In 1950, Laszlo Havas published a study in Nature that showed bee venom reduced the growth of tumors in plants. Since then, the European honeybee (Apis mellifera) has been the source of a number of medicinal products used by humans, but the molecular underpinnings of bee venom are still poorly understood.
Ciara Duffy’s latest research and paper set out to change that. Using the venom of 312 honeybees and bumblebees from Australia, Ireland and England, the scientist showed honeybee venom can rapidly destroy triple-negative breast cancer, which has limited clinical treatment options. The study, published in Precision Oncology, is the first to test and compare honeybee venom across the three different subtypes of breast cancer in addition to normal cells.
Duffy and her team from Harry Perkins Institute of Medical Research in Australia first extracted bee venom from honeybees and bumblebees, and then synthetically recreated melittin, the active ingredient in honeybee venom. Not only did melittin induce 100% cancer cell death, but it did so within 60 minutes while also having minimal effects on normal breast cells.
"The venom was extremely potent," Duffy said. “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.”
While both the venom and melittin were found to selectively target overexpressing breast cancer cells, the researchers noted melittin was potentially more toxic to breast cancer cells than natural venom, an avenue that warrants further investigation.
Melittin was also found to substantially reduce the chemical messages of cancer cells—which are essential to cancer cell growth and cell division. In cell assays, researchers saw honeybee venom and melittin shut down cell signaling pathways within 20 minutes.
"Melittin modulated the signaling in breast cancer cells by suppressing the activation of the receptor that is commonly overexpressed in triple-negative breast cancer, the epidermal growth factor receptor, and it suppressed the activation of HER2, which is overexpressed in HER2-enriched breast cancer," Duffy explained.
When Duffy and her team tested venom from the English bumblebee Bombus terrestris, they did not see similar results. In fact, even at high concentrations, venom from both worker bumblebees and queens elicited minimal cell death in breast cancer cells compared with honeybee venom.
Duffy’s research also examined possible synergies between melittin and current chemotherapeutic agents. Melittin boosted the ability of docetaxel and cisplatin (used most often with triple negative breast cancer) to cause cancer cell death, suggesting tumors resistant to either agent could be rendered sensitive once again with the addition of the peptide. Additionally, melittin reduced PD-L1 expression in tumors by 2.4% when used alone and 4.2% when used with a combination treatment. The PD-L1 immune checkpoint is a critical target for today’s immunotherapies.
The researchers say their work reveals new opportunities to modify specific regions of melittin to further increase the effectiveness and targeted specificity for malignant cells.
“Melittin decreases the immune-suppressive effects of the tumor microenvironment, which are prevalent in triple negative breast cancer cells in the presence of chemotherapy,” the authors write in their paper. “But the selectivity of melittin for HER2-driven tumors makes a further case for combination with HER2-targeted agents where the membrane-disrupting properties of melittin could enhance the internalization kinetics of the cytotoxic payload.”
Beyond breast cancer, tumors that overexpress EGFR and HER2 include lung, glioblastoma, colorectal, gastric, ovarian, endometrial, bladder, lung, colon, and head and neck cancers. Before human trials can begin, further research will need to address toxicity and optimum delivery method, including the efficacy of targeted nanoparticles.
Photo: Ciara Duffy at the Harry Perkins Institute of Medical Research. Credit: Harry Perkins Institute of Medical Research