Honeybee venom can kill aggressive breast cancer cells

BY MARK L. FUERST

 

The cancer community is abuzz with new research that suggests honeybee venom can induce cell death in triple-negative breast cancer (TNBC) and HER2-enriched breast cancers, with minimal effects on normal cells.

For thousands of years, humans have been using products from bees medicinally. In the last few decades, researchers have been investigating the effects of honeybee venom on cancer.

“It has been shown venom can kill cancer cells, but no one previously assessed whether it could be used specifically to affect breast cancer cells and the mechanism of action of how this works,” said Ciara Duffy, PhD, of the Harry Perkins Institute of Medical Research and the University of Western Australia, Perth.


Dr. Ciara Duffy
Credit: Harry Perkins Institute of Medical Research

“Interestingly, when we tested bumblebee venom, it had no effect at killing cells, even at high concentrations. There’s something special in honeybee venom – the very small, positively charged peptide melittin. Melittin enters the membranes of cells and forms holes or pores, damages the cells, and causes them to die quickly,” Dr. Duffy explained.

“We reproduced melittin synthetically and found that the synthetic product mirrored the majority of the anticancer effects of honeybee venom,” she added.

Dr. Duffy and colleagues described this research in NPJ Precision Oncology.

The researchers tested venom collected from European honeybees (Apis mellifera) and buff-tailed bumblebees (Bombus terrestris audax) in Perth, Dublin, and London. Regardless of the bees’ origin, honeybee venom significantly reduced the viability of breast cancer cells, while bumblebee venom did not.

“We found that [honeybee] venom was remarkably effective in killing aggressive TNBC and HER2-enriched breast cancer cells at concentrations that don’t damage normal cells,” Dr. Duffy said.


She noted that about 50% of TNBCs overexpress epidermal growth factor receptor (EGFR). The researchers found that honeybee venom and melittin suppress the activation of EGFR and HER2 by interfering with the phosphorylation of these receptors in the plasma membrane of breast cancer cells.

The researchers also found that melittin concentrations were similar in the different honeybees, but melittin concentrations were significantly higher in honeybee samples than in bumblebee samples.

The team then combined melittin with the chemotherapy drug docetaxel and observed a potent, synergistic antitumor response in a highly aggressive TNBC mouse model. This highlights the potential for melittin to be used in combination therapies to increase the efficacy or reduce the dose of cytotoxic agents.

Additive and synergistic anticancer effects have been reported between honeybee venom and other therapies, including with cisplatin in cervical and laryngeal malignancies and with docetaxel in lung cancer cells, the researchers reported.

Combining the membrane-disrupting properties of melittin with HER2-targeted agents, including monoclonal antibodies, trastuzumab-emtansine, and other antibody-drug conjugates, could enhance the cytotoxic effects, according to the researchers. They suggested that engineered targeted peptides of melittin could be delivered intravenously to enable more selective uptake into tumor cells, or melittin could be delivered through targeted nanoparticle approaches.

Beyond breast cancer, tumors overexpressing EGFR include lung and colorectal cancer as well as glioblastoma. Tumors that can overexpress HER2 include gastric, ovarian, endometrial, bladder, lung, colon, and head and neck cancers.


“Our results could be leveraged to aid the development of new therapeutic modalities for many cancer types associated with frequent drug resistance and poor prognosis,” the researchers wrote.

In the future, Dr. Duffy said, “we need to test the optimum method to deliver melittin into the body, as well as tolerated doses and toxicity. We plan to look into other cancers to see if melittin can specifically affect cells.”

“Melittin is an example of a natural product component that, by virtue of a novel mechanism of action, can circumvent limitations of more standard therapies,” said Michael Barish, PhD, of the department of developmental and stem cell biology at City of Hope National Medical Center in Duarte, Calif., who was not involved in this research.

He noted that aggressive tumors evade standard therapies in many cases by expansion of rare therapy-resistant clones or by evolution under the selection pressure of the therapy.

“Because killing mechanisms employing natural products and their active components may not compete with those of small molecules or chemotherapeutics, natural products are particularly amenable to inclusion in combination therapies,” Dr. Barish said.

“This study is one of an increasing number employing toxin components of venoms from amphibians, cone snails, hymenopterans, scorpions, sea anemones, snakes, spiders, tetraodontiformes, bats, and shrews that have advanced to clinical trials for cancer and other diseases. A particularly useful property of many of these toxins is their exquisite specificity for particular molecular targets, refined by evolution of predator-prey interactions,” Dr. Barish said.

A review published in Frontiers in Pharmacology lists several components of venom that have exhibited anticancer activity, including the amphibian toxin bufalin (a component of toad venom used in Chinese traditional medicine), collinein-1 from snake venom, chlorotoxin from scorpion venom, and synthetic peptide SOR-C13 derived from a component of shrew salivary gland.

“The use of honeybee venom and melittin may also have a social impact, as they are broadly available to under-resourced communities and, as components of breast cancer treatments, may enhance the lives of women worldwide,” Dr. Barish added.

Dr. Duffy’s research was supported by grants from the Australian government, foundations, and academic institutions. Dr. Duffy and Dr. Barish have no conflicts of interest.