Antitumor Potential of Stingless Bee Propolis and Geopropolis

Antitumor Potential of Stingless Bee Propolis and Geopropolis: History

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Subjects: Oncology

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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] 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]
				Human epidermoid laryngeal carcinoma (HEp-2)	Decrease in cell viability from 25 to 100 μg/mL		Yes ^a	[30]
				Human epidermoid laryngeal carcinoma (HEp-2)	Inhibition of cell proliferation and migration		No	[25]
				Lung cancer (A549 and H460) and ovarian cancer (ES2 and A2780)	Dose- and time-dependent cytotoxicity		Yes ^a	[8]
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	[24]
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]
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 97.53 to 155.1 μg/mL	In vitro	Yes ^a	[17]
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]
Melipona quadrifasciata anthidioides (Lepeletier 1836)	Santa Catarina, Brazil		Ethanolic extract	Human melanoma (SK-MEL-28)	Decreased migration and invasion of melanoma cells		Yes ^a	[32]
Melipona orbignyi (Guérin-Méneville 1844)	Mato Grosso do Sul, Brazil		Ethanolic extract	Erythroleukemia cell line (K562)	Decrease in cell viability to less than 25% at 500 µg/mL		Yes ^b	[33]
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]
Trigona spp.	Indonesia		Hydroethanolic extract	Breast (MCF-7)	Decrease in cell growth to 47.71%		Partially	[34,35]
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]
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]
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]
Tetragonula sarawakensis (Schwarz 1939)							No
Tetragonula fuscobalteata (Cameron 1908)							No
Tetragonula laeviceps (Smith 1857)							No
Tetragonisca fiebrigi (Schwarz 1938)	Mato Grosso do Sul, Brazil	Propolis	Ethanolic extract	Erythroleukemia cell line (K562)	Dose-dependent cytotoxicity		Yes ^a	[20]
Trigona incisa (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]
Trigona apicalis (Smith 1857)							No	[38]
Trigona fuscobalteata (Cameron 1908)							No
Trigona fuscibisca (Friese 1900)							No
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]
Heterotrigona bakeri (Cockerell 1919)							No
Homotrigona fimbriata (Smith 1857)							Yes ^b
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	[27]
Trigona laeviceps (Smith 1857)	Samut Songkram, Thailand		Aqueous extract	Colon (SW620)	Decrease of cell viability to 23%		No	[41]
Trigona laeviceps (Smith 1857)	Samut Songkram, Thailand		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		No	[42]
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).	Cytotoxicity IC₅₀ 96.58 to 565.19 μg/mL		No	[27]
Geniotrigona thoracica (Smith 1857)	Perak, Malaysia		Ethanolic extract	Human breast adenocarcinoma (MCF-7)	Growth inhibition IC₅₀ 38.9 μg/mL		No	[43]
Plebeia remota (Holmberg 1903)	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)	IC₅₀ 41.76 to 76.1 μg/mL		Yes ^a	[17]
Tetragonula biroi (Friese 1898)	Lagunas, 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 ^a	[29]
Scaptotrigona aff. postica (Latreille 1807)	Maranhão, Brazil	Propolis	Hydroethanolic extract	Ehrlich solid tumor	Inhibition of tumor progression	In vivo	Partially ^a	[28]
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]
Scaptotrigona bipunctata (Lepeletier 1836)	Santa Catarina, Brazil		Ethanolic extract	Human melanoma (SK-MEL-28)	Decreased migration and invasion of melanoma cells		Yes ^a	[32]
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]
Scaptotrigona sp.	Maranhão, Brazil		Ethanolic extract	Human glioblastoma (U251 and U343)	Anti-proliferative activity		No	[22]
Tetrigona apicalis (Smith 1857)	Perak, Malaysia		Ethanolic extract	Human breast adenocarcinoma (MCF-7)	Proliferation inhibition IC₅₀ 32.70 μg/mL		Yes ^a	[44]

a = chemical composition detailed in Table 2. b = compound isolation shown in Figure 2.

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

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] 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].

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]
			Terpenes	α-Amyrin/β-amyrin and 4R,5R,9R,10R-13-hydroxypodocarp-8(14)-en-19-oic acid
			Phenolic compounds (phenolic acids, flavonoids, coumarin, stilbenes, phenylpropanoids, and tannins)	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
			Fatty acids	Palmitic acid, oleic acid, stearic acid, and eicosapentaenoic acid
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-xylose	HPLC/MS	[8,30]
			Terpenes	Lupeol, α-amyrin, β-amyrin, α-amyrenone, β-amyrenone, triterpene ketone, taraxerone, dipterocarpol, marsformosanone, and 3-[Xyl]-28-Glc-phytophthalacagenin
			Anthraquinone	Xantholaccaic acid A
			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]
Melipona quadrifasciata quadrifasciata (Lepetetier 1836))	Paraná, Brazil	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]
Melipona quadrifasciata quadrifasciata (Lepetetier 1836))	Paraná, Brazil	Propolis	Terpenes	Sugiol, pimaric acid, isocupressic acid, cupressic acid, junicedric acid, mangiferonic acid, and isomangiferolic acid	HPLC/MS	[17]
Melipona quadrifasciata anthidioides (Lepeletier 1836)	Mato Grosso do Sul, Brazil	Propolis	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]
	Mato Grosso do Sul, Brazil	Propolis	Terpenes	Stigmasterol, β-sitosterol, β-amyrin, taraxasterol, α-amyrin, β-amyrin acetate, and pinusenocarp	HPLC/MS; GC/MS	[31]
Melipona quadrifasciata anthidioides (Lepeletier 1836)	Santa Catarina, Brazil	Propolis	Phenolic compounds	7-O-methyl aromadendrin, 5-hydroxy-4′,7-dimethoxy flavone, 2′-hydroxynaringenin, narigenin, and p-coumaric	HPLC/MS	[32]
			Phenylpropanoids	4-O-(6″-O-p-coumaroyl-β-D-glucopyranosyl)- and 6-O-cinnamoyl-1-O-p-coumaroyl-β-D-glucopyranoside
			Terpenes	Abieta-8,11,13,15-tetraen-18-oic acid, abietic acid, 7-hydroxydehydroabietic acid, and inumakiol
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]
Melipona mondury (Smith 1863)	Bahia, Brazil	Geopropolis	Phenolic compounds	Gallic acid	HPLC/MS	[15]
Melipona mondury (Smith 1863)	Bahia, Brazil	Geopropolis	Terpenes	Not specified	HPLC/MS	[15]
Trigona spp.	Maharashtra, India	Propolis	Unidentified	Unidentified	-	[26]
Trigona spp.	Indonesia	Propolis	Alkaloids, flavonoids, saponins, tannins, steroids, and triterpenes	Unidentified	Chemical approach	[34]
Scaptotrigonaaff. postica (Latreille 1807)	Maranhão, Brazil	Propolis	Terpenes and coumarins	Unidentified	Phytochemical approach	[28]
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]
Scaptotrigona depilis (Moure 1942)	Mato Grosso do Sul, Brazil	Propolis	Phenolic compounds	Vanillin, p-coumaric acid, ferulic acid, benzoic acid, and cinnamic acid	GC/MS; HPLC/MS	[31]
Tetragonula biroi (Friese 1898)	Lagunas, Philippines	Propolis	Carbohydrates, steroids, alkaloids, anthraquinones, and phenols	Unidentified	Phytochemical approach	[29]
Tetragonisca fiebrigi (Schwartz 1938)	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]
			Phenylpropanoids	Cinnamyl caffeate, hydrocinnamic acid, and hydrocinnamic acid ethyl ester
			Terpene	Kaurenoic acid
			Sugars	Fructose and glucose
			Lipids	Tocopherol, cholesterol, and retinol
Tetrigona apicalis (Smith 1857)	Perak, Malaysia	Propolis	Hydrocarbon	Undecane	GC/MS	[44]
			Phenolic compound	Myristicin
			Terpenes	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-amyrin
Plebeia remota (Holmberg 1903)	Paraná, Brazil	Propolis	Fatty acid	Arachidonic acid	HPLC/MS	[17]
Plebeia remota (Holmberg 1903)	Paraná, Brazil	Propolis	Terpenes	Sugiol, totarol, communic acid, agathic acid, isocupressic acid, cupressic acid, dihydroagathic acid, and 15-acetoxy-cupressic acid	HPLC/MS	[17]

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

This entry is adapted from the peer-reviewed paper 10.3390/ph14111161

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