Bee products have long been used in traditional medicine. The raw materials, crude extracts and purified active compounds from them have been found to exhibit interesting bioactivities, such as antimicrobial, anti-inflammatory and antioxidant activities. In addition, they have been widely used in the treatment of many immune-related diseases, as well as in recent times in the treatment of tumors. Bee product peptides induce apoptotic cell death in vitro in several transformed (cancer) human cell lines, including those derived from renal, lung, liver, prostate, bladder and lymphoid cancers. These bioactive natural products may, therefore, prove to be useful as part of a novel targeted therapy for some types of cancer, such as prostate and breast cancer. This review summarizes the current knowledge regarding the in vivo and in vitro potential of selective bee products against tumor cells.

To screen crude extracts of propolis, bee pollen and honey from four stingless bee species [Trigona incisa (T. incisa)], Timia apicalis, Trigona fusco-balteata and Trigona fuscibasis) native to East Kalimantan, Indonesia for cytotoxic activity against five human cancer cell lines (HepG2, SW620, ChaGo-I, KATO-III and BT474). All samples were extracted with methanol, and then subpartitioned with n-hexane and ethyl acetate. Each crude extract was screened at 20 µg/mL for in vitro cytotoxicity against the cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. In addition, four previously shown bioactive components from propolis (apigenin, caffeic acid phenyl ester, kaempferol and naringenin) and two chemotherapeutic drugs (doxorubicin and 5-fluorouracil) were used to evaluate the sensitivity of the cell lines. Overall, crude extracts from propolis and honey had higher cytotoxic activities than bee pollen, but the activity was dependent upon the extraction solvent, bee species and cell line. Propolis extracts from T. incisa and Timia apicalis showed the highest and lowest cytotoxic activity, respectively. Only the HepG2 cell line was broadly sensitive to the honey extracts. For pure compounds, doxorubicin was the most cytotoxic, the four propolis compounds the least, but the ChaGo-I cell line was sensitive to kaempferol at 10 µg/mL and KATO-III was sensitive to kaempferol and apigenin at 10 µg/mL. All pure compounds were effective against the BT474 cell line. Propolis from T. incisa and Trigona fusco-balteata contain an in vitro cytotoxic activity against human cancer cell lines. Further study is required, including the isolation and characterization of the active antiproliferative agent(s).

Background: Propolis is a complex resinous honeybee product. It is reported to display diverse bioactivities, such as antimicrobial, anti-inflammatory and anti-tumor properties, which are mainly due to phenolic compounds, and especially flavonoids. The diversity of bioactive compounds depends on the geography and climate, since these factors affect the floral diversity. Here, Apis mellifera propolis from Nan province, Thailand, was evaluated for potential anti-cancer activity. Methods: Propolis was sequentially extracted with methanol, dichloromethane and hexane and the cytotoxic activity of each crude extract was assayed for antiproliferative/cytotoxic activity in vitro against five human cell lines derived from duet carcinoma (BT474), undifferentiated lung (Chaco), liver hepatoblastoma (Hep-G₂), gastric carcinoma (KATO-III) and colon adenocarcinoma (SW620) cancers. The human foreskin fibroblast cell line (Hs27) was used as a non-transformed control. Those crude extracts that displayed antiproliferative/cytotoxic activity were then further fractionated by column chromatography using TLC-pattern and MTT-cytotoxicity bioassay guided selection of the fractions. The chemical structure of each enriched bioactive compound was analyzed by nuclear magnetic resonance and mass spectroscopy. Results: The crude hexane and dichloromethane extracts of propolis displayed antiproliferative/cytotoxic activities with IC₅₀ values across the five cancer cell lines ranging from 41.3 to 52.4 μg/ml and from 43.8 to 53.5 μg/ml, respectively. Two main bioactive components were isolated, one cardanol and one cardol, with broadly similar in vitro antiproliferation/cytotoxicity IC₅₀ values across the five cancer cell lines and the control Hs27 cell line, ranging from 10.8 to 29.3 μg/ml for the cardanol and < 3.13 to 5.97 μg/ml (6.82 - 13.0 μM) for the cardol. Moreover, both compounds induced cytotoxicity and cell death without DNA fragmentation in the cancer cells, but only an antiproliferation response in the control Hs27 cells However, these two compounds did not account for the net antiproliferation/cytotoxic activity of the crude extracts suggesting the existence of other potent compounds or synergistic interactions in the propolis extracts_. Conclusion: This is the first report that Thai A. mellifera propolis contains at least two potentially new compounds (a cardanol and a cardol) with potential anti-cancer bioactivity. Both could be alternative antiproliferative agents for future development as anti-cancer drugs.

Teeranai Ittiudomrak, Songchan Puthong, Sittiruk Roytrakul and Chanpen Chanchao. ToxicolRes 2019;35:167-79. https://doi.org/10.5487/TR.2019.35.2.167

Background: Bronchogenic carcinoma (lung cancer) is one of the leading causes of death. Although manycompounds isolated from natural products have been used to treat it, drug resistance is a serious problem, and alternativeanti-cancer drugs are required. Here, melittin from Apis mellifera venom was used, and its effects on bronchogeniccarcinoma cell proliferation and tumour-associated macrophage differentiation were evaluated. Methods: The halfmaximal inhibitory concentration (IC50) of melittin was measured by MTT. Cell death was observed by annexin Vand propidium iodide (PI) co-staining followed by flow cytometry. Cell cycle arrest was revealed by PI staining andflow cytometry. To investigate the tumour microenvironment, differentiation of circulating monocytes (THP-1) intotumour-associated macrophages (TAMs) was assayed by sandwich-ELISA and interleukin (IL)-10 levels were determined.Cell proliferation and migration was observed by flat plate colony formation. Secretion of vascular endothelial growthfactor (VEGF) was detected by ELISA. The change in expression levels of CatS, Bcl-2, and MADD was measured byquantitative RT-PCR. Results: Melittin was significantly more cytotoxic (p < 0.01) to human bronchogenic carcinomacells (ChaGo-K1) than to the control human lung fibroblasts (Wi-38) cells. At 2.5 μM, melittin caused ChaGo-K1cells to undergo apoptosis and cell cycle arrest at the G1 phase. The IL-10 levels showed that melittin significantlyinhibited the differentiation of THP-1 cells into TAMs (p < 0.05) and reduced the number of colonies formed in thetreated ChaGo-K1 cells compared to the untreated cells. However, melittin did not affect angiogenesis in ChaGo-K1cells. Unlike MADD, Bcl-2 was up-regulated significantly (p < 0.05) in melittin-treated ChaGo-K1 cells. Conclusion:Melittin can be used as an alternative agent for lung cancer treatment because of its cytotoxicity against ChaGo-K1cells and the inhibition of differentiation of THP-1 cells into TAMs.

Background: Bee pollen is composed of floral pollen mixed with nectar and bee secretion that is collected by foraging honey (Apissp.) and stingless bees. It is rich in nutrients, such as sugars, proteins, lipids, vitamins and flavonoids, and has been ascribed antiproliferative, anti-allergenic, anti-angiogenic and free radical scavenging activities. This research aimed at a preliminary investigation of the chemical constituents and free radical scavenging activity inA. melliferabee pollen.Methods: Bee pollen was directly collected fromA. melliferacolonies in Nan province, Thailand, in June, 2010, whilst floral corn (Zea maysL.) pollen was collected from the nearby corn fields. The pollen was then sequentially extracted with methanol, dichloromethane (DCM) and hexane, and each crude extract was tested for free radical scavenging activity using the DPPH assay, evaluating the percentage scavenging activity and the effective concentration at 50% (EC₅₀). The most active crude fraction from the bee pollen was then further enriched for bioactive components by silica gel 60 quick and adsorption or Sephadex LH-20 size exclusion chromatography. The purity of all fractions in each step was observed by thin layer chromatography and the bioactivity assessed by the DPPH assay. The chemical structures of the most active fractions were analyzed by nuclear magnetic resonance.Results: The crude DCM extract of both the bee corn pollen and floral corn pollen provided the highest active free radical scavenging activity of the three solvent extracts, but it was significantly (over 28-fold) higher in the bee corn pollen (EC₅₀ = 7.42 ± 0.12 μg/ml), than the floral corn pollen (EC₅₀ = 212 ± 13.6% μg/ml). After fractionation to homogeneity, the phenolic hydroquinone and the flavone 7-O-R-apigenin were found as the minor and major bioactive compounds, respectively. Bee corn pollen contained a reasonably diverse array of nutritional components, including biotin (56.7 μg/100 g), invert sugar (19.9 g/100 g), vitamin A and β carotene (1.53 mg/100 g).Conclusions: Bee pollen derived from corn (Z. mays), a non-toxic or edible plant, provided a better free radical scavenging activity than floral corn pollen.