YAŞAR GÜLMEZ, ALİ AYDIN, İLYAS CAN, ŞABAN TEKİN, Ercan CACAN

Cellular toxicity and biological activities of honey bee (Apis mellifera L.) venom

Bee venom (BV) has been suggested as an apitherapy tool to be considered for various diseases including cancer. However, the mechanisms action of BV and its toxicity on tumorigenic and nontumorigenic cells are poorly understood. Here, we investigated the antiproliferative, cytotoxic and antibacterial activities of honey bee (Apis mellifera L.) venom on nontumorigenic cells, several tumor cell lines and multidrug resistant human pathogens (MDRP) such as Extended Spectrum Beta-Lactamases producing Escherichia coli and Vancomycin- resistant Enterococcus Enterococcus faecium. BV treatment showed significant antiproliferative, cytotoxic and antibacterial activities. Our results suggest that BV is highly toxic not only to cancer cell lines but also to nontumorigenic cell line as well. We also investigated the mechanism action of BV, which caused a cleavage of genomic DNA and inhibition of cell migration, indicating induction of apoptosis. Immunohistochemistry studies demonstrated that BV decreased the expression of Bcl-2 and P16. BV showed antimicrobial activity against several tested-MDRP. Our results indicate that clinic consideration of BV for the treatment of malignancy needs to be re-evaluated due to its cytotoxicity against normal cells.

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Son DJ, Lee JW, Lee YH, Song HS, Lee CK, Hong JT.Therapeutic application of anti-arthritis, pain-releasing,and anti-cancer effects of bee venom and its constituentcompounds. Pharmacol Ther 2007; 115: 246-70.

Hider RC. Honeybee venom: A rich source ofpharmacologically active peptides. Endeavour 1988; 12: 60-5.

Garaj-Vrhovac V, Gajski G. Evaluation of the cytogenetic statusof human lymphocytes after exposure to a high concentrationof bee venom in vitro. Arh Hig Rada Toksikol 2009; 60: 27-34.

Gajski G, Garaj-Vrhovac V. Bee venom induced cytogeneticdamage and decreased cell viability in human white bloodcells after treatment in vitro: a multi-biomarker approach.Environ Toxicol Pharmacol 2011; 32: 201-11.

Cherniack EP. Bugs as drugs, Part 1: Insects: the “new”alternative medicine for the 21st century? Altern Med Rev2010; 15: 124-35.

Orsolic N. Bee venom in cancer therapy. Cancer MetastasisRev 2012; 31: 173-94.

Hong SJ, Rim GS, Yang HI, Yin CS, Koh HG, Jang MH, et al.Bee venom induces apoptosis through caspase-3 activationin synovial fibroblasts of patients with rheumatoid arthritis.Toxicon 2005; 46: 39-45.

Ip SW, Chu YL, Yu CS, Chen PY, Ho HC, Yang JS, Huang HY,Chueh FS, Lai TY, Chung JG. Bee venom induces apoptosisthrough intracellular Ca2+ -modulated intrinsic deathpathway in human bladder cancer cells. Int J Urol 2012; 19:61-70.

Ip SW, Liao SS, Lin SY, Lin JP, Yang JS, Lin ML, Chen GW, LuHF, Lin MW, Han SM, Chung JG.The role of mitochondria inbee venom-induced apoptosis in human breast cancer MCF7cells. In Vivo 2008; 22: 237-45.

Tu WC, Wu CC, Hsieh HL, Chen CY, Hsu SL. Honeybeevenom induces calcium-dependent but caspase-independentapoptotic cell death in human melanoma A2058 cells. Toxicon2008; 52: 318-29.

Moon DO, Park SY, Choi YH, Kim ND, Lee C, Kim GY.Melittin induces Bcl-2 and caspase-3-dependent apoptosisthrough downregulation of Akt phosphorylation in humanleukemic U937 cells. Toxicon 2008; 51: 112-20.

Son DJ, Ha SJ, Song HS, Lim Y, Yun YP, Lee JW, et al. Melittininhibits vascular smooth muscle cell proliferation throughinduction of apoptosis via suppression of nuclear factorkappaBand Akt activation and enhancement of apoptoticprotein expression. J Pharmacol Exp Ther 2006; 317: 627-34.

Cho HJ, Jeong YJ, Park KK, Park YY, Chung IK, Lee KG, et al.Bee venom suppresses PMA-mediated MMP-9 gene activationvia JNK/p38 and NF-kappaB-dependent mechanisms. JEthnopharmacol 2010; 127: 662-8.

Hamedani M, Vatanpour H, Saadat F, Reza KhorramizahehM, Mirshafiey A. Bee venom, immunostimulant orimmunosuppressor? Insight into the effect on matrixmetalloproteinases and interferons. ImmunopharmacolImmunotoxicol 2005; 27: 671-81.

Jeong YJ, Choi Y, Shin JM, Cho HJ, Kang JH, Park KK, et al.Melittin suppresses EGF-induced cell motility and invasionby inhibiting PI3K/Akt/mTOR signaling pathway in breastcancer cells. Food Chem Toxicol 2014; 68: 218-25.

Hu H, Chen D, Li Y, Zhang X. Effect of polypeptides in beevenom on growth inhibition and apoptosis induction of thehuman hepatoma cell line SMMC-7721 in-vitro and Balb/cnude mice in-vivo. J Pharm Pharmacol 2006; 58: 83-9.

Aydin A, Korkmaz N, Tekin S, Karadag A. Anticanceractivities and mechanism of action of 2 novel metal complexes,C16H34N8O5Ag2Cd and C11H16N7O2Ag3Ni. Turk J Biol2014; 38: 948-55.

Gong J, Traganos F, Darzynkiewicz Z. A selective procedurefor DNA extraction from apoptotic cells applicable for gelelectrophoresis and flow cytometry. Anal Biochem 1994; 218:314-9.

Wayne, PA. Clinical and Laboratory Standards Institute.Clinical and Laboratory Standards Institute. 2014.Performance standards for antimicrobial susceptibility testing;24th informational supplement. CLSI document M100-S24.

Heinen TE, da Veiga AB. Arthropod venoms and cancer.Toxicon 2011; 57: 497-511.

Abd-Elhakim YM, Khalil SR, Awad A, Al-Ayadhi LY.Combined cytogenotoxic effects of bee venom and bleomycinon rat lymphocytes: An in vitro study. Biomed Res Int 2014;2014: 173903.

Ownby CL, Powell JR, Jiang MS, Fletcher JE. Melittin andphospholipase A2 from bee (Apis mellifera) venom causenecrosis of murine skeletal muscle in vivo. Toxicon 1997; 35:67-80.

Dotimas EM, Hamid KR, Hider RC, Ragnarsson U. Isolationand structure analysis of bee venom mast cell degranulatingpeptide. Biochim Biophys Acta 1987; 911: 285-93.

Habermann E. Bee and wasp venoms. Science 1972; 177: 314-22.

Han SM, Park KK, Nicholls YM, Macfarlane N, Duncan G.Effects of honeybee (Apis mellifera) venom on keratinocytemigration in vitro. Pharmacogn Mag 2013; 9: 220-6.

Jeon S, Kim NH, Koo BS, Lee HJ, Lee AY. Bee venom stimulateshuman melanocyte proliferation, melanogenesis, dendricityand migration. Exp Mol Med 2007; 39: 603-13.

Zheng J, Lee HL, Ham YW, Song HS, Song MJ, Hong JT. Anticancereffect of bee venom on colon cancer cell growth byactivation of death receptors and inhibition of nuclear factorkappa B. Oncotarget 2015; 6: 44437-51.

Choi KE, Hwang CJ, Gu SM, Park MH, Kim JH, Park JH, et al.Cancer cell growth inhibitory effect of bee venom via increaseof death receptor 3 expression and inactivation of NF-kappa Bin NSCLC cells. Toxins (Basel) 2014; 6: 2210-28.

Lee YJ, Kang SJ, Kim BM, Kim YJ, Woo HD, Chung HW.Cytotoxicity of honeybee (Apis mellifera) venom in normalhuman lymphocytes and HL-60 cells. Chem Biol Interact2007; 169: 189-97.

Leandro LF, Mendes CA, Casemiro LA, Vinholis AH, CunhaWR, de Almeida R, et al. Antimicrobial activity of apitoxin,melittin and phospholipase A(2) of honey bee (Apis mellifera)venom against oral pathogens. An Acad Bras Cienc 2015; 87:147-55.

Slaninova J, Mlsova V, Kroupova H, Alan L, Tůmova T,Monincova L, Borovičkova L, Fučik V, Ceřovsky V. Toxicitystudy of antimicrobial peptides from wild bee venom andtheir analogs toward mammalian normal and cancer cells.Peptides 2012; 33: 18-26.