Background Melittin, a peptide component of honey bee venom, is an appealing candidate for cancer therapy. In the current study, melittin, melittin-loaded niosome, and empty niosome had been optimized and the anticancer effect assessed in vitro on 4T1 and SKBR3 breast cell lines and in vivo on BALB/C inbred mice. "Thin-layer hydration method" was used for preparing the niosomes; different niosomal formulations of melittin were prepared and characterized in terms of morphology, size, polydispersity index, encapsulation efficiency, release kinetics, and stability. A niosome was formulated and loaded with melittin as a promising drug carrier system for chemotherapy of the breast cancer cells. Hemolysis, apoptosis, cell cytotoxicity, invasion and migration of selected concentrations of melittin, and melittin-loaded niosome were evaluated on 4T1 and SKBR3 cells using hemolytic activity assay, flow cytometry, MTT assay, soft agar colony assay, and wound healing assay. Real-time PCR was used to determine the gene expression. 40 BALB/c inbred mice were used; then, the histopathology, P53 immunohistochemical assay and estimate of renal and liver enzyme activity for all groups had been done. Results This study showed melittin-loaded niosome is an excellent substitute in breast cancer treatment due to enhanced targeting, encapsulation efficiency, PDI, and release rate and shows a high anticancer effect on cell lines. The melittin-loaded niosome affects the genes expression by studied cells were higher than other samples; down-regulates the expression of Bcl2 , MMP2 , and MMP9 genes while they up-regulate the expression of Bax , Caspase3 and Caspase9 genes. They have also enhanced the apoptosis rate and inhibited cell migration, invasion in both cell lines compared to the melittin samples. Results of histopathology showed reduce mitosis index, invasion and pleomorphism in melittin-loaded niosome. Renal and hepatic biomarker activity did not significantly differ in melittin-loaded niosome and melittin compared to healthy control. In immunohistochemistry, P53 expression did not show a significant change in all groups. Conclusions Our study successfully declares that melittin-loaded niosome had more anti-cancer effects than free melittin. This project has demonstrated that niosomes are suitable vesicle carriers for melittin, compare to the free form.

Bee venom is a very complex mixture produced and secreted by the honeybee (Apis mellifera). Melittin is a major component of bee venom that accounts for about 52% of its dry mass. A vast number of studies have been dedicated to the effects of melittin’s regulation of apoptosis and to the factors that induce apoptosis in various types of cancer such as breast, ovarian, prostate, lung. The latest evidence indicates its potential as a therapeutic agent in the treatment of leukaemia. The aim of our present study is to evaluate melittin’s ability to induce apoptosis in leukaemia cell lines of different origin acute lymphoblastic leukaemia (CCRF-CEM) and chronic myelogenous leukaemia (K-562). We demonstrated that melittin strongly reduced cell viability in both leukaemia cell lines but not in physiological peripheral blood mononuclear cells (PMBCs). Subsequent estimated parameters (mitochondrial membrane potential, Annexin V binding and Caspases 3/7 activity) clearly demonstrated that melittin induced apoptosis in leukaemia cells. This is a very important step for research into the development of new potential anti-leukaemia as well as anticancer therapies. Further analyses on the molecular level have been also planned (analysis of proapoptotic genes expression and DNA damages) for our next research project, which will also focus on melittin.

5-fluorouracil (5-FU) and doxorubicin (DOX) are potent anti-tumour agents commonly used for colon and breast cancer therapy, respectively. However, their clinical application is limited by their side effects and the development of drug resistance. Honeybee venom is a complex mixture of substances that has been reported to be effective against different cancer cells. Its active compound is melittin, a positively charged amphipathic peptide that interacts with the phospholipids of the cell membrane, forming pores that enable the internalization of small molecules with cytotoxic activities,. and consequently, causing cell death. Some central nervous system (CNS) drugs have recently demonstrated great anti-cancer potential, both in vitro, in vivo and in clinical trials, being promising candidates for drug repurposing in oncology. The present work evaluated the anti-cancer efficacy of honeybee venom in combination with chemotherapeutic or CNS drugs in HT-29 colon and MCF-7 breast cancer cell lines. The chemical characterization of a Portuguese sample of honeybee venom was done by LC-DAD-ESI/MSn analysis. For single treatments, cells were incubated with increasing concentrations of bee venom. For combination treatments, increasing concentrations of bee venom were first combined with the half-maximal inhibitory concentration (IC50) of 5-FU and DOX, in HT-29 and MCF-7 cells, respectively. Cells were also treated with increasing concentrations of bee venom in combination with the IC50 value of four CNS drugs (fluphenazine, fluoxetine, sertraline and thioridazine). Cytotoxicity was evaluated by MTT and SRB assays. The combination index (CI) value was calculated using CompuSyn software, based on the Chou–Talalay method. Synergy scores of different reference models (HSA, Loewe, ZIP and Bliss) were also calculated using SynergyFinder. The results demonstrate that honeybee venom is active against HT-29 colon and MCF-7 breast cancer cells, having better anti-tumour activity in MCF-7 cells. It was found that bee venom combined with 5-FU and fluphenazine in HT-29 cells resulted in less cytotoxic effects compared to the co-treatment of fluoxetine, sertraline and thioridazine plus bee venom, which resulted in less than 15% of viable cells for the whole range of concentrations. The combination of MCF-7 cells with repurposed drugs plus honeybee venom resulted in better anti-cancer efficacies than with DOX, notably for lower concentrations. A combination of fluoxetine and thioridazine plus honeybee venom resulted in less than 40% of viable cells for all ranges of concentrations. These results support that the combination of honeybee venom with repurposed drugs and chemotherapeutic agents can help improve their anti-cancer activity, especially for lower concentrations, in both cell lines. Overall, the present study corroborates the enormous bioactive potential of honeybee venom for colon and breast cancer treatments, both alone and in combination with chemotherapy or repurposed drugs.

Among the various natural compounds used in alternative and Oriental medicine, toxins isolated from different organisms have had their application for many years, and <i>Apis mellifera</i> venom has been studied the most extensively. Numerous studies dealing with the positive assets of bee venom (BV) indicated its beneficial properties. The usage of bee products to prevent the occurrence of diseases and for their treatment is often referred to as apitherapy and is based mainly on the experience of the traditional system of medical practice in diverse ethnic communities. Today, a large number of studies are focused on the antitumor effects of BV, which are mainly attributed to its basic polypeptide melittin (MEL). Previous studies have indicated that BV and its major constituent MEL cause a strong toxic effect on different cancer cells, such as liver, lung, bladder, kidney, prostate, breast, and leukemia cells, while a less pronounced effect was observed in normal non-target cells. Their proposed mechanisms of action, such as the effect on proliferation and growth inhibition, cell cycle alterations, and induction of cell death through several cancer cell death mechanisms, are associated with the activation of phospholipase A₂ (PLA₂), caspases, and matrix metalloproteinases that destroy cancer cells. Numerous cellular effects of BV and MEL need to be elucidated on the molecular level, while the key issue has to do with the trigger of the apoptotic cascade. Apoptosis could be either a consequence of the plasmatic membrane fenestration or the result of the direct interaction of the BV components with pro-apoptotic and anti-apoptotic factors. The interaction of BV peptides and enzymes with the plasma membrane is a crucial step in the whole process. However, before its possible application as a remedy, it is crucial to identify the correct route of exposure and dosage of BV and MEL for potential therapeutic use as well as potential side effects on normal cells and tissues to avoid any possible adverse event.

Background: Breast cancer is the most common and life-threatening cancer in females characterized by the abnormal proliferation of tumor cells in lobules and ducts. For years, many anti-breast cancer drugs have been tested with some of them showing severe health problems and drug resistance. Recently, different biological and pharmacological actions of bee venom have been indicated to play anti-bacterial, anti-viral and anti-inflammatory role against different cancers especially breast cancer. Methods: This review study is based on PubMed, Google Scholar and PubMed search. Search terms used were Melittin, Breast cancer and Honey Bee Venom. Results: Many studies have shown that a positively charged C-terminal sequence of mellitin facilitates plasma membrane contact and antitumor action. Precise targeting and selective activity of melittin has been found in recent studies as it suppresses the activation of growth factor receptors in HER2-enriched and triple-negative breast cancer that are generally difficult to treat. Significantly, it leaves healthy cells intact. The most striking feature of melittin is the pore formation property. Monomers of melittin bind to the plasma membrane of cancer cells in a collective manner and start forming pores, ultimately bringing cell lysis. Conclusion: Since melittin has a very selective action against the HER-2 related tumors, a combinational therapy of melittin and HER-2 targeted agents could be a very potent strategy in breast cancer. This review reflects the importance of honey bee venom and melittin as a potential therapy for aggressive breast cancer.

Breast cancer is one of the common cancers in women around the world, and metastasis potential of cancer is the main shortcoming for a high rate of survival. Apitherapy as an alternative medicine is promised to deal with cancer. Bee venom and its major component, melittin, are known to be effective for cytotoxicity in cancer cells. In this study, the expression profiles of three anti-metastatic genes including _BRMS1_,_ DRG1_ and _KAI1/CD82 _were revealed for the first time after bee venom and melittin treatment, and two pro-metastatic genes including _EGFR_ and _WNT7B_ in metastatic breast cancer cells (MDA-MB-231) were also examined while comparing to normal breast epithelial cells (MCF10A). Selective cytotoxicity of bee venom and melittin were higher compared to cisplatin. Melittin at 0.5 µg/ml was effective at 24h for anti-metastatic function whereas 4 µg/ml was significant in treatments with bee venom or cisplatin. Melittin induced overexpression of _BRMS1_ and _DRG1_, however bee venom induced _DRG1_ and _KAI1/CD82 _expression in breast cancer cells. _WNT7B_ was downregulated in bee venom-treated breast cancer cells. These results suggest that both bee venom and melittin may act via upregulation of some anti-metastatic genes (_BRMS1_, _DRG1_ and _KAI1/CD82)_, and down-regulation of a pro-metastatic gene, _WNT7B_.

nalyzed the effect of bee venom and its components on breast cancer cells and reviewed the mechanism underlying the anticancer effects of bee venom. Data up to March 2022 were searched from PubMed, EMBASE, OASIS, KISS, and Science Direct online databases, and studies that met the inclusion criteria were reviewed. Among 612 studies, 11 were selected for this research. Diverse drugs were administered, including crude bee venom, melittin, phospholipase A2, and their complexes. All drugs reduced the number of breast cancer cells in proportion to the dose and time. The mechanisms of anticancer effects included cytotoxicity, apoptosis, cell targeting, gene expression regulation, and cell lysis. Summarily, bee venom and its components exert anticancer effects on human breast cancer cells. Depending on the mechanisms of anticancer effects, side effects are expected to be reduced by using various vehicles. Bee venom and its components have the potential to prevent and treat breast cancer in the future. Keywords: bee venom, melittin, phospholipase A2, breast cancer 1. Introduction Breast cancer is one of the most common cancers among women, accounting for 30% of all newly diagnosed cancers [ 1 , 2 ]. According to the American Cancer Society, approximately 2.3 million new patients with breast cancer were diagnosed and 685,000 deaths had resulted from breast cancer, making it the fifth leading cause of cancer mortality worldwide in 2020 [ 3 ]. Female breast cancer has a 5-year relative survival rate of 90% for all stages combined, which represents the third highest survival rate among major cancers in the United States [ 4 ]. However, as the stage progresses, the survival rate also rapidly decreases [ 5 ]. Breast cancer can be classified into three subtypes, depending on the presence of molecular markers: hormone receptor positive/human epidermal growth factor receptor-2 gene (ERBB2) negative, ERBB2 positive, and triple-negative [ 6 ]. These subtypes determine the recurrence ra

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