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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 [1][2][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 | [3][23] |
| Human epidermoid laryngeal carcinoma (HEp-2) | Decrease in cell viability from 25 to 100 μg/mL | Yes a |
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. [28][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 [29][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 | [9][11][17, | |||||||||
| [ | 4 | ] | [30] | ||||||||||||
| 32 | ] | ||||||||||||||
| 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) | [ | 5 | ][25] | ||||||||||||
| 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 | [6][8] | |||||||||||
| 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-xylose | 7] | HPLC/MS | [24] | |||||||
| [ | 6 | ] | [ | 4 | ] | [8,30] | 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 | [8][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 | ||||||||||
| 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 | [ | 9 | ][17] | |||||||
| 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 | [10][31] | |||||
| Santa Catarina, Brazil | Ethanolic extract | Human melanoma (SK-MEL-28) | Decreased migration and invasion of melanoma cells | Yes a | [11][32] | ||||||||||
| 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 | [7][24] | Ethanolic extract | Erythroleukemia cell line (K562) | Decrease in cell viability to less than 25% at 500 µg/mL | Yes b | [12] | ||||
| Melipona quadrifasciata quadrifasciata (Lepetetier 1836)) | [ | Paraná, Brazil | 33 | 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 | [ | 9 | ] | [17] | 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 | [13 | ||
| Terpenes | Sugiol, pimaric acid, isocupressic acid, cupressic acid, junicedric acid, mangiferonic acid, and isomangiferolic acid | ] | [ | 26 | ] | ||||||||||
| Indonesia | Hydroethanolic extract | ||||||||||||||
| Melipona quadrifasciata anthidioides | Breast (MCF-7) | (Lepeletier 1836) | Mato Grosso do Sul, Brazil | Decrease in cell growth to 47.71% | Partially | [14] | Propolis | [15][34,35] | |||||||
| Phenolic compounds | p-Coumaric acid, vanilic acid, caffeic acid, vanillin, ferulic acid, benzoic acid, quercetin, luteolin, cinnamic acid, and apigenin | HPLC/MS; GC/MS | [ | 10 | ] | [31] | 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 | [16] | ||
| Terpenes | Stigmasterol, β-sitosterol, β-amyrin, taraxasterol, α-amyrin, β-amyrin acetate, and pinusenocarp | [ | 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 | [17] | |||||||
| Melipona quadrifasciata anthidioides (Lepeletier 1836) | [ | 27 | ] | ||||||||||||
| 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 | [18][37] | ||||||||
| Propolis | Phenolic compounds | 7- | O | -methyl aromadendrin, 5-hydroxy-4′,7-dimethoxy flavone, 2′-hydroxynaringenin, narigenin, and p-coumaric | HPLC/MS | [11][32] | 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 | [12][33] | Tetragonula laeviceps (Smith 1857) | No | |||||||
| Melipona mondury (Smith 1863) | Bahia, Brazil | Geopropolis | Phenolic compounds | Gallic acid | HPLC/MS | [8][15] | Tetragonisca fiebrigi (Schwarz 1938) | Mato Grosso do Sul, Brazil | Propolis | Ethanolic extract | Erythroleukemia cell line (K562) | Dose-dependent cytotoxicity | Yes a | [19][20] | |
| 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 | [20][21][22][38,39,40] | |||||
| Trigona spp. | Maharashtra, India | Propolis | Unidentified | Unidentified | - | [13][26] | Trigona apicalis (Smith 1857) |
No | [20][38] | ||||||
| Indonesia | Propolis | Alkaloids, flavonoids, saponins, tannins, steroids, and triterpenes | Unidentified | Chemical approach | [14][34] | Trigona fuscobalteata (Cameron 1908) | No | ||||||||
| Scaptotrigonaaff. postica (Latreille 1807) | Maranhão, Brazil | Propolis | Terpenes and coumarins |
Unidentified | Phytochemical approach | [1][28 | 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 | [10][31] | 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 | [18][37] | ||
| 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 | [2][29] | 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 | [ | 19][20] | 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 | [ |
| Phenylpropanoids | 17 | ] | [ | Cinnamyl caffeate, hydrocinnamic acid, and hydrocinnamic acid ethyl ester | 27 | ] | |||||||||
| Trigona laeviceps (Smith 1857) |
Samut Songkram, Thailand | Aqueous extract | Colon (SW620) | Decrease of cell viability to 23% | No | [23] | |||||||||
| Terpene | [ | 41 | ] | ||||||||||||
| 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 | ||||||||||||
| Sugars | No | [ | Fructose and glucose | 24][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). | ||||||||||||
| Lipids | Cytotoxicity IC | 50 | 96.58 to 565.19 μg/mL | No | [ | 17][27] | |||||||||
| Tocopherol, cholesterol, and retinol | Geniotrigona thoracica (Smith 1857) | Perak, Malaysia | |||||||||||||
| Tetrigona apicalis | Ethanolic extract | (Smith 1857) | Human breast adenocarcinoma (MCF-7) | Growth inhibition IC50 38.9 μg/mL | No | [25][43] | |||||||||
| Perak, Malaysia | Propolis | Hydrocarbon | Undecane | GC/MS | [ | 27][44] | Plebeia remota (Holmberg 1903) |
Paraná, Brazil | Ethanolic extract | ||||||
| Phenolic compound | Myristicin | 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) | IC | 50 41.76 to 76.1 μg/mL | Yes a | [9][17] | |||||||||
| Tetragonula biroi (Friese 1898) | |||||||||||||||
| Terpenes | 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 | 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 | [2][29] | |||||||
| Scaptotrigona aff. postica (Latreille 1807) | Maranhão, Brazil |
Propolis | Hydroethanolic extract | Ehrlich solid tumor | Inhibition of tumor progression | In vivo | Partially a | [1][28] | |||||||
| Plebeia remota (Holmberg 1903) | Paraná, Brazil | Propolis | Fatty acid | Arachidonic acid | HPLC/MS | [9][17] | 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 | [9][17] | |
| Terpenes | Scaptotrigona bipunctata (Lepeletier 1836) | Santa Catarina, Brazil | Ethanolic extract | Human melanoma (SK-MEL-28) | Decreased migration and invasion of melanoma cells | Yes a | [11][32] | ||||||||
| 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 | [10][31] | ||||||||
| Scaptotrigona sp. | Maranhão, Brazil |
Ethanolic extract | Human glioblastoma (U251 and U343) | Anti-proliferative activity | No | [26][22] | |||||||||
| Tetrigona apicalis (Smith 1857) |
Perak, Malaysia | Ethanolic extract | Human breast adenocarcinoma (MCF-7) | Proliferation inhibition IC50 32.70 μg/mL | Yes a | [27][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
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.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.
