The Pharmacological Potential of Novel Melittin Variants from the Honeybee and Solitary Bees against Inflammation and Cancer

Abstract

The venom of honeybees is composed of numerous peptides and proteins and has been used for decades as an anti-inflammatory and anti-cancer agent in traditional medicine. However, the bioactivity of specific biomolecular components has been evaluated for the predominant constituent, melittin. So far, only a few melittin-like peptides from solitary bee species have been investigated, and the molecular mechanisms of bee venoms as therapeutic agents remain largely unknown. Here, the preclinical pharmacological activities of known and proteo-transcriptomically discovered new melittin variants from the honeybee and more ancestral variants from phylogenetically older solitary bees were explored in the context of cancer and inflammation. We studied the effects of melittin peptides on cytotoxicity, second messenger release, and inflammatory markers using primary human cells, non-cancer, and cancerous cell lines. Melittin and some of its variants showed cytotoxic effects, induced Ca2+ signaling and inhibited cAMP production, and prevented LPS-induced NO synthesis but did not affect the IP3 signaling and pro-inflammatory activation of endothelial cells. Compared to the originally-described melittin, some phylogenetically more ancestral variants from solitary bees offer potential therapeutic modalities in modulating the in vitro inflammatory processes, and hindering cancer cell viability/proliferation, including aggressive breast cancers, and are worth further investigation.

Can Bee Venom Be Used as Anticancer Agent in Modern Medicine?

“…The authors also point to the synergy of BV with cisplatin [57], hesperidin and piperine [60], 5-fluorouracil and fluphenazine [37]. BV or melittin, alone or in combination with above mentioned chemotherapeutic agents, induced apoptosis in breast cancer cells, showed antiproliferative activity, and inhibited cell migration [34,66,74]. Tetiko glu et al [28] indicate the genotoxicity of BV to both breast cancer cells and physiological cells by the interaction of phosphorylated H2A histone family member (XγH2AX) and β-actin.…”

“…In addition, the authors noticed the decreased levels of carnitines, polyamines, adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NAD + ) under the influence of melittin [63,65]. Erkoc et al [34] reports the induction of calcium signaling apoptosis and inhibition of cAMP under the influence of melittin in breast cancer cells which leads to apoptosis and antiproliferative effect. BV also affects cell morphology leading to DNA and protein fragmentation [58].…”

The genome sequence of the Violet Carpenter Bee, Xylocopa violacea (Linnaeus, 1785): a hymenopteran species undergoing range expansion.

“…Xylocopa violacea is a solitary bee (Vicidomini, 1996), although within the genus there is evidence for several independent transitions to sociality (Gerling et al, 1989;Sless and Rehan, 2023). X. violacea also exhibits lineage specific traits such as its microbiome (Alberoni et al, 2019;Holley et al, 2022;Handy et al, 2023) and a distinctive venom profile with novel melittin variants that show potential for anticancer applications (von Reumont et al, 2022;Erkoc et al, 2022). There is only a contig-level assembly of the X. violacea genome currently available (Koludarov et al, 2023).…”

Prevalent bee venom genes evolved before the aculeate stinger and eusociality

“…The venoms of the remaining species of the hymenopteran radiation, however, including the majority of bees, remain largely unexplored despite recent proteo-transcriptomic studies on ant and wasp species [ 19 – 22 ]. Where studies of lesser-known Hymenoptera have been conducted, they typically deal with single crude fractions or even individual components either due to technical limitations at the time or because of applied research focus [ 5 , 23 – 25 ]. An exception is the recent study on aculeate venoms by Dashevsky and colleagues in which more extensively sampled venoms from aculeates were proteomically characterized and few bioactivities for each tested [ 26 ].…”