Honeybee venom and melittin suppress growth factor receptor activation in HER2-enriched and triple-negative breast cancer

Abstract

Despite decades of study, the molecular mechanisms and selectivity of the biomolecular components of honeybee (Apis mellifera) venom as anticancer agents remain largely unknown. Here, we demonstrate that honeybee venom and its major component melittin potently induce cell death, particularly in the aggressive triple-negative and HER2-enriched breast cancer subtypes. 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 carcinoma cells. Mutational studies reveal that a positively charged C-terminal melittin sequence mediates plasma membrane interaction and anticancer activity. Engineering of an RGD motif further enhances targeting of melittin to malignant cells with minimal toxicity to normal cells. Lastly, administration of melittin enhances the effect of docetaxel in suppressing breast tumor growth in an allograft model. Our work unveils a molecular mechanism underpinning the anticancer selectivity of melittin, and outlines treatment strategies to target aggressive breast cancers.

Cytotoxic and Pro-Apoptotic Effects of a Sub-Toxic Concentration of Fluvastatin on OVCAR3 Ovarian Cancer Cells After its Optimized Formulation to Melittin Nano-Conjugates

“…Despite the significantly highest antineoplastic activity showed by FLV-MEL combination, the activity of MEL alone is also worth of mention. In fact, as showed in almost all in vitro cell experiments, the antineoplastic activity of MEL alone used at a sub-toxic concentration (IC10) was higher than that of the free drug (FLV-R) and is in accordance with several recent research studies ( Sangboonruang et al, 2020 ; Yu et al, 2020 ) such as that carried out by Duffy et al showing the ability of MEL to suppress epidermal growth factor receptors 1 and 2 (EGFR and HER2) activation in the aggressive triple-negative and HER2-enriched breast cancer subtypes ( Duffy et al, 2020 ). The present findings also confirm that the combination of this natural product with other antineoplastic drugs results in a more powerful anticancer activity.…”

Bacteria primed by antimicrobial peptides develop tolerance and persist

“…Melittin is a 26 amino acid residue linear peptide from the honeybee, which kills bacterial cells by permeabilisation of the membrane [ 25 ]. Melittin is also active against eukaryotic parasites such as Leishmania and cancer cells [ 26 ]. The second AMP, pexiganan, also a linear peptide, is the first eukaryotic AMP developed as a drug mainly to treat foot ulcers.…”

Scorpion-Venom-Derived Antimicrobial Peptide Css54 Exerts Potent Antimicrobial Activity by Disrupting Bacterial Membrane of Zoonotic Bacteria

“…Css 54 exerted antimicrobial activity with low MIC compared to antibiotics against some strains. In a previous study, treatment with melittin showed no adverse effects on stomach tissue, including its function, and melittin was confirmed to have a protective effect against gastric inflammation and antitumor effects in vivo [39][40][41]. These reports indicate that Css54 can be developed as an effective treatment because of its lower toxicity (versus melittin).…”