INVESTIGATION OF THE ANTI-CANCER PROPERTIES OF BEE VENOM AND MELLITIN PEPTIDE

Öz

Mellitin (MEL) and thus bee venom (BV) are potential animal drug source candidates for cancer treatment. In various cell culture and animal model studies, MEL has anti-cancer properties such as cytotoxicity, hemolytic activity, and growth inhibition. However, this peptide is not yet suitable for human use due to its specific cytotoxic protection. However, various appropriate transportation systems are being used to resolve the problems. With this study, we present information about the anti-cancer properties of bee venom and MEL, the studies carried out and the current perspective, and their possible effect systems.

Anahtar Kelimeler

• Melittin
• Bee Venom
• Anticancer drug
• Biotechnology
• Biochemistry

ARI ZEHRİ VE MELLİTİN PEPTİDİNİN ANTİKANSER ÖZELLİKLERİNİN İNCELENMESİ

Öz

Mellitin (MEL) ve dolayısıyla arı zehri (BV) kanser tedavisinde kullanılmaya aday önemli hayvansal ilaç kaynağı potansiyelidir. Çeşitli hücre kültürü ve hayvan modeli çalışmalarında anti-kanser özellikler gösteren MEL, sitotoksisite, hemolitik aktivite ve büyüme inhibisyonu gibi etkilere sahiptir. Bunun yanında bu peptid spesifik sitotoksik olmadığından dolayı insan kullanımına henüz uygun değildir. Fakat sorunları alt etmek için çeşitli uygun transport sistemler üzerinde optimizasyon çalışmaları yürütülmektedir. Bu çalışma ile arı zehri ve MEL’in anti-kanser özelliklerine dair yapılan çalışmalara ve mevcut bakış açısına işaret ederek olası etki sistemlerine dair bilgiler sunmaktayız.

Anahtar Kelimeler

• Mellitin
• Arı Zehri
• Anti-kanser ilaç
• Biyoteknoloji
• Biyokimya

Kaynakça

1. Adhami, V.M., Bailey, H.H., Mukhtar, H., 2014, Cancer chemoprevention is not a failure, Carcinogenesis 35 2154e2155.
2. Adhami, V.M., Mukhtar, H., 2013, Human cancer chemoprevention: hurdles and challenges, Top. Curr. Chem. 329 203e220.
3. Al-Sadoon, M.K., Rabah, D.M., Badr, G., 2013, Enhanced anticancer efficacy of snake venom combined with silica nanoparticles in a murine model of human multiple myeloma: molecular targets for cell cycle arrest and apoptosis induction, Cell Immunol. 284 129e138.
4. Amin, A.R., Kucuk, O., Khuri, F.R., Shin, D.M., 2009. Perspectives for cancer prevention with natural compounds. J. Clin. Oncol. 27, 2712–2725.
5. Baek, Y.H., Huh, J.E., Lee, J.D., Choi do, Y., Park, D.S., 2006. Antinociceptive effect and the mechanism of bee venom acupuncture (Apipuncture) on inflammatory pain in the rat model of collagen-induced arthritis: Mediation by alpha2-Adrenoceptors. Brain Res. 1073-1074, 305–310.
6. Bechinger, B., 1997. Structure and functions of channel-forming peptides: magainins, cecropins, melittin and alamethicin. J. Membr. Biol. 156, 197–211.
7. Bechinger, B., Lohner, K., 2006. Detergent-like actions of linear amphipathic cationic antimicrobial peptides. Biochim. Biophys. Acta 1758, 1529–1539. Brown, L.R., Lauterwein, J., Wüthrich, K., 1980. High-resolution 1H NMR studies of self-aggregation of melittin in aqueous solution. Biochim. Biophys. Acta 622, 231–244.
8. Borkow, G., Chaim-Matyas, A., Ovadia, M., 1992. Binding of cytotoxin P4 from Naja nigricollis nigricollis to B16F10 melanoma and WEHI-3B leukemia cells. FEMS Microbiol. Immunol. 5, 139–145. Carrasquer, G., Li, M., Yang, S., Schwartz, M., 1998. Effect of melittin on PD, resistance and short-circuit current in the frog gastric mucosa. Biochim. Biophys. Acta 1369, 346–354.

9. Cherniak, E.P., 2010. Bugs as drugs, Part 1: insects: the new alternative medicine for the 21st century? Altern. Med. Rev. 15, 124–135.
10. Das Gupta, S., Debnath, A., Saha, A., Giri, B., Tripathi, G., Vedasiromoni, J.R., Gomes, A., Gomes, A., 2007. Indian black scorpion (Heterometrus bengalensis Koch) venom induced antiproliferative and apoptogenic activity against human leukemic cell lines U937 and K562. Leuk. Res. 31, 817–825. Da Rocha, A.B., Lopes, R.M., Schwartsmann, G., 2001. Natural products in anticancer therapy. Curr. Opin. Pharmacol. 1, 364–369.
11. Debnath, A., Chatterjee, U., Das, M., Vedasiromoni, J.R., Gomes, A., 2007. Venom of Indian monocellate cobra and Russell’s viper show anticancer activity in experimental models. J. Ethnopharmacol. 111, 681–684.
12. Dempsey, C.E., 1990. The actions of melittin on membranes. Biochim. Biophys. Acta 1031, 143–161.
13. Diaz-Garcia, A., Morier-Diaz, L., Frion-Herrera, Y., Rodriguez-Sanchez, H., Caballero-Lorenzo, Y., Mendoza-Llanes, D., vd.., 2013, In vitro anticancer effect of venom from Cuban scorpion Rhopalurus junceus against a panel of human cancer cell lines, J. Venom. Res. 4 5e12.
14. Dotimas, E.M., Hamid, K.R., Hider, R.C., Ragnarsson, U., 1987. Isolation and structure analysis of bee venom mast cell degranulating peptide. Biochim. Biophys. Acta 911, 285–293.
15. Duke, R.C., Witter, R.Z., Nash, P.B., Young, J.D., Ojcius, D.M., 1994. Cytolysis mediated by ionophores and pore-forming agents: role of intracellular calcium in apoptosis. FASEB J. 8, 237–246.
16. Eiseman, J.L., von Bredow, J., Alvares, A.P., 1982. Effect of honeybee (Apis mellifera) venom on the course of adjuvant-induced arthritis and depression of drug metabolism in the rat. Biochem. Pharmacol. 31, 1139–1146.
17. Feofanov, A.V., Sharonov, G.V., Astapova, M.V., Rodionov, D.I., Utkin, Y.N., Arseniev, A.S., 2005. Cancer cell injury by cytotoxins from cobra venom is mediated through lysosomal damage. Biochem. J. 390, 11–18.
18. Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, 2012, Cancer incidence and mortality worldwide: sources, methods and majör patterns in GLOBOCAN, Int. J. Cancer 136 (2015) E359eE386.
19. Findlay, R.D., Taeusch, H.W., David-Cu, R., Walther, F.J., 1995. Lysis of red blood cells and alveolar epithelial toxicity by therapeutic pulmonary surfactants. Pediatr. Res. 37, 26–30.
20. Fletcher, J.E., Jiang, M.S., 1993. Possible mechanisms of action of cobra snake venom cardiotoxins and bee venom melittin. Toxicon 31, 669–695.
21. Frankish, H., 2003, 15 million new cancer cases per year by 2020, says WHO, Lancet 361 1278.
22. Gajski, G., Garaj-Vrhovac, V., 2008. Genotoxic potential of bee venom (Apis Mellifera) on human peripheral blood lymphocytes in vitro using single cell gel electrophoresis assay. J. Environ. Sci. Health A: Toxic Hazard. Subst. Environ. Eng. 43, 1279–1287.
23. Gajski, G., Garaj-Vrhovac, V., 2009. Radioprotective effects of honeybee venom (Apis Mellifera) against 915-MHz microwave radiation-induced DNA damage in Wistar rat lymphocytes. In vitro study. Int. J. Toxicol. 28, 88–98.
24. Gajski, G., Garaj-Vrhovac, V., 2010. Increased frequency of sister chromatid exchanges and decrease in cell viability and proliferation kinetics in human peripheral blood lymphocytes after in vitro exposure to whole bee venom. J. Environ. Sci. Health A: Toxic Hazard. Subst. Environ. Eng. 45, 1654–1659.
25. Gajski, G., Cˇ imbora-Zovko, T., Osmak, M., Garaj-Vrhovac, V., 2011. Bee venom and melittin are cytotoxic against different types of tumor and non-tumor cell lines in vitro. Cancer Res. J. 4, 159–174.
26. Gajski, G., Garaj-Vrhovac, V., 2011. Bee venom induced cytogenetic damage and decreased cell viability in human white blood cells after treatment in vitro: a multi-biomarker approach. Environ. Toxicol. Pharmacol. 32, 201–211.
27. Gajski, G., Domijan, A.M., Garaj-Vrhovac, V., 2012. Alterations of GSH and MDA levels and their association with bee venom-induced DNA damage in human peripheral blood leukocytes. Environ. Mol. Mutagen. 53, 469–477.
28. Gajski, G., Garaj-Vrhovac, V., 2013. Melittin: A lytic peptide with anticancer properties. Environmental toxicology and pharmacology 36, 697–705
29. Garaj-Vrhovac, V., Gajski, G., 2009. Evaluation of the cytogenetic status of human lymphocytes after exposure to a high concentration of bee venom in vitro. Arh. Hig. Rada Toksikol. 60, 27–34.
30. Gao, L., Yu, S., Wu, Y., Shan, B., 2007. Effect of spider venom on cell apoptosis and necrosis rates in MCF-7 cells. DNA Cell Biol. 26, 485–489.
31. Gevod, V.S., Birdi, K.S., 1984. Melittin and the 8–26 fragment. Differences in ionophoric properties as measured by monolayer method. Biophys. J. 45, 1079–1083.
32. Giuliani, A., Pirri, G., Nicoletto, S., 2007. Antimicrobial peptides: an overview of a promising class of therapeutics. Cent. Eur. J. Biol. 2, 1–33.
33. Gomes, A., Bhattacharjee, P., Mishra, R., Biswas, A.K., Dasgupta, S.C., Giri, B., Debnath, A., Gupta, S.D., Das, T., Gomes, A., 2010. Anticancer potential of animal venoms and toxins. Indian J. Exp. Biol. 48, 93–103.
34. Gotay, C.C., 2010. Cancer prevention: major initiatives and looking into the future. Expert. Rev. Pharmacoecon. Outcomes Res. 10, 143–154.
35. Graziose, R., Lila, M.A., Raskin, I., 2010. Merging traditional Chinese medicine with modern drug discovery technologies to find novel drugs and functional foods. Curr. Drug. Discov. Technol. 7, 2–12.
36. Guilford, J.M., Pezzuto, J.M., 2008. Natural products as inhibitors of carcinogenesis. Expert. Opin. Investig. Drugs 17, 1341–1352.
37. Haase, I., Czarnetzki, B.M., Rosenbach, T., 1996. Thrombin and melittin activate phospholipase C in human HaCaT keratinocytes. Exp. Dermatol. 5, 84–88.
38. Habermann, E., 1972. Bee and wasp venoms: the biochemistry and pharmacology of their peptides and enzymes are reviewed. Science 177, 314–322.
39. Hait, W.N., Grais, L., Benz, C., Cadman, E.C., 1985. Inhibition of growth of leukemic cells by inhibitors of calmodulin: phenothiazines and melittin. Cancer Chemother. Pharmacol. 14, 202–205.
40. Hait, W.N., Lee, G.L., 1985. Characteristics of the cytotoxic effects of the phenothiazine class of calmodulin antagonists. Biochem. Pharmacol. 34, 3973–3978.
41. Harvey, A., 1998. From demons to darlings: drugs from venoms. Drug Discov. Today 3, 531–532.
42. Harvey, A., 2000. Strategies for discovering drugs from previously unexplored natural products. Drug Discov. Today 5, 294–300.
43. Havas, L.J., 1950. Effect of bee venom on colchicine-induced tumours. Nature 166, 567–568.
44. Heinen, T.E., da Veiga, A.B., 2011, Arthropod venoms and cancer, Toxicon 57 497e511.
45. Hider, H.C., 1988, Honeybee venom: a rich source of pharmacologically active peptides, Endeavour 12 60e65.
46. Hider, R.C., Ragnarsson, U., 1980. A proposal for the structure of apamin. FEBS Lett. 111, 189–193.
47. Holle, L., Song, W., Holle, E., Wei, Y., Wagner, T., Yu, X., 2003. A matrix metalloproteinase 2 cleavable melittin/avidin conjugate specifically targets tumor cells in vitro and in vivo. Int. J. Oncol. 22, 93–98.
48. Hoskin, D.W., Ramamoorthy, A., 2008. Studies on anticancer activities of antimicrobial peptides. Biochim. Biophys. Acta 1778, 357–375.
49. Huang, T.,Gong,W.H., Li, X.C., Zou, C.P., Jiang,G.J., Li, X.H., 2012, Efficient killing effect of osteosarcoma cells by cinobufacini and cisplatin in combination, Asian Pac J. Cancer Prev. 13 2847e2851.
50. Hui, S.W., Stewart, C.M., Cherry, R.J., 1990. Electron microscopic observation of the aggregation of membrane proteins in human erythrocyte by melittin. Biochim. Biophys. Acta 1023, 335–340.
51. Hui, L., Leung, K., Chen, H.M., 2002. The combined effects of antibacterial peptide cecropin A and anti-cancer agents on leukemia cells. Anticancer Res. 22, 2811–2816.
52. Ip, S.W., Liao, S.S., Lin, S.Y., Lin, J.P., Yang, J.S., Lin, M.L., Chen, G.W., Lu, H.F., Lin, M.W., Han, S.M., Chung, J.G., 2008a. The role of mitochondria in bee venom-induced apoptosis in human breast cancer MCF7 cells. In Vivo 22, 237–245.
53. Ip, S.W., Wei, H.C., Lin, J.P., Kuo, H.M., Liu, K.C., Hsu, S.C., Yang, J.S., Mei-Dueyang Chiu, T.H., Han, S.M., Chung, J.G., 2008b. Bee venom induced cell cycle arrest and apoptosis in human cervical epidermoid carcinoma Ca Ski cells. Anticancer Res. 28, 833–842.
54. Jang, M.H., Shin, M.C., Lim, S., Han, S.M., Park, H.J., Shin, I., 2003. Bee venom induces apoptosis and inhibits expression of cyclooxygenase-2 mRNA in human lung cancer cell line NCI-H1299. J. Pharmacol. Sci. 91, 95–104.
55. Kiesel, L., Rabe, T., Hauser, G., Przylipiak, A., Jadali, F., Runnebaum, B., 1987. Stimulation of luteinizing hormone release by melittin and phospholipase A2 in rat pituitary cells. Mol. Cell. Endocrinol. 51, 1–6.
56. Killion, J.J., Dunn, J.D., 1986. Differential cytolysis of murine spleen, bone-marrow and leukemia cells by melittin reveals differences in membrane topography. Biochem. Biophys. Res. Commun. 139, 222–227.
57. Knowles, B.H., Farndale, R.W., 1988. Activation of insect cell adenylate cyclase by Bacillus thuringiensis delta-endotoxins and melittin. Toxicity is independent of cyclic AMP. Biochem. J. 253, 235–241.
58. Kotecha, R., Takami, A., Espinoza, J.L., 2016, Dietary phytochemicals and cancer chemoprevention: a review of the clinical evidence, Oncotarget 7 52517e52529.
59. Lad, P.J., Shier, W.T., 1979. Activation of microsomal guanylate cyclase by a cytotoxic polypeptide: melittin. Biochem. Biophys. Res. Commun. 89, 315–321.
60. Ladokhin, A.S., White, S.H., 1999. Folding of amphipathic alpha-helices on membranes: energetics of helix formation by melittin. J. Mol. Biol. 285, 1363–1369.
61. Lai, D., Visser-Grieve, S., Yang, X., 2012, Tumour suppressor genes in chemotherapeutic drug response, Biosci. Rep. 32 361e374.
62. Lariviere, W.R., Melzack, R., 1996. The bee venom test: a new tonic-pain test. Pain 66, 271–277. Lauterwein, J., Bösch, C., Brown, L.R., Wüthrich, K., 1979. Physicochemical studies of the protein–lipid interactions in melittin-containing micelles. Biochim. Biophys. Acta 556, 244–264.
63. Lauterwein, J., Brown, L.R., Wüthrich, K., 1980. High-resolution 1H NMR studies of monomeric melittin in aqueous solution. Biochim. Biophys. Acta 622, 219–230.
64. Lavialle, F., Levin, I.W., Mollay, C., 1980. Interaction of melittin with dimyristoyl phosphatidylcholine liposomes: evidence for boundary lipid by Raman spectroscopy. Biochim. Biophys. Acta 600, 62–71.
65. Lazo, J.S., Hait, W.N., Kennedy, K.A., Braun, I.D., Meandzija, B., 1985. Enhanced bleomycin-induced DNA damage and cytotoxicity with calmodulin antagonists. Mol. Pharmacol. 27, 387–393. Lazo, J.S., Chen, D.L., Gallicchio, V.S., Hait, W.N., 1986. Increased lethality of calmodulin antagonists and bleomycin to human bone marrow and bleomycin-resistant malignant cells. Cancer Res. 46, 2236–2240.
66. Lee, G.L., Hait, W.N., 1985. Inhibition of growth of C6 astrocytoma cells by inhibitors of calmodulin. Life Sci. 36, 347–354.
67. Lee, Y.J., Kang, S.J., Kim, B.M., Kim, Y.J., Woo, H.D., Chung, H.W., 2007. Cytotoxicity of honeybee (Apis Mellifera) venom in normal human lymphocytes and HL-60 cells. Chem. Biol. Interact. 169, 189–197.
68. Leuschner, C., Hansel, W., 2004. Membrane disrupting lytic peptides for cancer treatments. Curr. Pharm. Des. 10, 2299–2310.
69. Lewis, R.J., Garcia, M.L., 2003. Therapeutic potential of venom peptides. Nat. Rev. Drug Discov. 2, 790–802. Li, S.X., Ling, C.Q., Liu, X.Y., 2003. Impact of infection with recombinant adenovirus carrying melittin gene on CD54 expression in HepG2 cells. Di Yi Jun Yi Da Xue Xue Bao 23, 300–305.
70. Li, B., Ling, C.Q., Zhang, C., Gu, W., Li, S.X., Huang, X.Q., Zhang, Y.N., Yu, C.Q., 2004. The induced apoptosis of recombinant adenovirus carrying melittin gene for hepatocellular carcinoma cell. Zhonghua Gan Zang Bing Za Zhi 12, 453–455.
71. Ling, C.Q., Li, B., Zhang, C., Gu, W., Li, S.X., Huang, X.Q., Zhang, Y.N., 2004. Anti-hepatocarcinoma effect of recombinant adenovirus carrying melittin gene. Zhonghua Gan Zang Bing Za Zhi 12, 741–744.
72. Ling, C.Q., Li, B., Zhang, C., Zhu, D.Z., Huang, X.Q., Gu, W., Li, S.X., 2005. Inhibitory effect of recombinant adenovirus carrying melittin gene on hepatocellular carcinoma. Ann. Oncol. 16, 109–115.
73. Liu, X., Chen, D., Xie, L., Zhang, R., 2002. Effect of honey bee venom on proliferation of K1735M2 mouse melanoma cells in vitro and growth of murine B16 melanomas in vivo. J. Pharm. Pharmacol. 54, 1083–1089.
74. Mahady, G.B., Liu, C., Beecher, C.W., 1998. Involvement of protein kinase and G proteins in the signal transduction of benzophenanthridine alkaloid biosynthesis. Phytochemistry 48, 93–102.
75. Maher, S., McClean, S., 2006. Investigation of the cytotoxicity of eukaryotic and prokaryotic antimicrobial peptides in intestinal epithelial cells in vitro. Biochem. Pharmacol. 71, 1289–1298.
76. Maher, S., McClean, S., 2008. Melittin exhibits necrotic cytotoxicity in gastrointestinal cells which is attenuated by cholesterol. Biochem. Pharmacol. 75, 1104–1114.
77. Majtan, J., 2009, [Apitherapyethe role of honey in the chronic wound healing process], Epidemiol. Mikrobiol. Imunol. 58 137e140.
78. Mau, S.E., Vilhardt, H., 1997. Cross talk between substance P and melittin-activated cellular signaling pathways in rat lactotroph-enriched cell cultures. J. Neurochem. 69, 762–772.
79. McDonald, J.A., Li, F.P., Mehta, C.R., 1979. Cancer mortality among beekeepers. J. Occup. Med. 21, 811–813.
80. Mehta, R.G., Pezzuto, J.M., 2002. Discovery of cancer preventive agents from natural products: from plants to prevention. Curr. Oncol. Rep. 4, 478–486.
81. Mehta, R.G., Murillo, G., Naithani, R., Peng, X., 2010. Cancer chemoprevention by natural products: how far have we come? Pharm. Res. 27, 950–961.
82. Meunier, F.A., Frangez, R., Benoit, E., Ouanounou, G., Rouzaire-Dubois, B., Suput, D., Molgó, J., 2000. Ca(2+) and Na(+) contribute to the swelling of differentiated neuroblastoma cells induced by equinatoxin-II. Toxicon 38, 1547–1560.
83. Mufson, R.A., Laskin, J.D., Fisher, P.B., Weinstein, I.B., 1979. Melittin shares certain cellular effects with phorbol ester tumour promoters. Nature 280, 72–74.
84. Mukhtar, H., 2012, Chemoprevention: making it a success story for controlling human cancer, Cancer Lett. 326 123e127.
85. Nagaraju, S., Mahadeswaraswamy, Y.H., Girish, K.S., Kemparaju, K., 2006. Venom from spiders of the genus Hippasa: biochemical and pharmacological studies. Comp. Biochem. Physiol. C: Toxicol. Pharmacol. 144, 1–9.
86. Nishioka, D., Marcell, V., Cunningham, M., Khan, M., Von Hoff, D.D., Izbicka, E., 2003. The use of early sea urchin embryos in anticancer drug testing. Methods Mol. Med. 85, 265–276.
87. Nobili, S., Lippi, D., Witort, E., Donnini, M., Bausi, L., Mini, E., Capaccioli, S., 2009. Natural compounds for cancer treatment and prevention. Pharmacol. Res. 59, 365–378.
88. Orsolic, N., 2012. Bee venom in cancer therapy. Cancer Metastasis Rev. 31, 173–194.
89. Ownby, C.L., Powell, J.R., Jiang, M.S., Fletcher, J.E., 1997. Melittin and phospholipase A2 from bee (Apis Mellifera) venom cause necrosis of murine skeletal muscle in vivo. Toxicon 35, 67–80. Pan, H., Soman, N.R., Schlesinger, P.H., Lanza, G.M., Wickline, S.A., 2011. Cytolytic peptide nanoparticles (‘NanoBees’) for cancer therapy. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 3, 318–327. Papo, N., Shai, Y., 2005. Host defense peptides as new weapons in cancer treatment. Cell. Mol. Life Sci. 62, 784–790.
90. Parekh, H.S., Liu, G., Wei, M.Q., 2009. A new dawn for the use of traditional Chinese medicine in cancer therapy. Mol. Cancer 8, 21.
91. Park, J.W., Jeon, J.H., Yoon, J., Jung, T.Y., Kwon, K.R., Cho, C.K.,2012, Effects of sweet bee venom pharmacopuncture treatment for chemotherapy-induced peripheral neuropathy: a case series, Integr. Cancer Ther. 11 166e171.
92. Pettit, G.R., Hasler, J.A., Paull, K.D., Herald, C.L., 1981. Antineoplastic agents. 76. The sea urchin Strongylocentrotus droebachiensis. J. Nat. Prod. 44, 701–704.
93. Pratt, J.P., Ravnic, D.J., Huss, H.T., Jiang, X., Orozco, B.S., Mentzer, S.J., 2005. Melittin-induced membrane permeability: a nonosmotic mechanism of cell death. In Vitro Cell. Dev. Biol. Anim. 41, 349–355.
94. Premratanachai,P., Chanchao, C., 2014, Review of the anticancer activities of bee products, Asian Pac J. Trop. Biomed. 4 337e344.
95. Raghuraman, H., Chattopadhyay, A., 2007. Melittin: a membrane-active peptide with diverse functions. Biosci. Rep. 27, 189–223.
96. Russell, P.J., Hewish, D., Carter, T., Sterling-Levis, K., Ow, K., Hattarki, M., Doughty, L., Guthrie, R., Shapira, D., Molloy, P.L., Werkmeister, J.A., Kortt, A.A., 2004. Cytotoxic properties of immunoconjugates containing melittin-like peptide 101 against prostate cancer: in vitro and in vivo studies. Cancer Immunol. Immunother. 53, 411–421.
97. Schweitz, H., Bidard, J.N., Frelin, C., Pauron, D., Vijverberg, H.P., Mahasneh, D.M., Lazdunski, M., Vilbois, F., Tsugita, A., 1985. Purification, sequence, and pharmacological properties of sea anemone toxins from Radianthus paumotensis. A new class of sea anemone toxins acting on the sodium channel. Biochemistry 24, 3554–3561. Saini, S.S., Chopra, A.K., Peterson, J.W., 1999. Melittin activates endogenous phospholipase D during cytolysis of human monocytic leukemia cells. Toxicon 37, 1605–1619.
98. Sakamoto, T., Repasky, W.T., Uchida, K., Hirata, A., Hirata, F., 1996. Modulation of cell death pathways to apoptosis and necrosis of H2O2-treated rat thymocytes by lipocortin I. Biochem. Biophys. Res. Commun. 220, 643–647.
99. Shier, W.T., 1979. Activation of high levels of endogenous phospholipase A2 in cultured cells. Proc. Natl. Acad. Sci. U.S.A. 76, 195–199.
100. Shaposhnikova, V.V., Egorova, M.V., Kudryavtsev, A.A., Levitman, M.Kh., Korystov, YuN., 1997. The effect of melittin on proliferation and death of thymocytes. FEBS Lett. 410, 285–288. Sharma, S.V., 1992. Melittin resistance: a counterselection for ras transformation. Oncogene 7, 193–201.
101. Sharma, S.V., 1993. Melittin-induced hyperactivation of phospholipase A2 activity and calcium influx in ras-transformed cells. Oncogene 8, 939–947.
102. Shipolini, R.A., 1984. Biochemistry of bee venom. In: Tu, T.A. (Ed.), Handbook of Natural Toxins Vol. 2. Insect Poisons, Allergens, and Other Invertebrate Venoms. Marcel Dekker Inc., New York and Basel, pp. 49–85.
103. Siegel, R.L., Miller, K.D., Jemal, A.,2016, Cancer statistics, CA Cancer J. Clin. 66 (2016) 7e30.
104. Siddiqui, I.A. Sanna, V., 2016, Impact of nanotechnology on the delivery of natural products for cancer prevention and therapy, Mol. Nutr. Food Res. 60 1330e1341.
105. Soletti, R.C., de Faria, G.P., Vernal, J., Terenzi, H., Anderluh, G., Borges, H.L., Moura-Neto, V., Gabilan, N.H., 2008. Potentiation of anticancer-drug cytotoxicity by sea anemone pore-forming proteins in human glioblastoma cells. Anticancer Drugs 19, 517–525.
106. Song, C.C., Lu, X., Cheng, B.B., Du, J., Li, B., Ling, C.Q., 2007. Effects of melittin on growth and angiogenesis of human hepatocellular carcinoma BEL-7402 cell xenografts in nude mice. Ai Zheng 26, 1315–1322.
107. Soman, N.R., Baldwin, S.L., Hu, G., Marsh, J.N., Lanza, G.M., Heuser, J.E., Arbeit, J.M., Wickline, S.A., Schlesinger, P.H., 2009. Molecularly targeted nanocarriers deliver the cytolytic peptide melittin specifically to tumor cells in mice, reducing tumor growth. J. Clin. Invest. 119, 2830–2842.
108. Son, D.J., Ha, S.J., Song, H.S., Lim, Y., Yun, Y.P., Lee, J.W., Moon, D.C., Park, Y.H., Park, B.S., Song, M.J., Hong, J.T., 2006. Melittin inhibits vascular smooth muscle cell proliferation through induction of apoptosis via suppression of nuclear factor-kappaB and Akt activation and enhancement of apoptotic protein expression. J. Pharmacol. Exp. Ther. 317, 627–634. Soroceanu, L., Gillespie, Y., Khazaeli, M.B., Sontheimer, H., 1998. Use of chlorotoxin for targeting of primary brain tumors. Cancer Res. 58, 4871–4879.
109. Stewart, B.W., Kleihues, P., 2003. World Cancer Report, second ed. IARC Press, Lyon. Stuhlmeier, K.M., 2007. Apis Mellifera venom and melittin block neither NF-kappa B-p50-DNA interactions nor the activation of NF-kappa B, instead they activate the transcription of proinflammatory genes and the release of reactive oxygen intermediates. J. Immunol. 179, 655–664.
110. Terra, R.M., Guimarães, J.A., Verli, H., 2007. Structural and functional behavior of biologically active monomeric melittin. J. Mol. Graph. Model. 25, 767–772.
111. Terwilliger, T.C., Eisenberg, D., 1982a. The structure of melittin. I. Structure determination and partial refinement. J. Biol. Chem. 257, 6010–6015.
112. Terwilliger, T.C., Eisenberg, D., 1982b. The structure of melittin. II. Interpretation of the structure. J. Biol. Chem. 257, 6016–6022.
113. Terwilliger, T.C., Weissman, L., Eisenberg, D., 1982. The structure of melittin in the form I crystals and its implication for melittin’s lytic and surface activities. Biophys. J. 37, 353–361.
114. Torre, L.A., Bray, F., Siegel, R.L., Ferlay, J., Lortet-Tieulent, J., Jemal, A., 2012, Global cancer statistics, CA Cancer J. Clin. 65 (2015) 87e108.
115. Tosteson, M.T., Holmes, S.J., Razin, M., Tosteson, D.C., 1985. Melittin lysis of red cells. J. Membr. Biol. 87, 35–44.
116. Van Den Berg, C.W., De Andrade, R.M., Magnoli, F.C., Marchbank, K.J., Tambourgi, D.V., 2002. Loxosceles spider venom induces metalloproteinase mediated cleavage of MCP/CD46 and MHCI and induces protection against C-mediated lysis. Immunology 107, 102–110.
117. Varanda, E.A., Monti, R., Tavares, D.C., 1999. Inhibitory effect of propolis and bee venom on the mutagenicity of some directand indirect-acting mutagens. Teratog. Carcinog. Mutagen. 19, 403–413.
118. Vogel, H., 1981. Incorporation of melittin into phosphatidylcholine bilayers. Study of binding and conformational changes. FEBS Lett. 134, 37–42.
119. Wang, W.X., Ji, Y.H., 2005. Scorpion venom induces glioma cell apoptosis in vivo and inhibits glioma tumor growth in vitro. J. Neurooncol. 73, 1–7.
120. Wang, S., Shen, P., Zhou, Y., Lu, Y., 2017, Diet phytochemicals and cutaneous carcinoma chemoprevention: a review, Pharmacol. Res. 119 327e346.
121. Watala, C., Gwoz´dzin´ ski, K., 1992. Melittin-induced alterations in dynamic properties of human red blood cell membranes. Chem. Biol. Interact. 82, 135–149.
122. Watala, C., Kowalczyk, J.K., 1990. Hemolytic potency and phospholipase activity of some bee and wasp venoms. Comp. Biochem. Physiol. C 97, 187–194.
123. Weston, K.M., Raison, R.L., 1998. Interaction of melittin with a human lymphoblastoid cell line, HMy2. J. Cell. Biochem. 68, 164–173.
124. Yang, R.S., Tang, C.H., Chuang, W.J., Huang, T.H., Peng, H.C., Huang, T.F., Fu, W.M., 2005. Inhibition of tumor formation by snake venom disintegrin. Toxicon 45, 661–669.
125. Zhang, Y., 2015, Why do we study animal toxins? Dongwuxue Yanjiu 36 183e222.
126. Zhu, H.G., Tayeh, I., Israel, L., Castagna, M., 1991. Different susceptibility of lung cell lines to inhibitors of tumor promotion and inducers of differentiation. J. Biol. Regul. Homeost. Agents 5, 52–58.
127. Zugazagoitia, J., Guedes, C., Ponce, S., Ferrer, I., Molina-Pinelo, S., Paz-Ares, L., 2016, Current challenges in cancer treatment, Clin. Ther. 38 1551e1566.