Melittin from Bee Venom and Cancer

Dr. Weeks’ Comment: The idea that honeybee venom offers anti-cancer properties seems implausible until one penetrates the very biochemistry of this remarkable and highly refined biologically active substance.  I have worked intensively with apitherapy since co-founding the American Apitherapy Society with master Bee-keeper Charlie Mraz in the early 1980’s.  So enjoy the brilliant science that follows.


“…Melittin is a major polypeptide in honey bee venom that has been used traditionally against chronic inflammation and cancer…”


“…Apis mellifera venom consists of many biologically active molecules and has been reported to exhibit remarkable anti-cancer effects, often promoting an apoptosis-like death phenotype…”





Environ Toxicol Pharmacol. 2013 Jun 28;36(2):697-705. doi: 10.1016/j.etap.2013.06.009. [Epub ahead of print]

Melittin: A lytic peptide with anticancer properties.

Gajski G, Garaj-Vrhovac V.


Institute for Medical Research and Occupational Health, Mutagenesis Unit, 10000 Zagreb, Croatia. Electronic address:


Melittin (MEL) is a major peptide constituent of bee venom that has been proposed as one of the upcoming possibilities for anticancer therapy. Recent reports point to several mechanisms of MEL cytotoxicity in different types of cancer cells such as cell cycle alterations, effect on proliferation and/or growth inhibition, and induction of apoptotic and necrotic cell death trough several cancer cell death mechanisms, including the activation of caspases and matrix metalloproteinases. Although cytotoxic to a broad spectrum of tumour cells, the peptide is also toxic to normal cells. Therefore its therapeutic potential cannot be achieved without a proper delivery vehicle which could be overcome by MEL nanoparticles that possess the ability to safely deliver significant amount of MEL intravenously, and to target and kill tumours. This review paper summarizes the current knowledge and brings latest research findings on the anticancer potential of this lytic peptide with diverse functions.



Cancer Immunol Immunother. 2013 May;62(5):889-95. doi: 10.1007/s00262-013-1401-2. Epub 2013 Feb 27.

A novel melittin-MhIL-2 fusion protein inhibits the growth of human ovarian cancer SKOV3 cells in vitro and in vivo tumor growth.

Liu M, Zong J, Liu Z, Li L, Zheng X, Wang B, Sun G.


Department of Clinical Laboratory, The Affiliated Hospital of Medical College, Qingdao University, No.16 Jiangsu Road, Qingdao, 266003, China.


In the current study, we produced a novel fusion protein (melittin-mutant human interleukin 2, melittin-MhIL-2) comprising a mutant human interleukin 2 (Arg88/Ala125) genetically linked to melittin. The plasmid pET15b-melittin-MhIL-2 (Arg88/Ala125) was transformed into E. coli for protein expression. The expressed melittin-MhIL-2 protein was purified using a series of purification steps. The interleukin 2 (IL-2) activity of melittin-MhIL-2 fusion protein was compared with recombinant human interleukin 2 (rhIL-2) for its ability to induce CTLL-2 proliferation. Moreover, the fusion protein directly inhibits the growth of human ovarian cancer SKOV3 cells in vitro. In an in vivo initial experiment, the fusion protein inhibited tumor growth in ovarian cancer mice. In conclusion, we generated a novel melittin-MhIL-2 fusion protein that retained functional activity of IL-2 and melittin and inhibited tumor growth in vivo.




J Venom Res. 2012;3:22-7. Epub 2012 Oct 23.

The synergistic cytotoxic effect of cisplatin and honey bee venom on human ovarian cancer cell line A2780cp.

Alizadehnohi M, Nabiuni M, Nazari Z, Safaeinejad Z, Irian S.


Department of Cell and Molecular Biology, Cell and Developmental Biology Research Lab, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran.


Ovarian cancer is considered to be one of the most important causes of death among women. Cisplatin is one of the oldest chemotherapeutical compounds used for treating ovarian cancer. Previous studies have shown the inhibitory effects of bee venom on certain types of cancer. The aim of the present study was to evaluate the cytotoxic effect of bee venom alone and its synergistic cytological effects in combination with cisplatin on ovarian cancerous cisplatin resistant A2780cp cells. To investigate the cytotoxic effect of bee venom on A2780cp cells and its synergetic effect with cisplatin, MTT assay, morphological examination, DNA fragmentation assay, flow cytometric and immune-cytochemical analysis were performed. MTT assay revealed that 8µg/ml bee venom, 25mg/ml cisplatin and 4µg/ml bee venom/10mg/ml cisplatin cause an approximately 50% A2780cp cell death after 24hr. Morphological and biochemical analysis indicated an apoptotic type of cell death induced by bee venom and cisplatin, separately and in combination. Immunocytochemistry demonstrated a reduction in the levels of the Bcl2 protein. Overall, our findings suggest that components of bee venom may exert an anti-tumor effect on human ovarian cancer and that has the potential for enhancing the cytotoxic effect of the antitumor agent cisplatin.



J Nat Prod. 2012 Oct 30. [Epub ahead of print]

Melittin Suppresses VEGF-A-Induced Tumor Growth by Blocking VEGFR-2 and the COX-2-Mediated MAPK Signaling Pathway.

Huh JE, Kang JW, Nam D, Baek YH, Choi DY, Park DS, Lee JD.


Oriental Medicine Research Center for Bone and Joint Disease, East-West Bone & Joint Research Institute, Kyung Hee University , 149, Sangil-dong, Gangdong-gu, Seoul, 134-727, Korea.


Melittin (1) is a major polypeptide in honey bee venom that has been used traditionally against chronic inflammation and cancer. However, its molecular mechanism has not been determined. In this study, the antitumor effect of 1 was compared with that of NS398, a cyclooxygenase-2 (COX-2) inhibitor, in vivo and in vitro. Subcutaneous injection of 1 at 0.5 and 5 mg/kg suppressed significantly vascular endothelial growth factor (VEGF)-A-transfected highly metastatic Lewis lung cancer (VEGF-A-hm LLC) tumor growth by 25% and 57%, respectively. Also, 1 inhibited significantly the number of vessels around VEGF-A-hm LLC cells. The results were superior to those obtained in the mice treated with NS398. Compound 1 dose-dependently inhibited proliferation and tube formation in human umbilical vein endothelial cells (VEGF-A-HUVECs), without affecting cell viability in native HUVECs. In addition, 1 decreased the expression of VEGF receptor-2 (VEGFR-2), COX-2, and prostaglandin E(2) (PGE(2)) in VEGF-A-transfected HUVECs. These effects were accompanied by a reduction of the phosphorylation of extracellular signal-regulated kinase 1/2 and c-jun N-terminal kinase, whereas it increased the phosphorylation of p38 mitogen-activated protein kinase (MAPK). SB203580 abolished the down-regulation of COX-2 and VEGFR-2 and the inhibition of cell proliferation by 1. The antitumor activity of 1 may be associated with antiangiogenic actions via inhibiting VEGFR-2 and inflammatory mediators involved in the MAPK signaling pathway.



Parasitology. 2012 Sep;139(11):1444-61. doi: 10.1017/S0031182012000790.

Apis mellifera venom induces different cell death pathways in Trypanosoma cruzi.

Adade CM, Chagas GS, Souto-Padrón T.


Laboratório de Biologia Celular e Ultraestrutura, Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes, Centro de Ciências da Saúde, bloco I and Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagens, Universidade Federal do Rio de Janeiro, Ilha do Fundão, Rio de Janeiro, RJ 21941-590, Brazil.


Chagas disease chemotherapy is based on drugs that exhibit toxic effects and have limited efficacy, such as Benznidazole. Therefore, research into new chemotherapeutic agents from natural sources needs to be exploited. Apis mellifera venom consists of many biologically active molecules and has been reported to exhibit remarkable anti-cancer effects, often promoting an apoptosis-like death phenotype. This study demonstrates that A. mellifera venom can affect the growth, viability and ultrastructure of all Trypanosoma cruzi developmental forms, including intracellular amastigotes, at concentrations 15- to 100-fold lower than those required to cause toxic effects in mammalian cells. The ultrastructural changes induced by the venom in the different developmental forms led us to hypothesize the occurrence of different programmed cell death pathways. Autophagic cell death, characterized by the presence of autophagosomes-like organelles and a strong monodansyl cadaverine labelling, appears to be the main death mechanism in epimastigotes. In contrast, increased TUNEL staining, abnormal nuclear chromatin condensation and kDNA disorganization was observed in venom-treated trypomastigotes, suggesting cell death by an apoptotic mechanism. On the other hand, intracellular amastigotes presented a heterogeneous cell death phenotype profile, where apoptosis-like death seemed to be predominant. Our findings confirm the great potential of A. mellifera venom as a source for the development of new drugs for the treatment of neglected diseases such as Chagas disease.




Biol Chem. 2012 Aug;393(8):817-27. doi: 10.1515/hsz-2012-0136.

Anticancer peptide NK-2 targets cell surface sulphated glycans rather than sialic acids.

Gross S, Andrä J.


Division of Biophysics, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, D-23845 Borstel, Germany.


Some antimicrobial peptides have emerged as potential anticancer agents. In contrast to chemotherapeutics, they act primarily by physical disruption of the cancer cell membrane. Selective targeting of these cationic peptides still remains elusive. We focus on the interaction of α-helical peptides NK-2, cathelicidin LL32, and melittin with PC-3 prostate cancer cells, and we provide strong evidence that, amongst the anionic glycans covering the cell surface, sulphated carbohydrates rather than sialic acids are the preferred interaction sites of the peptides. To test the significance of cell surface carbohydrates, a glycan microarray screen with fluorescently labelled peptides has been performed. Amongst 465 mammalian glycan structures on the chip, more than 20 different sulphated glycans were detected as the preferred binding partners of the peptide NK-2. The amount of peptide bound to sialic acid containing oligosaccharides was close to background level. These findings were consistent with microcalorimetric experiments revealing high and low binding enthalpies of peptides to sulphated carbohydrates and to sialic acid, respectively. Enzymatic desialylation of PC-3 cells did not affect peptide-mediated changes in cell metabolism, cell membrane permeabilisation, killing rate, and kinetics. Finally, the cytotoxicity of all peptides could be drastically impaired through the competitive inhibition by chondroitin sulphate, but not by sialic acid and sialylated fetuin.




Curr Med Chem. 2012;19(5):697-713.

Targeting SKCa channels in cancer: potential new therapeutic approaches.

Girault A, Haelters JP, Potier-Cartereau M, Chantôme A, Jaffrés PA, Bougnoux P, Joulin V, Vandier C.


Inserm, U921, Tours, F-37032 France.


Many studies have reported changes in potassium channel expression in many cancers and the involvement of these channels in various stages of cancer progression. By contrast, data concerning SKCa channels (small conductance calcium-activated potassium channels) have only recently become available. This review aims i) to present the structure and physiology of SKCa channels, ii) to provide an overview of published data concerning the SKCa proteins produced in tumor cells, and, whenever possible, the biological function assigned to them and iii) to review previous and novel modulators of SKCa channels. SKCa channels are activated by low concentrations of intracellular calcium and consist of homo- or heteromeric assemblies of α-subunits named SK1, SK2 and SK3. SK2-3 channels are expressed in tumors and have been assigned a biological function in cancer cells: the enhancement of cell proliferation and cell migration by hijacking the functions of SK2 and SK3 channels, respectively. Two major classes of SKCa modulators have been described: toxins (apamin) and small synthetic molecules. Most SKCa blockers are pore blockers, but some modify the calcium sensitivity of SKCa channels without interacting with the apamin binding site. In this review, we present edelfosine and ohmline as atypical anticancer agents and novel SK3 inhibitors. Edelfosine and ohmline are synthetic alkyl-lipids with structures different from all previously described SKCa modulators. They should pave the way for the development of a new class of migration-targeted anticancer agents. We believe that such blockers have potential for use in the prevention or treatment of metastasis.




Int J Urol. 2012 Jan;19(1):61-70. doi: 10.1111/j.1442-2042.2011.02876.x. Epub 2011 Dec 11.

Bee venom induces apoptosis through intracellular Ca2+ -modulated intrinsic death pathway in human bladder cancer cells.

Ip SW, Chu YL, Yu CS, Chen PY, Ho HC, Yang JS, Huang HY, Chueh FS, Lai TY, Chung JG.


Department of Nutrition, China Medical, Taipei, Taiwan.



To focus on bee venom-induced apoptosis in human bladder cancer TSGH-8301 cells and to investigate its signaling pathway to ascertain whether intracellular calcium iron (Ca(2+)) is involved in this effect.


Bee venom-induced cytotoxic effects, productions of reactive oxygen species and Ca(2+) and the level of mitochondrial membrane potential (ΔΨm) were analyzed by flow cytometry. Apoptosis-associated proteins were examined by Western blot analysis and confocal laser microscopy.


Bee venom-induced cell morphological changes and decreased cell viability through the induction of apoptosis in TSGH-8301 cell were found. Bee venom promoted the protein levels of Bax, caspase-9, caspase-3 and endonuclease G. The enhancements of endoplasmic reticulum stress-related protein levels were shown in bee venom-provoked apoptosis of TSGH-8301 cells. Bee venom promoted the activities of caspase-3, caspase-8, and caspase-9, increased Ca(2+) release and decreased the level of ΔΨm. Co-localization of immunofluorescence analysis showed the releases of endonuclease G and apoptosis-inducing factor trafficking to nuclei for bee venom-mediated apoptosis. The images revealed evidence of nuclear condensation and formation of apoptotic bodies by 4′,6-diamidino-2-phenylindole staining and DNA gel electrophoresis showed the DNA fragmentation in TSGH-8301 cells.


Bee venom treatment induces both caspase-dependent and caspase-independent apoptotic death through intracellular Ca(2+) -modulated intrinsic death pathway in TSGH-8301 cells.




Cancer Metastasis Rev. 2012 Jun;31(1-2):173-94. doi: 10.1007/s10555-011-9339-3.

Bee venom in cancer therapy.

Oršolić N.


Department of Animal Physiology, University of Zagreb, Zagreb, Croatia.


Bee venom (BV) (api-toxin) has been widely used in the treatment of some immune-related diseases, as well as in recent times in treatment of tumors. Several cancer cells, including renal, lung, liver, prostate, bladder, and mammary cancer cells as well as leukemia cells, can be targets of bee venom peptides such as melittin and phospholipase A2. The cell cytotoxic effects through the activation of PLA2 by melittin have been suggested to be the critical mechanism for the anti-cancer activity of BV. The induction of apoptotic cell death through several cancer cell death mechanisms, including the activation of caspase and matrix metalloproteinases, is important for the melittin-induced anti-cancer effects. The conjugation of cell lytic peptide (melittin) with hormone receptors and gene therapy carrying melittin can be useful as a novel targeted therapy for some types of cancer, such as prostate and breast cancer. This review summarizes the current knowledge regarding potential of bee venom and its compounds such as melittin to induce cytotoxic, antitumor, immunomodulatory, and apoptotic effects in different tumor cells in vivo or in vitro. The recent applications of melittin in various cancers and a molecular explanation for the antiproliferative properties of bee venom are discussed.




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