivo
tests, the extract showed a significant reduction in plasma activation
of alanine aminotransferase (ALT) and malondialdehyde (MDA) levels
promoting hepatoprotection against alcohol-induced injury.
A recent study led by Kalil et al. (2019) revealed the efficacy of a
green propolis-based ointment (20%) rich in Artepillin C in the post-
surgical treatment of caseous lymphadenitis in sheep. The group of
sheep treated with the green propolis extract showed complete
healing of the surgical wound one week before the control group
treated with iodine. The results also showed no sign of toxicity from
that green propolis-based ointment, showing it to be highly promising
in the treatment of skin wounds. Batista et al. (2012) showed a signifi-
cant healing effect in rat skin wounds treated with green and red
propolis-based ointment after 15 days. Although both extracts
showed almost the same number of phenolic compounds in their
extracts, macroscopic and histological analyzes revealed a better
repair in the skin tissue of rats after treatment with the green propolis
ointment. There was no sign of toxicity in the study (Batista
et al., 2012).
3.7 | Pharmacokinetic aspects of Artepillin C
Pharmacokinetics describes the time patterns of response to drug
administration after acute or chronic administration, providing infor-
mation on how these drugs are absorbed, distributed, metabolized
and excreted (Crotti et al., 2017). There are few reports in the litera-
ture on studies of the pharmacokinetics of Art-C. Konishi (2005) was
one of the first to study the pharmacokinetics of Art-C. The author
examined the absorption characteristics of Art-C by measuring perme-
ation across Caco-2 cell monolayers. The results demonstrated that
the Art-C is mainly permeated across Caco-2 cells by transcellular pas-
sive diffusion and is also taken up intracellular by the monocarboxylic

2282
acid transporter on the apical side and not transported out across the
basolateral membrane, suggesting that different subtypes of monocar-
boxylic acid transporter are involved.
Konishi and co-workers also assessed the pharmacokinetics and
bioavailability of Art-C in rats, in comparison with p-coumaric acid
(CA), a substrate of monocarboxylic acid transporter (MCT). The
results showed that the absorption efficiency of CA was approxi-
mately 17-fold greater than that of Art-C, indicating that there is a
specific difference in the absorption characteristics of these two phe-
nolic acids in vivo. The bioavailability of Art-C was extremely low
in vivo, in comparison with that of CA, which is absorbed and distrib-
uted by the MCT-mediated transport system, suggesting that Art-C
may be more susceptible to hepatic elimination in comparison with
CA (Konishi, Hitomi, Yoshida, & Yoshioka, 2005).
A pharmacokinetic study of Art-C interaction in bloodstream was
carried out by Chaves, De Oliveira Pires, Castro, Sant'Anna, and
Netto-Ferreira (2019) through spectroscopic techniques, zeta poten-
tial and molecular docking. To perform this, the study approached the
interaction of Art-C and human serum albumin, the main carrier of
small molecules in the bloodstream. The results of the research
showed that human serum albumin and Art-C interaction is moderate
and causes a weak perturbation of secondary structure of albumin.
Furthermore, the interaction occurs through a ground-state associa-
tion and Art-C can bind with amino acids tryptophan-214, serine-201,
valine-343, serine-453, and leucine-480 via hydrogen bounding or
van der Waals and hydrophobic forces.
In vitro metabolism of Art-C was investigated by measuring
enzymatic kinetic parameters in rat liver microsomes and human
liver microsomes by Carr~ao et al. (2017). Two new metabolites of
Art-C have been reported in both models and the chemical struc-
tures of metabolites formed by rat liver microsomes were elucidated
by mass spectrometry. The major CYP450 isoforms responsible for
the formation of the Art-C metabolite were identified as CYP2E1
and CYP2C9.
An experimental and computational study carried out by Pazin
et al. (Pazin et al., 2017) investigated the interaction and permeabil-
ity capacity of Art-C between membranes composed of
dimyristoylphosphatidylcholine (DMPC), a model of cell membranes
most abundant in eukaryotes. They found that Art-C was capable of
being adsorbed through the DMPC monolayers. Its presence in the
lipid suspension pointed to an increased tendency towards
unilamellar vesicles and decreased thickness of the bilayer. The com-
putational molecular studies concluded that the Art-C: was added to
the aqueous phase before entering the bilayer; was able to orient
itself in the normal direction of the surface; was accommodated in
the polar region of the membrane by its negatively charged group;
was found in the thinner regions of the membrane. Recently, the
same group studied the interaction of Art-C with Langmuir mono-
layers and giant unilamellar vesicles of 1,2-dipalmitoyl-sn-glycerol-
3-phosphocholine used as model membranes, in physiological and
acidic environments. They found strong evidence that the Art-C is
capable of altering and damaging lipid structures of cell membranes
in acidic environments. The neutral Art-C appears to selectively
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BESERRA ET AL.
partition the more acidic extracellular microenvironment of tumor
cells (Pazin, Ruiz, Oliveira-Junior, & Constantino, 2019).
4 | CONC LU SIONS
The search for substances of natural origin has increased significantly
in recent years, in order to obtain health products with greater bio-
compatibility, less toxicity, and therapeutic potentials, associated with
more accessible costs to the population. This review addressed chemi-
cal and biological aspects of Art-C, emphasizing its wide range of
pharmacological activities. Although it has been considered a sub-
stance with a wide variety of pharmacological effects, pharmacody-
namic studies of Art-C are yet to be detailed. Clinical research is
needed to better determine the pharmacodynamic aspects of Art-C,
since most of these effects have only been demonstrated in labora-
tory experiments. Additionally, genomic, proteomic and metabolomic
analyses can be the main strategies implemented to determine param-
eters related to bioavailability, the half-life, adverse reactions and
toxicity.
AC KNOWLEDG EME NT S
Authors are thankful to S~
ao Paulo Research Foundation (FAPESP, pro-
cess number: 2017/04138–8), Coordination for the Improvement of
Higher Education Personnel (CAPES), and the National Council for
Scientific and Technological Development (CNPq) for financial
support.
CONFLICTS OF INTEREST
The authors declare no conflicts of interest.
OR CID
Fernando Pereira Beserra https://orcid.org/0000-0002-0498-4444
Lucas Fernando Sérgio Gushiken https://orcid.org/0000-0001-
9143-3706
Maria Fernanda Hussni https://orcid.org/0000-0001-9607-5768
Victor Pena Ribeiro https://orcid.org/0000-0002-5015-2446
Flávia Bonamin https://orcid.org/0000-0001-6072-4113
Christopher John Jackson https://orcid.org/0000-0002-9234-9116
Cláudia Helena Pellizzon https://orcid.org/0000-0002-4494-4180
Jairo Kenupp Bastos https://orcid.org/0000-0001-8641-9686
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