Artepillin C

Artepillin C

1. Identity: Chemical Name, Botanical Source, and Common Forms

Chemical Identity

Artepillin C (3,5-diprenyl-4-hydroxycinnamic acid; ARC) is a prenylated derivative of p-coumaric acid (pCA). Its systematic IUPAC name, as catalogued in the chemical literature, is (E)-3-[4-hydroxy-3,5-bis(3-methylbut-2-enyl)phenyl]prop-2-enoic acid. It belongs to the broader class of hydroxycinnamic acid derivatives and, more specifically, to the subgroup of prenylated phenolic acids. Artepillin C is a simple phenol constructed of a single ring with two prenyl groups. ARC exists in two configurations — E and Z — and isomerization occurs at the vinyl double bond. Its molecular formula is C₁₉H₂₄O₃, and it is registered in PubChem under CID 5472440.

Botanical Source

Propolis is a viscous resin consisting of plant material (shoots, flowers, and plant exudates), salivary secretions, and waxes produced by Apis mellifera bees. Its popular use aroused the interests of scientific research, which proved it to be a potential source of various bioactive substances. The chemical composition of propolis depends on several factors, such as the different types of plant sources collected by bees, geographic origin, and the time of year in which they are produced, but it is known that phenolics represent the main bioactive constituents of propolis.

Baccharis dracunculifolia DC (Asteraceae) is the most important botanical source of propolis and is native to southeastern Brazil. It is widely known as the green propolis because of its deep green color. One of its major phenolic acids is artepillin C (Art-C), a diprenyl-p-hydroxycinnamic acid derivative. It is one of the major biologically active phenolic components of Brazilian green propolis (BGP), which is sourced from the plant Baccharis dracunculifolia in southeastern and west-central Brazil.

While the highest amounts of ARC are reported in BGP, various quantities have also been reported in Brazilian brown propolis, in Artemisia, Flourensia, and Relhania species, and recently it has been identified in Chinese poplar propolis.

Artepillin C was isolated and identified by Aga et al. (1994). Shimizu et al. (2004) and Matsuda and Almeida-Muradian (2008) demonstrated that artepillin C is one of the most important active ingredients of Brazilian propolis.

ARC is the significant biologically active phenolic ingredient and a primary assessment criterion for quality control in Brazilian green propolis. There are mainly three types of propolis whose major anticancer ingredients are entirely different: (1) CAPE (caffeic acid phenethyl ester)-based propolis in Europe, the Far East, and New Zealand; (2) artepillin C (ARC)-based Brazilian green propolis; and (3) Brazilian red propolis.

Common Forms and Preparations

As a dietary supplement, artepillin C is almost exclusively consumed as a constituent of Brazilian green propolis rather than as an isolated compound. Brazilian green propolis is a popular health supplement available as ethanol extract (EEBP), which is characteristic for its herb-like smell and unique pungent taste. Commercial preparations include standardized ethanolic extracts (e.g., EPP-AF®), raw propolis in capsule or tablet form, tinctures, and topical preparations such as creams and ointments. The COOH moiety on ARC makes it repulsive to negatively charged phospholipid-based plasma membranes, and thus its cell-permeability is poor. To increase cell permeability of ARC without losing its water solubility, a Japanese research group esterized ARC with a water-soluble 1,2,3-triazolyl alcohol moiety using a click-chemistry technique. HPLC-based quantification methods have been validated specifically for artepillin C content in propolis preparations, providing a basis for standardized quality control.

Artepillin C and baccharin activated the TRPA1 channel strongly. Because the EC₅₀ value of artepillin C was 1.8 µM, artepillin C was more potent than the typical TRPA1 agonist allyl isothiocyanate. These findings strongly indicate that artepillin C is the main pungent ingredient in the ethanol extract of Brazilian green propolis and stimulates a pungent taste by activating TRPA1 channels.

2. Traditional and Historical Use

Propolis has been used as a traditional folk medicine for thousands of years in various regions worldwide. Propolis is a plant mastic produced by honeybees from resinous substances collected from tree buds and sap. Bees bring the resin to the hive and mix it with their own secretions, such as bee wax and saliva. Propolis is thought to be used to seal unnecessary holes and cracks in the hive and to protect the bee colony against intruders, viruses, fungi, and bacteria.

Artepillin C itself is not a compound with an independent traditional use history; its ethnobotanical background is entirely embedded within the use of propolis and, to a lesser extent, preparations of Baccharis dracunculifolia. Baccharis is well known for being the source of innumerable chemical compounds widely used in folk medicine and in the cosmetics and pharmaceutical industries. In Brazil, preparations of Baccharis dracunculifolia (known locally as alecrim-do-campo or "rosemary of the field") have a documented history of use in popular medicine for inflammation, wound healing, and gastrointestinal complaints. However, artepillin C as a distinct phytochemical was only chemically characterized and named in the 1990s; prior to that, its biological effects were attributed to propolis or the plant as a whole rather than to this specific molecule.

Propolis, a compound produced by honeybees, has long been used in food and beverages to improve health and prevent diseases. Historically, propolis was used in ancient Egypt for embalming and in Greek and Roman medicine as a wound disinfectant and antimicrobial agent. Greek and Roman physicians originally used it as a mouth disinfectant, and modern research has backed this up. Brazilian populations have a particularly well-documented tradition of using green propolis topically on wounds, skin infections, and inflammatory lesions, as well as taking it orally for immune support and to address oral infections. The distinctive chemical profile of Brazilian green propolis — dominated by artepillin C and other prenylated phenylpropanoids derived from Baccharis dracunculifolia — sets it apart from the European and Asian poplar-type propolis with which most ancient accounts are associated.

3. Chemistry: Key Constituents and Co-occurring Compounds

Among the constituents of BGP, prenylated derivatives are the salient chemical feature. Artepillin C typically represents one of the highest-concentration individual phenolic compounds in Brazilian green propolis, making it a chemical marker of quality and geographical origin. The signature compounds of green propolis are prenylated coumaric acids, particularly artepillin C.

When medium-polar to polar organic and hydroalcoholic extracts of B. dracunculifolia are studied, phenolic acids are common components: p-coumaric, dihydrocoumaric, ferulic, (E)-cinnamic, dihydrocinnamic, hydroxycinnamic, gallic, caffeic, (E)-4-(2,3-dihydrocinnamoyloxy)cinnamic acid, and several caffeoylquinic acid derivatives. Other significant compounds co-occurring with artepillin C in BGP include drupanin, baccharin, kaempferol, kaempferide, and aromadendrin-4′-O-methyl-ether. Propolis comprises various chemical components, including phenolics such as cinnamic acid and flavonoid derivatives, fatty acids, hydrocarbons, and other organic compounds as well as minerals.

The prenyl (3-methylbut-2-enyl) substituents at the 3 and 5 positions of the phenolic ring are central to artepillin C's chemical behavior. This prenylation markedly increases lipophilicity relative to the parent p-coumaric acid skeleton, which influences cell membrane penetration, protein binding, and metabolic stability. The carboxylic acid group at the end of the propenoic acid chain simultaneously confers some water solubility and is a key determinant of its interaction with serum albumin and cellular transporters.

4. Established Mechanisms of Action

Antioxidant Activity

Antioxidant activity of artepillin C was investigated using two different methods for stable DPPH• and ABTS•⁺. The compound exhibited strong scavenging potential against DPPH• (ED₅₀ of 24.6 µM) and ABTS•⁺ (ED₅₀ of 19.5 µM) compared with ascorbic acid (ED₅₀ of 89.8 µM and 57.5 µM, respectively). Artepillin C at the concentrations of 1–50 µM suppressed reactive oxygen/nitrogen species (ROS/RNS) production in PMA-treated RAW264.7 cells in a dose-dependent manner with an ED₅₀ of 7.32 µM. Artepillin C as a main ingredient of Brazilian green propolis might represent a new class of bioavailable dietary-derived antioxidant with potent anti-inflammatory activity.

Anti-inflammatory Mechanisms

Artepillin C exerted strong antioxidant activity, significantly inhibited the production of ROS, RNS, NO, and cytokines IL-1β, IL-3, IL-4, IL-5, IL-9, IL-12p40, IL-13, IL-17, TNF-α, G-CSF, GM-CSF, MCP-1, MIP-1α, MIP-1β, RANTES, and KC, and markedly blocked NF-κB expression in stimulated RAW264.7 macrophages. Artepillin C is distinguished by its potent anti-inflammatory properties, achieved through the modulation of nuclear factor kappa B (NF-κB) and the inhibition of prostaglandin E₂ and nitric oxide. Absorption and bioavailability of artepillin C was measured in plasma from mice by GC-MS after a single oral dose (10 mg/kg). In vivo, artepillin C produced a maximal inhibition of 38% after 360 min on paw oedema.

Anti-cancer Mechanisms

Mechanisms underlying the anti-cancer properties of ARC are apoptosis induction, cell cycle arrest, and the inhibition of p21-activated kinase 1 (PAK1), a protein characterized in many human diseases/disorders including COVID-19 infection. Antitumor activity of artepillin C is mediated by: (i) inducing cell cycle arrest in cancer cells; (ii) inhibition of angiogenesis; and (iii) inhibition of the oncogenic PAK1 signaling cascade.

ARC suppresses angiogenesis, suggesting the possibility that ARC blocks oncogenic PAK1 signaling. Both ARC and green propolis extract (GPE) block PAK1 signaling selectively, without affecting another kinase known as AKT. A Japanese research group's esterization technique boosted the anti-cancer effects of ARC by 100-fold against PAK1-dependent growth of A549 lung cancer cells, but showed no effects on PAK1-independent growth of B16F10 melanoma cells, suggesting selective inhibition towards PAK1 in cell culture with an IC₅₀ value of 5 µM. The PAK1 inhibitory effect of ARC triazolyl derivative was 30-fold higher than that of ARC itself.

Autophagy inhibitors enhance artepillin C-evoked apoptosis and anticancer efficacy, and co-treatment with artepillin C and autophagy inhibitors induces necroptosis. Propolis possesses various biological actions including anticancer activity towards tumor cells. The ethanol extract of Brazilian green propolis has been shown to induce autophagy, which is known to be induced in the treatment of cancer cells with anticancer drugs, leading to cancer cell survival and decreased sensitivity to anticancer agents.

Only artepillin C, when compared with other constituents of the ethanolic extract of Brazilian green propolis, was found to significantly inhibit the tube formation of human umbilical vein endothelial cells (HUVECs) in a concentration-dependent manner (3.13–50 µg/mL). Artepillin C significantly suppressed the proliferation of HUVECs in a concentration-dependent manner. Furthermore, artepillin C significantly reduced the number of newly formed vessels in an in vivo angiogenesis assay. Judging from its antiangiogenic activity in vitro and in vivo, artepillin C is at least in part responsible for the antiangiogenic activity of the extract in vivo.

Neuroprotective Mechanisms

Artepillin C inhibited both tunicamycin-induced protein aggregation in HT22 cells and the spontaneous protein aggregation of mutant canine superoxide dismutase 1 (E40K-SOD1-EGFP) in Neuro2a cells. These findings indicate that in addition to oxidative stress, the ethanol extracts of Brazilian green propolis help prevent endoplasmic reticulum stress-related neuronal cell death, which is involved in several neurodegenerative diseases. Moreover, artepillin C, a major constituent of Brazilian green propolis, may exhibit chemical chaperone-like properties.

Genotoxic/Antimutagenic Activity

Artepillin C has no genotoxic effects, while it shows protective activity at all tested concentrations (2.5, 5, and 10 µM) against methyl methanesulfonate-induced genotoxicity. Neto et al. (2011) showed that artepillin C, in Swiss mice, not only had no genotoxic effect, but also presented a protective effect against DNA damage induced by mutagenic substances using the micronucleus and comet assays. They further showed that artepillin C at low concentrations was effective in reducing genotoxicity induced by MMS in V79 cells (cultures of Chinese hamster lung fibroblasts).

TRPA1 Channel Activation

Artepillin C and baccharin activate the TRPA1 channel strongly, with an EC₅₀ value of 1.8 µM for artepillin C. This makes artepillin C more potent than the typical TRPA1 agonist allyl isothiocyanate (EC₅₀ 6.2 µM). These findings strongly indicate that artepillin C is the main pungent ingredient in the ethanol extract of Brazilian green propolis and stimulates a pungent taste by activating TRPA1 channels. TRPA1 activation has been implicated in pain signaling, thermosensation, and potentially in some anti-inflammatory responses.

5. Scientific Evidence by Area of Use

5.1 Antioxidant Activity

The antioxidant properties of artepillin C are among the most extensively characterized at the preclinical level. In validated in vitro assays, artepillin C exhibited strong scavenging potential against DPPH• (ED₅₀ of 24.6 µM) and ABTS•⁺ (ED₅₀ of 19.5 µM), outperforming ascorbic acid (ED₅₀ of 89.8 µM and 57.5 µM, respectively). ARC was easily incorporated into Caco-2 monolayers and transported to the basolateral part in free form without metabolic conversion or interference. These results suggest favorable intestinal transport, though the overall bioavailability picture from animal studies is more complex (see Section 7). Evidence remains primarily preclinical (in vitro and animal); no human interventional trials have been conducted to specifically assess ARC's antioxidant effects in vivo as an isolated compound.

5.2 Anti-inflammatory Activity

In vitro: A well-characterized study using LPS/IFN-γ- and PMA-stimulated RAW264.7 macrophages demonstrated that artepillin C significantly inhibited the production of ROS, RNS, NO, and a broad panel of cytokines including IL-1β, TNF-α, and MCP-1, and markedly blocked NF-κB expression, without reducing cell viability at tested concentrations.

Animal studies: Animals subjected to carrageenan-induced paw oedema (300 µg/paw) and carrageenan-induced peritonitis were used to evaluate anti-inflammatory effects. In vitro nitric oxide production by RAW 264.7 cells and NF-κB activity in HEK 293 cells were also measured. Absorption and bioavailability of artepillin C in plasma from mice were determined by GC-MS after a single oral dose (10 mg/kg). In vivo, artepillin C produced a maximal inhibition of 38% after 360 min on paw oedema.

Human/clinical evidence: No published clinical trials have specifically tested artepillin C in isolation for anti-inflammatory endpoints in human subjects. Evidence of systemic anti-inflammatory activity in humans is indirect and derives from trials on Brazilian green propolis preparations in which ARC is the major constituent (see Section 5.8 on muscle recovery). Overall, the anti-inflammatory evidence base for ARC itself is preclinical.

5.3 Anticancer Activity

Anticancer properties represent the most extensively studied area for artepillin C, though virtually all mechanistic data come from in vitro cell-culture studies and in vivo animal (xenograft) models.

PAK1 inhibition and tumor suppression: NF (neurofibromatosis)-associated tumors require kinase PAK1 for growth. ARC was demonstrated to suppress angiogenesis, and both ARC and green propolis extract (GPE) block PAK1 signaling selectively, without affecting AKT. Furthermore, ARC as well as GPE suppress almost completely the growth of human NF tumor xenografts in mice.

Leukemia cells: In vitro studies published as early as 2001 (Anticancer Res.) demonstrated induction of apoptosis of human leukemia cells by artepillin C. The study on apoptosis of human leukemia cells induced by artepillin C, an active ingredient of Brazilian propolis, was published in Anticancer Research (2001;21:221–228).

Prostate cancer: Artepillin C (3,5-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP prostate cancer cells to TRAIL-induced apoptosis, indicating synergistic potential with pro-apoptotic ligands.

Glioblastoma (pH-dependent cytotoxicity): At pH 6.0, MTT assays showed the pronounced cytotoxic effects of artepillin C, yielding a reduction in cell viability to less than 12% among glioblastoma cells following 24-hour exposure to 100 µM of artepillin C. LDH assays indicated significant membrane damage, affecting approximately 50% of total cells under the same conditions. Artepillin C induces autophagy and provokes a lipid membrane packing effect, contributing to cell death. These findings affirm the selective cytotoxicity of artepillin C within the acidic tumor microenvironment.

Antiangiogenic activity: Only artepillin C among constituents of the extract significantly inhibited tube formation of HUVECs in a concentration-dependent manner (3.13–50 µg/mL), suppressed HUVEC proliferation, and reduced the number of newly formed vessels in an in vivo angiogenesis assay.

Autophagy and necroptosis: At the cellular level, artepillin C can disrupt cell membranes in cancer cells and trigger autophagy; importantly, combining it with autophagy inhibitors can increase its anticancer efficacy.

Oral cancer: Ethanolic and hydroalcoholic extracts, in conjunction with the bioactive compounds caffeic acid phenethyl ester (CAPE), artepillin C, and chrysin, were identified as the primary candidates in reviews of propolis components with activity against oral cancer cells.

Evidence strength: All current anticancer evidence for ARC as an isolated compound is preclinical (cell culture and animal models). There are no published human clinical trials of artepillin C or artepillin C-standardized extracts for cancer treatment or prevention. Translation to clinical outcomes has not been established.

5.4 Antimicrobial Activity

This phenolic acid has been identified as having important biological properties that include antitumor, anticancer, antioxidant, anti-inflammatory, antiviral, and antifungal activities. ARC has been shown to possess various biological activities such as anti-viral, anti-bacterial, antioxidant, and anti-carcinogenic activities. Artepillin C modulates inflammatory pathways such as NF-κB, reducing prostaglandin and nitric oxide production. Propolis demonstrates synergistic effects with conventional antibiotics, enhancing their efficacy against drug-resistant strains by increasing membrane permeability and inhibiting resistance enzymes. These findings are based on in vitro assays; clinical antimicrobial studies specifically using artepillin C as an isolated agent have not been published.

5.5 Antidiabetic Activity

Numerous studies have proved that artepillin C holds wider potential, as it exhibits antidiabetic, gastroprotective, immunomodulatory, neuroprotective, and anticancer activity. Propolis extracts contain phenolic compounds which are classified into two major categories, phenolic acids and flavonoids. Phenolics are the predominant bioactive materials in propolis which have been reported to have multiple biological effects, including antidiabetes. Aqueous ethanol extracts of propolis may be used as nutraceuticals for the regulation of postprandial hyperglycemia. Mechanistic research has shown that artepillin C and related phenolics in BGP inhibit α-glucosidase activity, which is relevant to postprandial blood glucose control. Evidence for artepillin C's antidiabetic effects specifically in humans remains limited; it is mostly derived from in vitro enzyme assays and animal studies, though broader propolis preparations have been tested in small clinical trials for glycemic outcomes.

5.6 Neuroprotective Activity

Artepillin C inhibited both tunicamycin-induced protein aggregation in HT22 cells and the spontaneous protein aggregation of mutant canine superoxide dismutase 1 (E40K-SOD1-EGFP) in Neuro2a cells. These findings indicate that the ethanol extracts of Brazilian green propolis help prevent endoplasmic reticulum stress-related neuronal cell death, which is proposedly involved in several neurodegenerative diseases. Moreover, artepillin C may exhibit chemical chaperone-like properties. Neuroprotective evidence for ARC is preclinical. No clinical trials in neurodegenerative diseases have been conducted with artepillin C in isolation.

5.7 Gastroprotective Activity

Artepillin C, drupanin, aromadendrin-4′-O-methyl-ether, and kaempferide from Brazilian green propolis promote gastroprotective action by diversified modes of action. Animal models of gastric ulceration have been used to characterize this activity. Evidence is at the preclinical stage.

5.8 Allergic Airway Inflammation and Immunomodulation

A previous study showed that green propolis treatment reduced airway inflammation and mucus secretion in an OVA-induced asthma model, resulting in increased regulatory T cells (Treg) and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) frequencies in the lungs. In a subsequent study, the anti-inflammatory effects of artepillin C (ArtC), the major compound of green propolis, were evaluated specifically in the context of allergic airway inflammation. Some in vitro studies demonstrated that ArtC inhibits ROS production, cytokine secretion, and blocks NF-κB expression in IFN-γ-stimulated RAW264.7 macrophage cell lineage. Several preclinical studies demonstrated the therapeutic effects of propolis extracts against allergic inflammation, asthma, allergic rhinitis, atopic dermatitis, and food allergy, which may be partly attributed to their inhibitory effects on the activation of mast cells and basophils. Clinically, the consumption of propolis as a supplement or an adjunct therapy is safe and attenuates various pathological conditions in asthma. Although flavonoids (chrysin, kaempferol, galangin, and pinocembrin) and cinnamic acid derivatives (artepillin C and caffeic acid phenethyl ester) can contribute to the anti-allergic activities, they may not be present in all propolis samples due to variations in the chemical composition.

5.9 Intestinal Inflammation and Inflammatory Bowel Disease (IBD)

The Brazilian biodiversity may bring new perspectives to the therapy of inflammatory bowel diseases (IBD) and intestinal cancer. The effect of Brazilian green propolis in reducing ulcerative colitis in mice has already been described, as well as high amounts of artepillin C in those preparations. Among pharmacological targets for IBD is PAK1, which is overexpressed and activated in the intestinal mucosa during IBD and colitis-associated colorectal cancer (CAC). PAK1 contributes to tissue inflammation by reducing the expression of PPAR-γ and increasing activation of NF-κB. At least in vitro, inhibition of PAK1 has been reported to mitigate NF-κB-mediated inflammation in intestinal cells, and ARC inhibits PAK1 activation. Future studies employing in vitro and in vivo steps, using murine and human enterocytes and rodents submitted to ulcerative colitis and CAC models, are incentivized by the gathered data — mostly in vitro studies — before clinical trials. This perspective points to an interesting path in the search for a drug useful in inflammatory and neoplastic intestinal diseases, which may have ARC as a prototype. This area of application is at an early, theoretical stage.

5.10 Exercise-Induced Muscle Damage Recovery

Exercise-induced muscle damage (EIMD) results from intense or unaccustomed exercise, leading to inflammation, oxidative stress, and reduced muscle function due to excessive reactive oxygen species. Propolis, a natural bee-derived substance rich in bioactive compounds such as artepillin C, exhibits anti-inflammatory and antioxidant properties, suggesting its potential to mitigate EIMD.

A randomized, placebo-controlled trial published in the Journal of the International Society of Sports Nutrition (2025) investigated this: twenty-two trained female participants were randomly assigned to consume eight capsules of EPP-AF (containing approximately 54 mg artepillin C) or a placebo for seven days. On day four, participants performed 10 sets of 10 maximal eccentric contractions of the knee extensor muscles. The conclusion was that EPP-AF may alleviate the symptoms and attenuate markers of muscle damage in the knee extensor muscles of resistance-trained females. These findings highlight the potential of propolis as a natural intervention to enhance recovery from EIMD.

Evidence strength: This represents one of the few human randomized controlled trials specifically involving an artepillin C-standardized preparation. Limitations include a very small sample size (n = 22), an all-female population, and single-site design. It does not establish efficacy of artepillin C in isolation, as the preparation contains multiple bioactive compounds.

5.11 Serum Absorption — Human Bioavailability Study

A randomized, single-blind placebo-controlled study on the effect of Brazilian green propolis on serum artepillin C levels was conducted with healthy volunteers. The participants (n = 133) were randomly allocated in an approximately 2:1 ratio to two groups: propolis (n = 91) and placebo (n = 42). The participants took daily propolis or placebo, and blood tests were performed on day 0 (before propolis intake) and days 1, 3, and 7. Artepillin C was detected in serum in almost all individuals in the propolis group. No serum artepillin C was detected in the placebo group. Serum artepillin C levels in the female group tended to be higher than those in the male group. These results suggested that propolis intake might be more effective for females than for males. This study importantly confirmed that orally consumed BGP delivers ARC into human systemic circulation.

6. Pharmacokinetics and Bioavailability

Artepillin C, an active ingredient of Brazilian propolis, permeates intact across Caco-2 cells by transcellular passive diffusion. The serum concentration of intact ARC in the portal vein peaked at 5–10 min after oral administration in rats, with a C_max of 19.7 µmol/L. Pharmacological data in vivo showed that ARC's absorption efficiency and bioavailability in rat serum were low, which appears to be an inconsistency between the low absorption rate of oral ARC and its broad biological activity in the body.

In order to obtain elucidation, the physicochemical basis of ARC interacting with human serum albumin (HSA) was investigated in vitro. A unique dynamic mode interaction between ARC and HSA was found, which is completely different from other reported propolis bioactive components. Thermodynamic analysis showed that hydrophobic interactions and electrostatic forces are the main driving forces. The competitive assay indicates that the binding site of ARC with HSA is close to Sudlow's site I. This binding to albumin is significant because it provides a mechanism by which poorly bioavailable ARC may still exert systemic biological effects — albumin-bound ARC may be transported to tissues and released locally.

The COOH moiety on ARC makes it repulsive to negatively charged phospholipid-based plasma membranes, and thus its cell-permeability is poor. This structural limitation has motivated pharmaceutical research into prodrug and derivative strategies (see Section 3 on chemical identity), and the esterization work resulting in 100-fold improved activity against PAK1-dependent cancer cell lines.

A previous study has shown that propolis intake increases blood levels of artepillin C, which can exert biological effects. Circulating artepillin C levels have been demonstrated to be higher in females than in males, suggesting that daily propolis intake may be particularly effective in females. This difference may be due to sex-related variations in polyphenol metabolism and absorption.

7. Dosage Forms and Reported Dosages

Artepillin C is not currently available as a clinically standardized pharmaceutical. Dosages reported in studies refer to artepillin C as a constituent of standardized Brazilian green propolis preparations:

• In the 2025 muscle-recovery randomized controlled trial, participants consumed eight capsules of EPP-AF containing approximately 54 mg artepillin C per day for seven days.
• In the 133-participant bioavailability study (randomized, single-blind, placebo-controlled), participants took daily Brazilian green propolis, with blood tests on day 0, days 1, 3, and 7. The exact dose of ARC per dose was not specified in the published abstract.
• In the murine anti-inflammatory study, artepillin C was studied for its anti-inflammatory effects, absorption, and bioavailability after a single oral dose of 10 mg/kg in male Swiss mice, with paw oedema and peritonitis models.
• In the rat pharmacokinetic study, rats were given 100 µmol/kg of body weight of ARC or CA orally, and blood was subsequently collected from the portal vein and abdominal artery.
• In the murine antigenotoxicity study, the aim was to evaluate the genotoxic potential of artepillin C and its ability to prevent chemically induced chromosome breakage; animals were treated by gavage with different doses of artepillin C (0.4, 0.8, and 1.6 mg/kg body weight).

No human clinical dose has been established by a regulatory authority or clinical pharmacology program for artepillin C as an isolated ingredient. Because of the scarcity of human clinical studies on propolis, it has been suggested that dosage be taken into account. There have been insufficient studies on the acute and chronic toxicity of propolis in humans.

8. Body Systems and Health Areas of Association

Based on the cumulative preclinical and limited clinical literature, artepillin C has been studied in relation to the following body systems and health areas:

• Immune system and inflammation: Modulation of macrophage cytokine production, NF-κB signaling, prostaglandin E₂, and nitric oxide synthesis.
• Oncology (preclinical): Multiple cancer cell lines including leukemia, prostate, lung (A549), glioblastoma, and neurofibromatosis-associated tumors; angiogenesis inhibition.
• Nervous system: Protection against ER stress and protein aggregation in neuronal cell models relevant to neurodegenerative diseases.
• Gastrointestinal system: Gastroprotection in animal ulcer models; proposed activity in inflammatory bowel disease via PAK1/NF-κB modulation.
• Metabolic/endocrine: Alpha-glucosidase inhibition; potential relevance to postprandial glycemia in type 2 diabetes context.
• Respiratory system: Reduction of allergen-specific IgE, airway inflammation, and hyper-reactivity in preclinical asthma models; some clinical propolis data for asthma.
• Musculoskeletal system: Attenuation of exercise-induced muscle damage markers in a small RCT.
• Oral health: Proposed integration into dental materials for antimicrobial and anti-inflammatory effects; artepillin C was noted to lead to a reduction in the production of prostaglandin E₂ during instances of pain and inflammation, with anti-inflammatory responses noted through modulation of the NF-κB signaling pathway.

Numerous studies on ARC show that its beneficial health effects correlate with the health effects of both BGP and B. dracunculifolia. Its wide range of pharmacological benefits include antioxidant, antimicrobial, anti-inflammatory, anti-diabetic, neuroprotective, gastroprotective, immunomodulatory, and anti-cancer effects. Most studies have focused on anti-oxidation, inflammation, diabetes, and cancers using both in vitro and in vivo approaches.

9. Safety Considerations and Interactions

Toxicological Profile

Studies in mice and humans have not shown harmful or toxic effects of propolis. Propolis administration at doses of 200 and 5000 mg/kg body weight/day did not result in toxic deaths in experimental animals, and it was reported as safe. The LD₅₀ (lethal dose 50) value in mice ranges from 2 to 7.3 g/kg. The no observed adverse effect level (NOAEL) in mice was over 1470 mg/kg.

Genotoxicity

Artepillin C has no genotoxic effects and shows protective activity against methyl methanesulfonate-induced genotoxicity at all tested concentrations (2.5, 5, and 10 µM). Artepillin C shows anti-inflammatory, antibacterial, antiviral, antioxidant, and antitumoral activities. Studies have evaluated the genotoxic potential of artepillin C and its ability to prevent chemically induced chromosome breakage or loss and primary DNA damage using the micronucleus and comet assays in male Swiss mice.

Allergic Reactions

More than 26 allergenic substances have been identified in the composition of propolis. The most common allergic reaction is due to esters of caffeic acid and cinnamic acid obtained from poplar buds. They cause contact allergic reactions in hypersensitive individuals. The presence of these esters in other materials may also cause cross-allergic reactions. Artepillin C, as a cinnamic acid derivative, structurally belongs to the same class of compounds that have been implicated in contact allergy to propolis (contact dermatitis, airborne contact dermatitis). Individuals with known hypersensitivity to bee products, propolis, or cinnamic acid derivatives are at elevated risk.

Standardization and Compositional Variability

The therapeutic application of propolis faces key challenges. Its chemical composition varies by geographic origin, botanical source, and bee species, complicating standardization. Extraction methods also affect the yield and potency of active compounds. Clinical data are limited, especially regarding long-term safety in immunocompromised individuals and risks of allergic reactions. Because artepillin C concentration varies substantially between BGP batches, dose titration based on ARC content requires standardized extracts.

Drug Interactions

Artepillin C modulates inflammatory pathways such as NF-κB. Propolis demonstrates synergistic effects with conventional antibiotics, enhancing their efficacy against drug-resistant strains by increasing membrane permeability and inhibiting resistance enzymes. This suggests potential for reduced antibiotic dosages and side effects, though clinical validation is still required to optimize such combinations. Potential pharmacodynamic interactions with anticoagulants (through platelet function modulation), immunosuppressants (through immunomodulatory effects), and antidiabetic medications (through alpha-glucosidase inhibition and glycemic effects) are biologically plausible based on the pharmacological profile of artepillin C but have not been specifically characterized in human clinical studies. ARC has potential as an intervention for antioxidant, anti-inflammation, antidiabetic, neuroprotective, gastroprotective, immunomodulatory, and anti-cancer effects. It has been mostly studied against a variety of cancers and inhibits serine/threonine protein kinase PAK1, the abnormal activation of which is responsible for a variety of diseases via cross-talking.

Long-term Safety

Propolis represents a promising raw material in integrative medicine. Its multidirectional action, combined with relatively low toxicity, justifies further clinical research and standardization efforts. Long-term human safety data for artepillin C or ARC-standardized preparations specifically are not yet available in the published literature.

References

• Sharifi-Rad M et al. "Artepillin C: A comprehensive review of its chemistry, bioavailability, and pharmacological properties." Fitoterapia / ScienceDirect (2020). PubMed PMID: 33152464.
• Sharifi-Rad M et al. "Artepillin C: A comprehensive review of its chemistry, bioavailability, and pharmacological properties." Fitoterapia (2020). ScienceDirect.
• Beserra FP et al. "Artepillin C as an outstanding phenolic compound of Brazilian green propolis for disease treatment: A review on pharmacological aspects." Phytotherapy Research (2021); 35:2274–2286.
• Ding Z et al. "Daily Brazilian green propolis intake elevates blood artepillin C levels in humans." Journal of the Science of Food and Agriculture (2021). PubMed PMID: 33543484.
• Ding Z et al. "Daily Brazilian green propolis intake elevates blood artepillin C levels in humans." J Sci Food Agric (2021). Wiley Online Library.
• Messerli SM et al. "Artepillin C (ARC) in Brazilian green propolis selectively blocks oncogenic PAK1 signaling and suppresses the growth of NF tumors in mice." Phytother Res (2009); 23:423–427. PubMed PMID: 19003952.
• Konishi Y et al. "Absorption and bioavailability of artepillin C in rats after oral administration." J Agric Food Chem (2005); 53:9928–9933. PubMed PMID: 16366676.
• Konishi Y et al. "Absorption and Bioavailability of Artepillin C in Rats after Oral Administration." Journal of Agricultural and Food Chemistry (2005).
• Krol W et al. "Inhibition of Inflammatory Response by Artepillin C in Activated RAW264.7 Macrophages." Evidence-Based Complementary and Alternative Medicine (2013). PMC3679718.
• Hata T et al. "Artepillin C, a Major Ingredient of Brazilian Propolis, Induces a Pungent Taste by Activating TRPA1 Channels." PLoS ONE (2012). PMC3487895.
• PMC3582787. "Artepillin C (3,5-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP prostate cancer cells to TRAIL-induced apoptosis." PMC.
• Shinohara R et al. "Autophagy inhibition enhances anticancer efficacy of artepillin C, a cinnamic acid derivative in Brazilian green propolis." Biochemical and Biophysical Research Communications (2018).
• PMC8625726. "Artepillin C Reduces Allergic Airway Inflammation by Induction of Monocytic Myeloid-Derived Suppressor Cells." PMC (2021).
• PMC8816323. "Anti-Allergic Properties of Propolis: Evidence From Preclinical and Clinical Studies." Frontiers in Pharmacology (2021).
• PubMed 37185322. "Perspectives on the Role of P21-Activated Kinase 1 (PAK1) in the Intestinal Anti-inflammatory and Antitumor Potential of Artepillin C." PubMed (2023).
• Paulino N et al. "Anti-inflammatory effects of a bioavailable compound, Artepillin C, in Brazilian propolis." European Journal of Pharmacology (2008).
• Sun Y et al. "Unique dynamic mode between Artepillin C and human serum albumin implies the characteristics of Brazilian green propolis representative bioactive component." Scientific Reports (2020).
• PMC10672498. "pH-Dependence Cytotoxicity Evaluation of Artepillin C against Tumor Cells." PMC (2023).
• Oliveira PF et al. "Evaluation of genotoxicity and antigenotoxicity of artepillin C in V79 cells by the comet and micronucleus assays." Food and Chemical Toxicology (2013). PubMed PMID: 23915392.
• Neto G et al. "Antigenotoxicity of artepillin C in vivo evaluated by the micronucleus and comet assays." Mutation Research (2011). PubMed PMID: 21259290.
• Barth OM et al. "Botanical origin and Artepillin-C content of Brazilian propolis samples." Grana (2013).
• Chen C et al. "Inhibitory Properties of Aqueous Ethanol Extracts of Propolis on Alpha-Glucosidase." Evidence-Based Complementary and Alternative Medicine (2015). PMC4342172.
• Ramos Junior OJF et al. "Artepillin C-rich propolis extract supplementation promotes muscle recovery following exercise-induced muscle damage in resistance-trained young females: a randomized, placebo-controlled trial." J Int Soc Sports Nutr (2025). PMC12517410.
• Ramos Junior OJF et al. "Artepillin C-rich propolis extract supplementation promotes muscle recovery following exercise-induced muscle damage in resistance-trained young females." PubMed PMID: 41074544 (2025).
• PubChem. "Artepillin C | C₁₉H₂₄O₃ | CID 5472440." NIH National Library of Medicine.
• ResearchGate. "Artepillin C as an outstanding phenolic compound of Brazilian green propolis for disease treatment: A review on pharmacological aspects." Phytotherapy Research (2020).
• Raghavendra Swamy KN et al. "Exploring the Integration of Artepillin C, a Bioactive Constituent of Propolis, in Dental Materials: A Review." Oriental Journal of Chemistry (2025).