An introduction to Apitherapy
Apitherapy is the use of honeybee products – such as their honey, pollen, propolis, royal jelly and venom – for therapeutic purposes. It is a branch of alternative medicine that dates back thousands of years, with the apparent benefits of honeybee products discussed in religious texts such as the Bible and the Quran.1
If you've recently tuned into the Netflix documentary (Un)Well, you'll know that Apitherapy has been discussed with scepticism due to its association with the growing "wellness" trend, with Gwyneth Paltrow's controversial lifestyle brand Goop being just one of the platforms that praise it.
But a specific component of bee venom – melittin – has received attention in the oncology research community over recent years due to several scientific studies demonstrating its antitumoral effects in cancers such as glioblastoma, leukemia and cervical cancer.2,3,4 However, the molecular mechanisms behind such effects and the impact of bee venom on cancer signaling pathways remain elusive.
Now, a new body of work by scientists at the Harry Perkins Institute of Medical Research and The University of Western Australia demonstrates that honeybee venom induces cancer cell death in triple-negative breast cancer (TNBC) and HER-2 enriched breast cancer cells. The study, published in Nature Precision Oncology, also explores exactly how melittin interferes with cell signaling pathways in breast cancer cells to induce cell death.5
What is melittin?
Melittin, the main compound of bee venom, is a positively charged 26-residue peptide. It associates with the phospholipid membrane and causes cell death by mediating the formation of pores in the membrane, permitting entry of small molecules that are cytotoxic.
Honeybee venom and melittin kill breast cancer cells
The team of scientists led by Dr Ciara Duffy at the Harry Perkins Institute of Medical Research aimed to explore the impact of melittin on different types of breast cancer cells. "No-one had previously compared the effects of honeybee venom or melittin across all of the different subtypes of breast cancer and normal cells," Duffy said in a press release.
TNBC accounts for 10% of all breast cancers. There are fewer treatment options available due to the fact that the cancer cells do not express the estrogen or progesterone receptors (or HER2 protein) usually targeted by drugs or hormone therapy. In HER-2 enriched breast cancers, anti-HER2 therapeutics developed over recent years have increased long-term survival of patients, but resistance to the therapy often occurs in late-stage patients. As such, finding an effective treatment for these particularly aggressive forms of breast cancer is a large focus in oncology research.
Using cell lines
“I began with collecting Perth honeybee venom. Perth bees are some of the healthiest in the world," Duffy explained. “The bees were put to sleep with carbon dioxide and kept on ice before the venom barb was pulled out from the abdomen of the bee and the venom extracted by careful dissection."
The honeybee venom was tested on cell lines including normal breast cells and cells that were derived from clinical subtypes of breast cancer, TNBC and HER-2 enriched. The venom demonstrated high anti-cancer selectivity, with a significantly higher potency in TNBC and HER-2 enriched cell lines and had the lowest impact on normal breast cells. The research team described the venom as being "extremely potent".
Duffy and colleagues also applied melittin to the cell lines and assessed cell viability: " We tested a very small, positively charged peptide in honeybee venom called melittin, which we could reproduce synthetically," Duffy said.
She added: “We found both honeybee venom and melittin significantly, selectively and rapidly reduced the viability of triple-negative breast cancer and HER2-enriched breast cancer cells." Melittin was able to completely destroy the cell membrane within 60 minutes.
There are approximately 20,000 different species of bee, and so Duffy was interested to find out if the venom of other bee species would mimic the effects observed with the Perth honeybee venom. Indeed, the effect of applying venom from honeybees found in Ireland and England also reduced the viability of the cancer cell lines when compared to control cells. However, when testing the venom of the bumblebee Bombus terrestris from England, the scientists found that minimal cell death was elicited in the breast cancer cell lines compared to the honeybee venom – even at particularly high concentrations.
Dysregulating cancer cell signaling
How exactly is the honeybee venom killing cancer cells? “We looked at how honeybee venom and melittin affect the cancer signalling pathways, the chemical messages that are fundamental for cancer cell growth and reproduction, and we found that very quickly these signalling pathways were shut down," said Duffy.
Particularly, the venom and melittin supress the ligand-induced phosphorylation of the receptor that is overexpressed in TNBC: the epidermal growth factor receptor (EFGR), and supressed activation of HER2 that is overexpressed in HER-2 breast cancer cells.
“This is an incredibly exciting observation that melittin, a major component of honeybee venom, can suppress the growth of deadly breast cancer cells, particularly triple-negative breast cancer," said Western Australia’s Chief Scientist Professor Peter Klinken in a press release.
He added: "It provides another wonderful example of where compounds in nature can be used to treat human diseases."
But can these compounds found in nature be used in conjunction with chemically synthesized drugs to boost the anti-cancer effects? That was the next question for Duffy and colleagues.
Combining nature with chemistry
They tested a combination of melittin and the chemotherapy drug docetaxel (Taxotere) in a highly aggressive TNBC mouse model and reported a potent and synergistic antitumor response. “We found that melittin can be used with small molecules or chemotherapies, such as docetaxel, to treat highly-aggressive types of breast cancer. The combination of melittin and docetaxel was extremely efficient in reducing tumour growth in mice,” said Duffy.
The study was conducted in cell lines and an in vivo mouse model, so the anti-cancer effects of melittin and honeybee venom observed cannot be translated to humans at this stage. Nonetheless, the scientists acknowledge that their results could be utilized to help develop novel therapeutic treatments that extend beyond breast cancer. Going forward, it will be important for scientists to assess whether the venom of different bee species is more or less potent than the honeybee, exploring the impact of applying different doses and selecting the appropriate method for delivering melittin.
1. Wehbe R, Frangieh J, Rima M, El Obeid D, Sabatier JM, Fajloun Z. Bee venom: Overview of main compounds and bioactivities for therapeutic interests. Molecules. 2019;24(16):2997. Published 2019 Aug 19. doi:10.3390/molecules24162997.
2. Sisakht M, Mashkani B, Bazi A, et al. Bee venom induces apoptosis and suppresses matrix metaloprotease-2 expression in human glioblastoma cells. Revista Brasileira de Farmacognosia. 2017;27(3):324-328. doi:10.1016/j.bjp.2016.11.006
3. Killion JJ, Dunn JD. Differential cytolysis of murine spleen, bone-marrow and leukemia cells by melittin reveals differences in membrane topography. Biochem Biophys Res Commun. 1986;139(1):222-227. doi:10.1016/s0006-291x(86)80102-4
4. Zarrinnahad H, Mahmoodzadeh A, Hamidi MP, et al. Apoptotic effect of melittin purified from Iranian honey bee venom on human cervical cancer HeLa cell line. Int J Pept Res Ther. 2018;24(4):563-570. doi:10.1007/s10989-017-9641-1.
5. Duffy, C., Sorolla, A., Wang, E. et al. Honeybee venom and melittin suppress growth factor receptor activation in HER2-enriched and triple-negative breast cancer. npj Precis. Onc. 4, 24 (2020). https://doi.org/10.1038/s41698-020-00129-0