Antitumor Potential of Stingless Bee Propolis and Geopropolis: Comparison
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Stingless bees, also known as meliponines, live in colonies and are characterized by having atrophied stingers. Propolis is a mixture of salivary secretions and plant resins collected by bees and is produced to seal the hive and prevent the entry of air and invading insects, besides having antimicrobial activity, protecting the colony from diseases. The investigation of the biological activities of stingless bee products, especially propolis and geopropolis, has revealed promising therapeutic properties, especially in the research on new antineoplastic agents.

  • stingless bee products
  • propolis
  • geopropolis

1. Historical Research of Stingless Bees Producing Propolis and Geopropolis

A total of 33 species of stingless bees producing propolis and geopropolis with antitumor potential were identified, of which 20 species (Scaptotrigona affinis postica, Scaptotrigona bipunctata, Scaptotrigona depilis, Scaptotrigona sp., Melipona quadrifasciata quadrifasciata, Melipona quadrifasciata anthidioides, Melipona orbignyi, Trigona spp., Trigona incisa, Trigona apicalis, Trigona fuscobalteata, Trigona fuscibisca, Trigona laeviceps, Trigona sirindhornae, Tetragonisca fiebrigi, Tetrigona apicalis, Tetragonula pagdeni, Tetragonula biroi, Heterotrigona itama, Heterotrigona bakeri, Homotrigona fimbriata, Tetragonula testaceitarsis, Tetragonula sarawakensis, Tetragonula fuscobalteata, Tetragonula laeviceps, Lepidotrigona terminata, Lepidotrigona ventralis, Geniotrigona thoracica, Lisotrigona furva, and Plebeia remota) are producers of propolis and three species (Melipona fasciculata, Melipona mondury, and Melipona scutellaris) are producers of geopropolis (Table 1).
Only two studies on the propolis cytotoxicity of stingless bees (Scaptotrigona aff. postica and Tetragonula biroi) were found in animal models [28,29][1][2] with the remaining studies being in vitro tests. These stingless bee products have already been tested in vitro on tumor cell lines, such as breast (MDA-MB-231, MCF-7, and BT-474), lung (A549, H460, SK-LU-1, and ChaGo-1), ovarian (ES2, A2780, NCI-ADR/RES, and OVCAR-03) cancer, liver (HepG2), mouth (KB), pharynx (HN30 and HN31), larynx (HEp-2), colon (CaCo-2, COLO205, SW620, and KM12), stomach (KATO-III, AGS, MKN-45, NUGC-4, and MKN-74), colorectal (HRT-18), cervix (HeLa), kidney (786-0), prostate (PC-3), melanoma (UACC-62, SK-MEL-28, and B16-F10), human glioblastoma (U251 and U343), canine osteosarcoma (OSA), and leukemia (K562 and HL-60) (Table 1).
Stingless bee products with antitumor potential come from seven countries (Brazil, India, Indonesia, Thailand, Malaysia, Philippine, and Vietnam) (Figure 1).
Table 1. Propolis and geopropolis extracts of stingless bee species with anticancer activity in tumor cell lines.
Bee Species Place of Origin Product Type of Preparation Tumor Cells Result Type of Test Chemical Identification Ref.
Melipona fasciculata (Smith 1854) Maranhão,

Brazil		 Geopropolis Hydroethanolic extract Canine osteosarcoma (OSA) Dose- and time-dependent cytotoxicity In vitro No [23][3]
Human epidermoid laryngeal carcinoma (HEp-2) Decrease in cell viability from 25 to 100 μg/mL Yes a
The chemical composition of propolis and geopropolis from stingless bees is shown in Table 2. The main classes of compounds identified are phenolics compounds (comprising phenolic acids, flavonoids, coumarins, and benzophenones) terpenes, steroids, alkaloids, fatty acids, and sugars. Qualitative approaches were used to define the classes of compounds; and analytical techniques, such as high-performance liquid chromatography coupled to mass spectrometry (HPLC/MS), liquid chromatography coupled to mass spectrometry (LC/MS), and gas chromatography coupled to spectrometry (GC/MS), were employed to identify the compounds.
β-amyrin, a compound identified in samples from stingless bees Tetrigona apicalis, Scaptotrigona bipunctata, Melipona quadrifasciata anthidioides, and Melipona fasciculata, was the subject of a study by Wen et al. [55][28] that highlighted the significant cytotoxic activity of this substance against HepG2 (hepatocellular carcinoma) cells. The cytotoxic effects were justified by the induction of apoptosis and the arrest of the G2/M cycle in a dose-dependent manner.
Apigenin, presented in the ethanolic extract produced by Melipona quadrifasciata anthidioides propolis, inhibited proliferation, prevented cell cycle progression, and promoted apoptosis in both ovarian cancer cells (SKOV3) and cisplatin-resistant cells (SKOV3/DDP). In addition, apigenin reduced mitochondrial transmembrane potential and elevated caspase-3/cleaved caspase-3 and Bax/Bcl-2 ratios in both cell types. Quantitative reverse transcription PCR and Western blotting results demonstrated that apigenin significantly down-regulates Mcl-1 transcription and translation levels in SKOV3 and SKOV3/DDP cells, which is responsible for its cytotoxic functions and chemosensitizing effects [61][29]. Thus, the compounds identified in propolis and geopropolis extracts have already been studied by different researchers, demonstrating their antitumor potential. Phenolic compounds and terpenes were the most present classes of compounds in stingless bee products.
Table 2. Chemical composition of propolis and geopropolis extracts of stingless bee species.
Bee Species Place of Origin Product Class of Compounds Chemical Compounds Method Ref.
Scaptotrigona bipunctata (Latreille 1807) Paraná/Santa Catarina, Brazil Propolis Alkaloids Lelobanonoline, 2-[6-(2-hydroxy-propyl)-1-methyl-[2]piperidyl]-1-phenylethanone, norlobelanidine, norlobeline, lobeline, and lobelanidine HPLC/MS [17,32][9][
[30][4]
11]
Terpenes α-Amyrin/β-amyrin and 4R,5R,9R,10R-13-hydroxypodocarp-8(14)-en-19-oic acid Human epidermoid laryngeal carcinoma (HEp-2) Inhibition of cell proliferation and migration No
Phenolic compounds

(phenolic acids, flavonoids, coumarin, stilbenes, phenylpropanoids, and tannins)		[25][5]
Vicenin, liquiritigenin, formononetin, drupanin, p-coumaric acid, acid ferulic, biochanin A, kaempferol methyl ether, dihydrokaempferide, retusin 8-methyl ether, betuletol, artepillin C, 4-hydroxy-3(E)-(4-hydroxy-3- methyl-2-butenyl)-5-prenylcinnamic acid, 3-hydroxy-2,2-dimethyl-8-prenyl-2H-1-benzopyran-6-propenoic acid, artepillin C derivative, anacardic acid, dicaffeoylquinic, and (E)-3-{4-hydroxy-3-[(E)-4-(2,3-dihydrocinnamoyloxy)-3-methyl-2-butenyl]-5-prenylphenyl}-2-propenoic acid Lung cancer (A549 and H460) and ovarian cancer (ES2 and A2780) Dose- and time-dependent cytotoxicity Yes a [8][6]
Fatty acids Palmitic acid, oleic acid, stearic acid, and eicosapentaenoic acid Melipona scutellaris (Latreille 1811) Bahia,

Brazil		 Ethanolic extract Glioma (U251), melanoma (UACC-62), breast (MCF-7), multidrug-resistant ovarian (NCI-ADR/RES), kidney (786-0), lung (NCI-H460), prostate (PC-3), and ovary (OVCAR-03) Anti-proliferative activity Yes a
Melipona fasciculata (Smith 1854) Maranhão, Brazil[ Geopropolis Phenolic compounds Anacardic acid, heptedecenyl salicylic acid, nonadecenyl salicylic acid, pentadecenyl salicylic acid, heptadecadecylresorcinol, nonadecadecylresorcinol, pentadecadecadienylresorcinol, heptedecadienylresorcinol, taxifolin 7-O-rhamnoside, isoschaftoside, typhaneoside, dihydroquercetin-C-glycoside, narigenin-C-glycoside, vitexin-O-gallate, glycosylated pinobanksin, dihydroquercetin-3-O-rhamnoside, and gallocatechin-xylose24] HPLC/MS[7]
[8,30][6][4] Melipona mondury (Smith 1863) Bahia, Brazil Hydroethanolic extract B16-F10 (melanoma murine), HepG2 (human hepatocellular carcinoma), K562 (human chronic myeloid leukemia), and HL-60 (human promyelocytic leukemia) IC50 24.2 to 46.6 μg/mL Partially [15][8]
Melipona quadrifasciata quadrifasciata (Lepeletier 1836) Paraná, Brazil Propolis Ethanolic extract MDA-MB-231 (triple-negative human breast adenocarcinoma), MCF-7 (human breast adenocarcinoma), HeLa (human cervical adenocarcinoma), HepG2 (human hepatocellular carcinoma), HRT-18 (human colorectal adenocarcinoma) IC50
Terpenes Lupeol, α-amyrin, β-amyrin, α-amyrenone, β-amyrenone, triterpene ketone, taraxerone, dipterocarpol, marsformosanone, and 3-[Xyl]-28-Glc-phytophthalacagenin 97.53 to 155.1 μg/mL In vitro Yes a [17][9]
Anthraquinone Xantholaccaic acid A Melipona quadrifasciata anthidioides (Lepeletier 1836) Mato Grosso do Sul, Brazil Propolis Ethanolic extract Erythroleukemia cell line (K562) Decrease in cell growth to 21.2% ± 4.1% at 500 µg/mL In vitro Yes a [31][10]
Santa Catarina, Brazil Ethanolic extract Human melanoma (SK-MEL-28) Decreased migration and invasion of melanoma cells Yes a [32][11]
Melipona orbignyi (Guérin-Méneville 1844) Mato Grosso do Sul, Brazil
Organic acids Glycuronic acid, methylmalonic acid, and gluconic acid
Melipona scutellaris (Latreille 1811) Bahia, Brazil Geopropolis Benzofenones Propensaeure 3-phenyl-trimethylsilylester and 1,2-benzenedicarboxylic acid GC/MS [24][7] Ethanolic extract Erythroleukemia cell line (K562) Decrease in cell viability to less than 25% at 500 µg/mL Yes b [33]
Melipona quadrifasciata quadrifasciata (Lepetetier 1836))[ Paraná, Brazil12 Propolis]
Phenolic compounds p-Coumaric acid, ferulic acid, ellagic acid, gallic acid, naringenin, aromadendrin, isosakuranetin, dihydrokaempferide, aromadendrin methyl ether, cinnamoyl-galloyl-hexoside, anacardic acid, cinnamoyl-coumaroyl-hexoside, dicoumaroyl-hexoside, digalloyl-cinnamoyl-hexoside, digalloyl-coumaroyl-hexoside, cinnamoyl-coumaroyl-galloyl hexoside, and dicoumaroyl-galloyl-hexoside HPLC/MS [17][9] Trigona spp. Maharashtra, India Hydroethanolic extract Human breast adenocarcinoma (MCF-7), human colon adenocarcinoma (HT-29), human epithelial colorectal adenocarcinoma (CaCo-2), and murine melanoma cell lines (B16F1). Time- and dose-dependent cytotoxicity IC50 250 µg/mL No [26
Terpenes Sugiol, pimaric acid, isocupressic acid, cupressic acid, junicedric acid, mangiferonic acid, and isomangiferolic acid][13]
Indonesia Hydroethanolic extract
Melipona quadrifasciata anthidioidesBreast (MCF-7)  (Lepeletier 1836) Mato Grosso do Sul, BrazilDecrease in cell growth to 47.71% Partially [34, Propolis35][14][15]
Phenolic compounds p-Coumaric acid, vanilic acid, caffeic acid, vanillin, ferulic acid, benzoic acid, quercetin, luteolin, cinnamic acid, and apigenin HPLC/MS; GC/MS [31][10] Trigona sirindhornae (Michener and Boongird 2004) Chantaburi, Thailand Dichloromethane extract Primary lesions of the pharynx (HN30) and lymph node metastases (HN31) Dose-dependent cytotoxicity No [36]
  Terpenes Stigmasterol, β-sitosterol, β-amyrin, taraxasterol, α-amyrin, β-amyrin acetate, and pinusenocarp[16]
Tetragonula pagdeni (Schwarz 1939) Chanthaburi, Thailand Propolis Methanolic extract Squamous cell carcinoma of the mouth (KB), hepatocellular carcinoma (HepG2), colon adenocarcinoma (CaCo-2), and melanoma (SK-MEL-28) Cytotoxicity IC50 33.38 to 80.81 μg/mL In vitro Yes b [27]
Melipona quadrifasciata anthidioides (Lepeletier 1836)[17]
Santa Catarina, Brazil Tetragonula testaceitarsis (Cameron 1901) Kalimantan,

Indonesia		 Ethanolic extract Human breast cancer (MCF-7), human cervical adenocarcinoma (HeLa), and human colon cancer (CaCo-2) Moderate decrease in cell viability to 75 μg/mL No [37][18]
Propolis Phenolic compounds 7-O-methyl aromadendrin, 5-hydroxy-4′,7-dimethoxy flavone, 2′-hydroxynaringenin, narigenin, and p-coumaric HPLC/MS [32][11] Tetragonula sarawakensis
Phenylpropanoids 4-O-(6″-O-p-coumaroyl-β-D-glucopyranosyl)- and 6-O-cinnamoyl-1-O-p-coumaroyl-β-D-glucopyranoside (Schwarz 1939) No
Terpenes Abieta-8,11,13,15-tetraen-18-oic acid, abietic acid, 7-hydroxydehydroabietic acid, and inumakiol Tetragonula fuscobalteata (Cameron 1908) No
Melipona orbignyi (Guérin-Méneville 1844) Mato Grosso do Sul, Brazil Propolis Phenolic compounds Dihydrocinnamic acids, cinnamic acids, benzoic acids, coumarin C-prenylated acids, and long-chain caffeates GC/MS [33][12] Tetragonula laeviceps (Smith 1857) No
Melipona mondury (Smith 1863) Bahia, Brazil Geopropolis Phenolic compounds Gallic acid HPLC/MS [15][8] Tetragonisca fiebrigi (Schwarz 1938) Mato Grosso do Sul, Brazil Propolis Ethanolic extract Erythroleukemia cell line (K562) Dose-dependent cytotoxicity Yes a [20][19]
Trigona incisa
Terpenes Not specified

(Sakagami and Inoue 1989)		 Kalimantan,

Indonesia		 Propolis Methanolic extract Colon (SW620), liver (HepG2), stomach (KATO-III), lung (ChaGo-1), and breast (BT-474) Anti-proliferative activity In vitro Yes b [38,39,40][20][21][22]
Trigona spp. Maharashtra, India Propolis Unidentified Unidentified - [26][13] Trigona apicalis

(Smith 1857)		 No [38][20]
Indonesia Propolis Alkaloids, flavonoids, saponins, tannins, steroids, and triterpenes Unidentified Chemical approach [34][14] Trigona fuscobalteata (Cameron 1908) No
Scaptotrigonaaff. postica (Latreille 1807) Maranhão, Brazil Propolis Terpenes and

coumarins		 Unidentified Phytochemical approach [28][1 Trigona fuscibisca (Friese 1900)
]
Scaptotrigona depilis (Moure 1942) Mato Grosso do Sul, Brazil Propolis Terpenes β-Sitosterol, β-amyrin, α-amyrin, and β-amyrin acetate GC/MS; HPLC/MS [31][10] Heterotrigona itama (Cockerell 1918) Ethanolic extract Human breast cancer (MCF-7), human cervical adenocarcinoma (HeLa), and human colon cancer (CaCo-2) Moderate decrease in cell viability to 75 μg/mL In vitro No [37][18]
Phenolic compounds Heterotrigona bakeri (Cockerell 1919) No
Vanillin, p-coumaric acid, ferulic acid, benzoic acid, and cinnamic acid
Tetragonula biroi (Friese 1898) Lagunas, Philippines Propolis Carbohydrates, steroids, alkaloids, anthraquinones, and phenols Unidentified Phytochemical approach [29][2] Homotrigona fimbriata (Smith 1857)
Tetragonisca fiebrigi (Schwartz 1938)Yes b
Mato Grosso do Sul, Brazil Propolis Phenolic acids Benzoic acid, cinnamic acid, p-coumaric acid, 3-phenyl-p-coumaric acid, and benzyl caffeate GC/MS [20][19] Lepidotrigona terminata (Smith 1878) Chanthaburi, Thailand Propolis Methanolic extract Squamous cell carcinoma of the mouth (KB), hepatocellular carcinoma (HepG2), colon adenocarcinoma (CaCo-2), and melanoma (SK-MEL-28) Cytotoxicity IC50 74.30 to 264.78 μg/mL In vitro No [
Phenylpropanoids27][ Cinnamyl caffeate, hydrocinnamic acid, and hydrocinnamic acid ethyl ester17]
Trigona laeviceps

(Smith 1857)		 Samut Songkram, Thailand Aqueous extract Colon (SW620) Decrease of cell viability to 23% No [41]
Terpene[23]
Kaurenoic acid Ethanolic extract Colon (SW620), breast (BT-474), liver (HepG2), lung (ChaGo), and stomach (KATO-III) Anti-proliferative activity IC50 19.9 to 36.19 μg/mL
SugarsNo [ Fructose and glucose42][24]
Lepidotrigona ventralis (Smith 1857) Chanthaburi, Thailand Methanolic extract Squamous cell carcinoma of the mouth (KB), hepatocellular carcinoma (HepG2), colon adenocarcinoma (CaCo-2), and melanoma (SK-MEL-28).
LipidsCytotoxicity IC50 96.58 to 565.19 μg/mL No [27][17]
Tocopherol, cholesterol, and retinol Geniotrigona thoracica (Smith 1857) Perak, Malaysia
Tetrigona apicalisEthanolic extract  (Smith 1857)Human breast adenocarcinoma (MCF-7) Growth inhibition IC50 38.9 μg/mL No [43][25]
Perak, Malaysia Propolis Hydrocarbon Undecane GC/MS [44][27] Plebeia remota

(Holmberg 1903)		 Paraná, Brazil Ethanolic extract
Phenolic compound MyristicinMDA-MB-231 (triple-negative human breast adenocarcinoma), MCF-7 (human breast adenocarcinoma), HeLa (human cervical adenocarcinoma), HepG2 (human hepatocellular carcinoma), and HRT-18 (human colorectal adenocarcinoma) IC50 41.76 to 76.1 μg/mL Yes a [17][9]
Tetragonula biroi (Friese 1898)
TerpenesLagunas, Philippines Ethanolic extract Gastric cancer cell lines (AGS, MKN-45, NUGC-4, and MKN-74) Regression of macroscopic and histological lesions In vitro and in vivo Yes  β-Elemene, α-cubebene, copaene, cyperene, α-gurjunene, caryophyllene, α-caryophyllene, γ -cadinene, germacrene D, bicyclogermacrene, δ-amorphene, β-selinene, aromadendr-1-ene, spathulenol, caryophyllene oxide, 1, 2-dimethyl-3, 5-bis(1-methylethenyl)-, humulene epoxide II, α-cadinol, aristolene epoxide, taraxerone, β-amyrin, and α-amyrina [29][2]
Scaptotrigona aff. postica (Latreille 1807) Maranhão,

Brazil		 Propolis Hydroethanolic extract Ehrlich solid tumor Inhibition of tumor progression In vivo Partially a [28][1]
Plebeia remota (Holmberg 1903) Paraná, Brazil Propolis Fatty acid Arachidonic acid HPLC/MS [17][9] Scaptotrigona bipunctata (Lepeletier 1836) Paraná, Brazil Ethanolic extract MDA-MB-231 (triple-negative human breast adenocarcinoma), MCF-7 (human breast adenocarcinoma), HeLa (human cervical adenocarcinoma), HepG2 (human hepatocellular carcinoma), and HRT-18 (human colorectal adenocarcinoma) Cytotoxicity IC50 54.89 to 112.23 μg/mL In vitro Yes a [17][9]
Terpenes Scaptotrigona bipunctata (Lepeletier 1836) Santa Catarina, Brazil Ethanolic extract Human melanoma (SK-MEL-28) Decreased migration and invasion of melanoma cells Yes a [32][11]
Sugiol, totarol, communic acid, agathic acid, isocupressic acid, cupressic acid, dihydroagathic acid, and 15-acetoxy-cupressic acid Scaptotrigona depilis (Moure 1942) Mato Grosso do Sul, Brazil Ethanolic extract Human erythroleukemia cell line (K562) Decrease in cell growth to 32.6 ± 3.2% at 500 μg/mL Yes a [31][10]
Scaptotrigona sp. Maranhão,

Brazil		 Ethanolic extract Human glioblastoma (U251 and U343) Anti-proliferative activity No [22][26]
Tetrigona apicalis

(Smith 1857)		 Perak, Malaysia Ethanolic extract Human breast adenocarcinoma (MCF-7) Proliferation inhibition IC50 32.70 μg/mL Yes a [44][27]
a = chemical composition detailed in Table 2. b = compound isolation shown in Figure 2.
Pharmaceuticals 14 01161 g001 550
Figure 1. Locations of stingless bee species producing propolis and geopropolis with antitumor potential worldwide.

2. Chemical Identification of Antitumor Extracts from Propolis and Geopropolis

HPLC/MS = high-performance liquid chromatography coupled to mass spectrometry. GC/MS = gas chromatography coupled to mass spectrometry.

3. Isolation of Compounds

Compounds isolated from propolis and geopropolis of stingless bee species that were tested against tumor cell lines are shown in Figure 2.
Pharmaceuticals 14 01161 g002a 550Pharmaceuticals 14 01161 g002b 550
Figure 2. Compound 1 was isolated from the methanolic extract propolis of Trigona incisa. Compounds 2 and 3 were isolated from the hydroethanolic extract geopropolis of Melipona scutellaris. Compounds 4 and 5 were isolated from the methanolic extract propolis of Tetragonula pagdeni. Compounds 4, 6, 7, 8, and 9 were isolated from the hydroethanolic extract propolis of Lisotrigona furva. Compounds 10, 11, and 12 were isolated from the ethanolic extract propolis of Trigona minor. Compound 13 was isolated from the ethanolic extract propolis of Homotrigona fimbriata. Compound 14 was isolated from the acetate extract propolis of Lisotrigona furva.
Kustiawan et al. [20][21][22] submitted the methanolic propolis extract produced by Trigona incisa to chromatographic fractionation, isolating, among other compounds, cardol (1), which was identified by NMR spectrometric analysis. Biological cytotoxicity tests indicated that compound 1 induces cell death by apoptosis in the initial incubation period (≤6 h) and modulates cell cycle arrest in the G1 subphase in SW620 cells (colon cancer cells). Kustiawan et al. [22] observed that compound 1 promotes changes in cell morphology in SW620 cells; a significant increase in caspase-3 and caspase-9 activities; and cleavage of pro-caspase-3, pro-caspase-9, and PARP. Eight compounds were isolated from the hydroethanolic geopropolis extract produced by Melipona scutellaris by [30] and tested in vitro against two colon cancer cell lines (COLO205 and KM12). The coumarins mammeisin (2) and mammein (3) (Figure 2) showed a higher average percentage of growth inhibition, of 56% and 83%, respectively.

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