Cancer and Metastasis Reviews

, Volume 31, Issue 1–2, pp 173–194 | Cite as

Bee venom in cancer therapy

  • Nada OršolićEmail author


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.


Bee venom Tumors Cancer cells Melittin Phospholipase A2 


  1. 1.
    Habermann, E. (1972). Bee and wasp venoms. The biochemistry and pharmacology of their peptides and enzymes are reviewed. Science, 177, 314–322.PubMedCrossRefGoogle Scholar
  2. 2.
    Raghuraman, H., & Chattopadhyay, A. (2007). Melittin: a membrane-active peptide with diverse functions. Bioscience Reports, 27(4–5), 189S–223S.CrossRefGoogle Scholar
  3. 3.
    Kwon, Y. B., Lee, J. D., Lee, H. J., Han, H. J., Mar, W. C., Kang, S. K., Beitz, A. J., & Lee, J. H. (2001). Bee venom injection into an acupuncture point reduces arthritis associated edema and nociceptive responses. Pain, 90, 271–280.PubMedCrossRefGoogle Scholar
  4. 4.
    Park, H. J., Lee, S. H., Son, D. J., Oh, K. W., Kim, K. H., Song, H. S., Kim, G. J., Oh, G. T., Yoon, D. Y., & Hong, J. T. (2004). Antiarthritic effect of bee venom: inhibition of inflammation mediator generation by suppression of NF-kappaB through interaction with the p50 subunit. Arthritis and Rheumatism, 50(11), 3504–3515.PubMedCrossRefGoogle Scholar
  5. 5.
    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. Journal of Pharmacy and Pharmacology, 54(8), 1083–1089.PubMedCrossRefGoogle Scholar
  6. 6.
    Oršolić, N., Knežević, A., Šver, L., Terzić, S., Hackenberger, B. K., & Bašić, I. (2003). Influence of honey bee products on transplantable murine tumors. Veterinary and Comparative Oncology, 1(4), 216–226.PubMedCrossRefGoogle Scholar
  7. 7.
    Oršolić, N., Šver, L., Verstovšek, S., Terzić, S., & Bašić, I. (2003). Inhibition of mammary carcinoma cell proliferation in vitro and tumor growth in vivo by bee venom. Toxicon, 41(7), 861–870.PubMedCrossRefGoogle Scholar
  8. 8.
    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 Immunology, Immunotherapy, 53(5), 411–421.PubMedCrossRefGoogle Scholar
  9. 9.
    Moon, D. O., Park, S. Y., Heo, M. S., Kim, K. C., Park, C., & Ko, W. S. (2006). Key regulators in bee venom-induced apoptosis are Bcl-2 and caspase-3 in human leukemic U937 cells through downregulation of ERK and Akt. International Immunopharmacology, 6(12), 1796–1807.PubMedCrossRefGoogle Scholar
  10. 10.
    Varanda, E. A., & Tavares, D. C. (1998). Radioprotection: mechanism and radioprotective agents including honey bee venom. Venom Anim Toxins, 4(1), 5–21.Google Scholar
  11. 11.
    Varanda, E. A., Monti, R., & Tavares, D. C. (1999). Inhibitory effect of propolis and bee venom on the mutagenicity of some direct- and indirect-acting mutagens. Teratogenesis Carcinogenesis and Mutagenesis, 19(6), 403–413.CrossRefGoogle Scholar
  12. 12.
    Nam, K. W., Je, K. H., Lee, J. H., Han, H. J., Lee, H. J., Kang, S. K., & Mar, W. (2003). Inhibition of COX-2 activity and proinflammatory cytokines (TNF-alpha and IL-1beta) production by water-soluble sub-fractionated parts from bee (Apis mellifera) venom. Archives of Pharmacal Research, 26(5), 383–388.PubMedCrossRefGoogle Scholar
  13. 13.
    Kim, H. W., Kwon, Y. B., Ham, T. W., Roh, D. H., Yoon, S. Y., Lee, H. J., Han, H. J., Yang, I. S., Beitz, A. J., & Lee, J. H. (2003). Acupoint stimulation using bee venom attenuates formalin-induced pain behavior and spinal cord fos expression in rats. Journal of Veterinary and Medicine Science, 65(3), 349–355.CrossRefGoogle Scholar
  14. 14.
    Son, D. J., Lee, J. W., Lee, Y. H., Song, H. S., Lee, C. K., & Hong, J. T. (2007). Therapeutic application of anti-arthritis, pain-releasing, and anti-cancer effects of bee venom and its constituent compounds. Pharmacology & Therapeutics, 115(2), 246–270.CrossRefGoogle Scholar
  15. 15.
    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. Jounal of Pharmacology Science, 91(2), 95–104.CrossRefGoogle Scholar
  16. 16.
    Yin, C. S., Lee, H. J., Hong, S. J., Chung, J. H., & Koh, H. G. (2005). Microarray analysis of gene expression in chondrosarcoma cells treated with bee venom. Toxicon, 45(1), 81–91.PubMedCrossRefGoogle Scholar
  17. 17.
    Hu, H., Chen, D., Li, Y., & Zhang, X. (2006). Effect of polypeptides in bee venom on growth inhibition and apoptosis induction of the human hepatoma cell line SMMC-7721 in-vitro and Balb/c nude mice in-vivo. Journal of Pharmacy and Pharmacology, 58(1), 83–89.PubMedCrossRefGoogle Scholar
  18. 18.
    Han, S., Lee, K., Yeo, J., Kweon, H., Woo, S., Lee, M., Baek, H., Kim, S., & Park, K. (2007). Effect of honey bee venom on microglial cells nitric oxide and tumor necrosis factor-alpha production stimulated by LPS. Journal of Ethnopharmacology, 111(1), 176–181.PubMedCrossRefGoogle Scholar
  19. 19.
    Hong, S. J., Rim, G. S., Yang, H. I., Yin, C. S., Koh, H. G., Jang, M. H., Kim, C. J., Choe, B. K., & Chung, J. H. (2005). Bee venom induces apoptosis through caspase-3 activation in synovial fibroblasts of patients with rheumatoid arthritis. Toxicon, 46, 39–45.PubMedCrossRefGoogle Scholar
  20. 20.
    Yusuf, N., Irby, C., Katiyar, S. K., & Elmets, C. A. (2007). Photoprotective effects of green tea polyphenols. Photodermatology, Photoimmunology and Photomedicine, 23, 48–56.PubMedCrossRefGoogle Scholar
  21. 21.
    Leuschner, C., & Hansel, W. (2004). Membrane disrupting lytic peptides for cancer treatments. Current Pharmaceutical Desing, 10, 2299–2310.CrossRefGoogle Scholar
  22. 22.
    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(12), 741–744.PubMedGoogle Scholar
  23. 23.
    Eisenberg, D. (1984). Three-dimensional structure of membrane and surface proteins. Annual Review of Biochemistry, 53, 595–623.PubMedCrossRefGoogle Scholar
  24. 24.
    Wade, D., Boman, A., Wahlin, B., Drain, C. M., Andreu, D., Boman, H. G., & Merrifield, R. B. (1990). The Proceedings of the National Academy of Sciences USA, 87, 4761–4765.CrossRefGoogle Scholar
  25. 25.
    Katsu, T., Kuroko, M., Morikawa, T., Sanchika, K., Fujita, Y., Yamamura, H., & Uda, M. (1989). Mechanism of membrane damage induced by the amphipathic peptides gramicidin S and melittin. Biochimica et Biophysica Acta, 983, 135–141.PubMedCrossRefGoogle Scholar
  26. 26.
    Dempsey, C. E. (1990). The actions of melittin on membranes. Biochimica et Biophysica Acta, 1031, 143–161.PubMedGoogle Scholar
  27. 27.
    Ladokhin, A. S., Selsted, M. E., & White, S. H. (1997). Sizing membrane pores in lipid vesicles by leakage of co-encapsulated markers: pore formation by melittin. Biophysical Journal, 72, 1762–1766.PubMedCrossRefGoogle Scholar
  28. 28.
    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. Molecular and Cellular Endocrinology, 51, 1–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Hui, S. W., Stewart, C. M., & Cherry, R. J. (1990). Biochimica et Biophysica Acta, 1023, 335–340.PubMedCrossRefGoogle Scholar
  30. 30.
    Carrasquer, G., Li, M., Yang, S., & Schwartz, M. (1998). Effect of melittin on PD, resistance and short-circuit current in the frog gastric mucosa. Biochimica et Biophysica Acta, 1369, 346–354.PubMedCrossRefGoogle Scholar
  31. 31.
    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.PubMedCrossRefGoogle Scholar
  32. 32.
    Mau, S. E., & Vilhardt, H. (1997). Cross talk between substance P and melittin-activated cellular signaling pathways in rat lactotroph-enriched cell cultures. Journal of Neurochemistry, 69, 762–772.PubMedCrossRefGoogle Scholar
  33. 33.
    Knowles, B., & Farndale, R. W. (1988). Activation of insect cell adenylate cyclase by Bacillus thuringiensis delta-endotoxins and melittin. Toxicity is independent of cyclic AMP. Biochemistry Journal, 253, 235–241.Google Scholar
  34. 34.
    Haber, M. T., Fukui, T., Lebowitz, M. S., & Lowenstein, J. M. (1991). Activation of phosphoinositide-specific phospholipase C delta from rat liver by polyamines and basic proteins. Archives of Biochemistra and Biophysics, 288, 243–249.CrossRefGoogle Scholar
  35. 35.
    Haase, I., Czarnetzki, B. M., & Rosenbach, T. (1996). Thrombin and melittin activate phospholipase C in human HaCaT keratinocytes. Experimental Dermatology, 5, 84–88.PubMedCrossRefGoogle Scholar
  36. 36.
    Lee, S. Y., Yeo, E., & Choi, M.-U. (1998). Phospholipase D activity in L1210 cells: a model for oleate-activated phospholipase D in intact mammalian cells. Biochemistry and Biophysics Reserch Communication, 244, 825–831.CrossRefGoogle Scholar
  37. 37.
    Liu, S.-Y., Tappia, P. S., Dai, J., Williams, S. A., & Panagia, V. (1998). Phospholipase A2-mediated activation of phospholipase D in rat heart sarcolemma. Journal of Molecular and Cellular Cardiology, 30, 1203–1214.PubMedCrossRefGoogle Scholar
  38. 38.
    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.PubMedCrossRefGoogle Scholar
  39. 39.
    Fukushima, N., Kohno, M., Kato, T., Kawamoto, S., Okuda, K., Misu, Y., & Ueda, H. (1998). Melittin, a metabostatic peptide inhibiting Gs activity. Peptides, 19(5), 811–819.PubMedCrossRefGoogle Scholar
  40. 40.
    Dennis, E. A. (1994). Diversity of group types, regulation, and function of phospholipase A2. Journal of Biological Chemistry, 269, 13057–13060.PubMedGoogle Scholar
  41. 41.
    Six, D. A., & Dennis, E. A. (2000). The expanding superfamily of phospholipase A(2) enzymes: classification and characterization. Biochimica et Biophysica Acta, 1488, 1–19.PubMedGoogle Scholar
  42. 42.
    Valentin, E., & Lambeau, G. (2000). What can venom phospholipases A(2) tell us about the functional diversity of mammalian secreted phospholipases A(2)? Biochimie, 82, 815–831.PubMedCrossRefGoogle Scholar
  43. 43.
    Kudo, I., & Murakami, M. (2002). Phospholipase A2 enzymes. Prostaglandins & Other Lipid Mediators, 68–69, 3–58.CrossRefGoogle Scholar
  44. 44.
    Lambeau, G., Schmid-Alliana, A., Lazdunski, M., & Barhanin, J. (1990). Identification and purification of a very high affinity binding protein for toxic phospholipases A2 in skeletal muscle. Journal of Biology and Chemistry, 265, 9526–9532.Google Scholar
  45. 45.
    Lambeau, G., & Lazdunski, M. (1999). Receptors for a growing family of secreted phospholipases A2. Trends in Pharmacology Science, 20, 162–170.CrossRefGoogle Scholar
  46. 46.
    Fonteh, A. N., Atsumi, G., LaPorte, T., & Chiltonm, F. H. (2000). Secretory phospholipase A2 receptor-mediated activation of cytosolic phospholipase A2 in murine bone marrow-derived mast cells. Journal of Immunology, 165, 2773–2782.Google Scholar
  47. 47.
    Graler, M. H., & Goetzl, E. J. (2002). Lysophospholipids and their G protein-coupled receptors in inflammation and immunity. Biochimica et Biophysica Acta, 1582, 168–174.PubMedGoogle Scholar
  48. 48.
    Kabarowski, J. H., Xu, Y., & Witte, O. N. (2002). Lysophosphatidyl choline as a ligand for immunoregulation. Biochemistry and Pharmacology, 64, 161–167.CrossRefGoogle Scholar
  49. 49.
    Andresen, T. L., Jensen, S. S., Madsen, R., & Jorgensen, K. (2005). Synthesis and biological activity of anticancer ether lipids that are specifically released by phospholipase A2 in tumor tissue. Journal of Medicinal Chemistry, 48, 7305–7314.PubMedCrossRefGoogle Scholar
  50. 50.
    Ruiter, G. A., Verheij, M., Zerp, S. F., & van Blitterswijk, W. J. (2001). Alkyl-lysophospholipids as anticancer agents and enhancers of radiation-induced apoptosis. International Journal of Radiation Oncology, Biology, Physics, 49, 415–419.PubMedCrossRefGoogle Scholar
  51. 51.
    Ruiter, G. A., Zerp, S. F., Bartelink, H., van Blitterswijk, W. J., & Verheij, M. (2003). Anti-cancer alkyl-lysophospholipids inhibit the phosphatidylinositol 3-kinase-Akt/PKB survival pathway. Anti-Cancer Drugs, 14, 167–173.PubMedCrossRefGoogle Scholar
  52. 52.
    Samadder, P., Bittman, R., Byun, H. S., & Arthur, G. (2004). Synthesis and use of novel ether phospholipid enantiomers to probe the molecular basis of the antitumor effects of alkyllysophospholipids: correlation of diferential activation of c-Jun NH(2)-terminal protein kinase with antiproliferative effects in neuronal tumor cells. Journal of Medicinal Chemistry, 47, 2710–2713.PubMedCrossRefGoogle Scholar
  53. 53.
    Winder, D., Günzburg, W. H., Erfle, V., & Salmons, B. (1998). Expression of antimicrobial peptides has an antitumour effect in human cells. Biochemical and Biophysical Resech Commununication, 242(3), 608–612.CrossRefGoogle Scholar
  54. 54.
    Oršolić, N., Terzić, S., Šver, L., & Bašić, I. (2005). Honey-bee products in preventive and/or therapy of murine transplantable tumours. Journal of the Science of Food and Agriculture, 85, 363–370.CrossRefGoogle Scholar
  55. 55.
    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. The FASEB Journal, 8, 237–246.Google Scholar
  56. 56.
    Li, B., Gu, W., Zhang, C., Huang, X. Q., Han, K. Q., & Ling, C. Q. (2006). Growth arrest and apoptosis of the human hepatocellular carcinoma cell line BEL-7402 induced by melittin. Onkologie, 29(8–9), 367–371.PubMedCrossRefGoogle Scholar
  57. 57.
    Chu, S. T., Cheng, H. H., Huang, C. J., Chang, H. C., Chi, C. C., Su, H. H., Hsu, S. S., Wang, J. L., Chen, I. S., Liu, S. I., Lu, Y. C., Huang, J. K., Ho, C. M., & Jan, C. R. (2007). Phospholipase A2-independent Ca2+ entry and subsequent apoptosis induced by melittin in human MG63 osteosarcoma cells. Life Science, 80(4), 364–369.CrossRefGoogle Scholar
  58. 58.
    Zhang, C., Li, B., Lu, S. Q., Li, Y., Su, Y. H., & Ling, C. Q. (2007). Effects of melittin on expressions of mitochondria membrane protein 7A6, cell apoptosis-related gene products Fas and Fas ligand in hepatocarcinoma cells. Zhong Xi Yi Jie He Xue Bao, 5, 559–563.PubMedCrossRefGoogle Scholar
  59. 59.
    Liu, S., Yu, M., He, Y., Xiao, L., Wang, F., Song, C., Sun, S., Ling, C., & Xu, Z. (2008). Melittin prevents liver cancer cell metastasis through inhibition of the Rac1-dependent pathway. Hepatology, 47(6), 1964–1973.PubMedCrossRefGoogle Scholar
  60. 60.
    Sharma, S. V. (1993). Melittin-induced hyperactivation of phospholipase A2 activity and calcium influx in ras-transformed cells. Oncogene, 8(4), 939–947.PubMedGoogle Scholar
  61. 61.
    Sharma, S. V. (1992). Melittin resistance: a counterselection for ras transformation. Oncogene, 7, 193–201.PubMedGoogle Scholar
  62. 62.
    Oršolić, N. (2009). Potentiation of Bleomycin lethality on HeLa and V79 cells by bee venom. Arhives of Industrial Hygiene and Toxicology, 60, 317–326.CrossRefGoogle Scholar
  63. 63.
    Tsuro, T., Iida, H., Tsukagoshi, S., & Sakurai, Y. (1982). Increased accumulation of vineristine and adriamycin in drug-resistant P388 tumor cells following with calcium antagonists and calmodulin inhibitors. Cancer Reserch, 42, 4730–4733.Google Scholar
  64. 64.
    Chafouleas, J. G., Botton, W. E., & Means, A. R. (1984). Potentiation of bleomycin lethality by anti-calmodulin drugs: a role for calmodulin in DNA repair. Science, 224, 1346–1348.PubMedCrossRefGoogle Scholar
  65. 65.
    Lee, G. L., & Hait, W. N. (1985). Growth inhibition of C6 astrocytoma cells by inhibitions of calmodulin. Life Science, 36, 347–354.CrossRefGoogle Scholar
  66. 66.
    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. Molecular Pharmacology, 27(3), 387–393.PubMedGoogle Scholar
  67. 67.
    Killion, J. J., & Dunn, J. D. (1986). Differential cytolysis of murine spleen, bone-marrow and leukemia cells by melittin reveals differences in membrane topography. Biochemical and Biophysical Research Communication, 139, 222–227.CrossRefGoogle Scholar
  68. 68.
    Chueng, W. Y. (1982). Calmodulin: an overview. Federation Proceedings, 41(7), 2253–2257.Google Scholar
  69. 69.
    Gerst, J. E., & Salomon, Y. (1987). Inhibition by melittin and fluphenazine of melanotropin receptor function and adenylate cyclase in M2R melanoma cell membranes. Endocrinology, 121(5), 1766–1772.PubMedCrossRefGoogle Scholar
  70. 70.
    Vento, R., D'Alessandro, N., Giuliano, M., Lauricella, M., Carabillò, M., & Tesoriere, G. (2000). Induction of apoptosis by arachidonic acid in human retinoblastoma Y79 cells: involvement of oxidative stress. Experimental Eye Reserch, 70(4), 503–517.CrossRefGoogle Scholar
  71. 71.
    Arioka, M., Cheon, S. H., Ikeno, Y., Nakashima, S., & Kitamoto, K. (2005). A novel neurotrophic role of secretory phospholipases A2 for cerebellar granule neurons. FEBS Letters, 579(12), 2693–2701.PubMedCrossRefGoogle Scholar
  72. 72.
    Shaposhnikova, V. V., Egorova, M. V., Kudryavtsev, A. A., Levitman, M. Kh., & Korystov, Yu. N. (1997). The effect of melittin on proliferation and death of thymocytes. FEBS Letters, 410(2–3), 285–288.PubMedCrossRefGoogle Scholar
  73. 73.
    Oršolić, N., Šver, L., Bendelja, K., & Bašić, I. (2001). Antitumor activity of bee venom. Periodicum Biologorum, 103, 49–54.Google Scholar
  74. 74.
    Weston, K. M., & Raison, R. L. (1998). Interaction of melittin with a human lymphoblastoid cell line, HMy2. Journal Cell Biochemistry, 68(2), 164–173.CrossRefGoogle Scholar
  75. 75.
    Tosteson, M. T., & Tosteson, D. C. (1981). The sting: melittin forms channels in lipid bilayers. Biophysics Journal, 36, 109–116.CrossRefGoogle Scholar
  76. 76.
    Vogel, H., & Jähnig, F. (1986). The structure of melittin in membranes. Biophysical Journal, 50(4), 573–582.PubMedCrossRefGoogle Scholar
  77. 77.
    Laine, R. O., Morgan, B. P., & Esser, A. F. (1988). Comparison between complement and melittin hemolysis: anti-melittin antibodies inhibit complement lysis. Biochemistry, 27(14), 5308–5314.PubMedCrossRefGoogle Scholar
  78. 78.
    Pawlak Pawlak, M., Meseth, U., Dhanapal, B., Mutter, M., & Vogel, H. (1994). Template-assembled melittin: structural and functional characterization of a designed, synthetic channel-forming protein. Protein Science, 3(10), 1788–1805.CrossRefGoogle Scholar
  79. 79.
    Benachir, T., & Lafleur, M. (1995). Study of vesicle leakage induced by melittin. Biochimica et Biophysica Acta, 1235(2), 452–460.PubMedCrossRefGoogle Scholar
  80. 80.
    DeGrado, W. F., Musso, G. F., Lieber, M., Kaiser, E. T., & Kézdy, F. J. (1982). Kinetics and mechanism of hemolysis induced by melittin and by a synthetic melittin analogue. Biophysical Journal, 37(1), 329–338.PubMedCrossRefGoogle Scholar
  81. 81.
    Matsuzaki, K., Yoneyama, S., & Miyajima, K. (1997). Pore formation and translocation of melittin. Biophysical Journal, 73(2), 831–838.PubMedCrossRefGoogle Scholar
  82. 82.
    Shier, W. T. (1979). Activation of high levels of endogenous phospholipase A2 in cultured cells. The Proceedings of the National Academy of Sciences USA, 76(1), 195–199.CrossRefGoogle Scholar
  83. 83.
    Fletcher, J. E., & Jiang, M. S. (1993). Possible mechanisms of action of cobra snake venom cardiotoxins and bee venom melittin. Toxicon, 31(6), 669–695.PubMedCrossRefGoogle Scholar
  84. 84.
    Sarin, A., Adams, D. H., & Henkart, P. A. (1993). Protease inhibitors selectively block T cell receptor-triggered programmed cell death in a murine T cell hybridoma and activated peripheral T cells. The Journal of Experimental Medicine, 178(5), 1693–1700.PubMedCrossRefGoogle Scholar
  85. 85.
    Squìer, M. K., Miller, A. C., Malkinson, A. M., & Cohen, J. J. (1994). Calpain activation in apoptosis. Journal of Cell Physiology, 159(2), 229–237.CrossRefGoogle Scholar
  86. 86.
    Goodman, S. R., Krebs, K. E., Whitfield, C. F., Riederer, B. M., & Zagon, I. S. (1988). Spectrin and related molecules. CRC Critical Reviews in Biochemistry, 23(2), 171–234.PubMedCrossRefGoogle Scholar
  87. 87.
    Fox, J. E. B., Reynolds, C. C., Morrow, J. S., & Phillips, D. R. (1987). Spectrin is associated with membrane-bound actin filaments in platelets and is hydrolyzed by the Ca2+-dependent protease during platelet activation. Blood, 69, 537–545.PubMedGoogle Scholar
  88. 88.
    Harris, A. S., Croall, D. E., & Morrow, J. S. (1988). The calmodulin-binding site in alpha-fodrin is near the calcium-dependent protease-I cleavage site. Journal of Biological Chemistry, 263, 15754–15761.PubMedGoogle Scholar
  89. 89.
    Harris, A. S., & Morrow, J. S. (1990). Calmodulin and calcium-dependent protease I coordinately regulate the interaction of fodrin with actin. The Proceedings of the National Academy of Sciences USA, 87, 3009–3013.CrossRefGoogle Scholar
  90. 90.
    Arora, A.S., deGroen, P., Emori, Y., Gores, G.J. (1996) A cascade of degradative hydrolase activity contributes to hepatocyte necrosis during anoxia. The American Journal of Physiology, 270(2 Pt1), G238–G245.Google Scholar
  91. 91.
    Wu, Y. L., Jiang, X. R., Newland, A. C., & Kelsey, S. M. (1998). Failure to activate cytosolic phospholipase A2 causes TNF resistance in human leukemic cells. Journal of Immunology, 160(12), 5929–5935.Google Scholar
  92. 92.
    Midoux, P., Mayer, R., & Monsigny, M. (1995). Membrane permeabilization by alpha-helical peptides: a flow cytometry study. Biochimica et Biophysica Acta, 1239, 249–256.PubMedCrossRefGoogle Scholar
  93. 93.
    Clapp, L. E., Klette, K. L., DeCoster, M. A., Bernton, E., Petras, J. M., Dave, J. R., Laskosky, M. S., Smallridge, R. C., & Tortella, F. C. (1995). Phospholipase A2-induced neurotoxicity in vitro and in vivo in rats. Brain Reserch, 693, 101–111.CrossRefGoogle Scholar
  94. 94.
    Lee, S. Y., Park, H. S., Lee, S. J., & Choi, M. U. (2001). Melittin exerts multiple effects on the release of free fatty acids from L1210 cells: lack of selective activation of phospholipase A2 by melittin. Archives of Biochemistry and Biophysics, 389(1), 57–67.PubMedCrossRefGoogle Scholar
  95. 95.
    Mihajlovic, M., & Lazaridis, T. (2010). Antimicrobial peptides in toroidal and cylindrical pores. Biochimica et Biophysica Acta, 1798(8), 1485–1493.PubMedCrossRefGoogle Scholar
  96. 96.
    Putz, T., Ramoner, R., Gander, H., Rahm, A., Bartsch, G., & Thurnher, M. (2006). Antitumor action and immune activation through cooperation of bee venom secretory phospholipase A2 and phosphatidylinositol-(3,4)-bisphosphate. Cancer Immunology, Immunotherapy, 55(11), 1374–1383.PubMedCrossRefGoogle Scholar
  97. 97.
    Engers, R., & Gabbert, H. E. (2000). Mechanisms of tumor metastasis: cell biological aspects and clinical implications. Journal of Cancer Reserch and Clinical Oncology, 126, 682–692.CrossRefGoogle Scholar
  98. 98.
    Lester, B. R., & McCarthy, J. B. (1992). Tumor cell adhesion to the extracellular matrix and signal transduction mechanisms implicated in tumor cell motility, invasion and metastasis. Cancer Metastasis Review, 11, 31–44.CrossRefGoogle Scholar
  99. 99.
    Cho, H. J., Jeong, Y. J., Park, K. K., Park, Y. Y., Chung, I. K., Lee, K. G., Yeo, J. H., Han, S. M., Bae, Y. S., & Chang, Y. C. (2010). Bee venom suppresses PMA-mediated MMP-9 gene activation via JNK/p38 and NF-kappaB-dependent mechanisms. Journal of Ethnopharmacology, 127(3), 662–668.PubMedCrossRefGoogle Scholar
  100. 100.
    Park, J. H., Jeong, Y. J., Park, K. K., Cho, H. J., Chung, I. K., Min, K. S., Kim, M., Lee, K. G., Yeo, J. H., Park, K. K., & Chang, Y. C. (2010). Melittin suppresses PMA-induced tumor cell invasion by inhibiting NF-kappaB and AP-1-dependent MMP-9 expression. Molecular Cells, 29(2), 209–215.CrossRefGoogle Scholar
  101. 101.
    Zetter, B. R. (1990). The cellular basis of site-specific tumor metastasis. The New England Journal of Medicine, 322, 605–612.PubMedCrossRefGoogle Scholar
  102. 102.
    Tang, D. G., & Honn, K. V. (1994). Adhesion molecules and tumor metastasis: an update. Invasion & Metastasis, 14, 109–122.Google Scholar
  103. 103.
    Kannagi, R. (1997). Carbohydrate-mediated cell adhesion involved in hematogenous metastasis of cancer. Glycoconjugate Journal, 14, 577–584.PubMedCrossRefGoogle Scholar
  104. 104.
    Oršolić, N., & Bašić, I. (2003). Apoptosis and necrosis as possible mechanisms for antitumor activity of bee venom. Mellifera, 3, 34–42.Google Scholar
  105. 105.
    Ćurić, S., Oršolić, N., Krsnik, B., Balenović, T., Valpotić, I., Sulimanović, Đ., & Bašić, I. (1993). Immune responses of a mouse to bee venom. Stočarstvo, 47, 131–136.Google Scholar
  106. 106.
    Huh, J. E., Baek, Y. H., Lee, M. H., Choi, D. Y., Park, D. S., & Lee, J. D. (2010). Bee venom inhibits tumor angiogenesis and metastasis by inhibiting tyrosine phosphorylation of VEGFR-2 in LLC-tumor-bearing mice. Cancer Letters, 292(1), 98–110.PubMedCrossRefGoogle Scholar
  107. 107.
    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. Annals of Oncology, 16(1), 109–115.PubMedCrossRefGoogle Scholar
  108. 108.
    Hansel, W., Enright, F., & Leuschner, C. (2007). Destruction of breast cancers and their metastases by lytic peptide conjugates in vitro and in vivo. Molecular and Cellular Endocrinology, 260–262, 183–189.PubMedCrossRefGoogle Scholar
  109. 109.
    Hansel, W., Leuschner, C., & Enright, F. (2007). Conjugates of lytic peptides and LHRH or betaCG target and cause necrosis of prostate cancers and metastases. Molecular and Cellular Endocrinology, 269, 26–33.PubMedCrossRefGoogle Scholar
  110. 110.
    Kumar, C. S., Leuschner, C., Doomes, E. E., Henry, L., Juban, M., & Hormes, J. (2004). Efficacy of lytic peptide bound magnetite nanoparticles in destroying breast cancer cells. Journal of Nanoscience and Nanotechnology, 4, 245–249.PubMedCrossRefGoogle Scholar
  111. 111.
    Jaynes, J. M., Julian, G. R., Jeffers, G. W., White, K. L., & Enright, F. M. (1989). Peptide Research, 2, 157–160.PubMedGoogle Scholar
  112. 112.
    Moore, A. J., Devine, D. A., Bibby, M. C., Moore, A. J., Beazley, W. D., Bibby, M. C., & Devine, D. A. (1996). Antimicrobial activity of cecropins. Journal of Antimicrobial Chemotherapy, 37(6), 1077–1089.PubMedCrossRefGoogle Scholar
  113. 113.
    Werkmeister, J. A., Kirkpatrick, A., McKenzie, J. A., & Rivett, D. E. (1993). The effect of sequence variations and structure on the cytolytic activity of melittin peptides. Biochimica et Biophysica Acta, 1157, 50–54.PubMedCrossRefGoogle Scholar
  114. 114.
    Ferguson, E. L., & Duncan, R. (2009). Dextrin-phospholipase A2: synthesis and evaluation as a bioresponsive anticancer conjugate. Biomacromolecules, 10(6), 1358–1364.PubMedCrossRefGoogle Scholar
  115. 115.
    Barrajón-Catalán, E., Menéndez-Gutiérrez, M. P., Falco, A., Carrato, A., Saceda, M., & Micol, V. (2010). Selective death of human breast cancer cells by lytic immunoliposomes: correlation with their HER2 expression level. Cancer Letters, 290(2), 192–203.PubMedCrossRefGoogle Scholar
  116. 116.
    Baban, D. F., & Seymour, L. W. (1998). Control of tumor vascular permeability. Advanced Drug Delivery Reviews, 34, 109–119.PubMedCrossRefGoogle Scholar
  117. 117.
    Shubik, P. (1982). Vascularization of tumors: a review. Journal of Cancer Reserch and Clinical Oncology, 103, 211–226.CrossRefGoogle Scholar
  118. 118.
    Rubin, P., & Casarett, G. (1966). Microcirculation of tumors. I. Anatomy, function, and necrosis. Clinical Radiology, 17, 220–229.PubMedCrossRefGoogle Scholar
  119. 119.
    Hobbs, S. K., Monsky, W. L., Yuan, F., Roberts, W. G., Griffith, L., Torchilin, V. P., & Jain, R. K. (1998). Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. The Proceedings of the National Academy of Sciences USA, 95, 4607–4612.CrossRefGoogle Scholar
  120. 120.
    Soman, N. R., Baldwin, S. L., Hu, G., Marsh, J. N., Lanza, G. M., Heuser, J. E., Arbeit, J. M., & Wickline, S. A. (2009). Schlesinger PH. Molecularly targeted nanocarriers deliver the cytolytic peptide melittin specifically to tumor cells in mice, reducing tumor growth. Journal of Clincal Investigation, 119(9), 2830–2842.CrossRefGoogle Scholar
  121. 121.
    Holle, L., Song, W., Holle, E., Wei, Y., Li, J., Wagner, T. E., & Yu, X. (2009). In vitro- and in vivo-targeted tumor lysis by an MMP2 cleavable melittin-LAP fusion protein. International Journal of Oncology, 35(4), 829–835.PubMedGoogle Scholar
  122. 122.
    Gawronska, B., Leuschner, C., Enright, F. M., & Hansel, W. (2002). Effects of a lytic peptide conjugated to beta HCG on ovarian cancer: studies in vitro and in vivo. Gynecologic Oncology, 85(1), 45–52.PubMedCrossRefGoogle Scholar
  123. 123.
    Leuschner, C., Enright, F. M., Melrose, P. A., & Hansel, W. (2001). Targeted destruction of androgen-sensitive and -insensitive prostate cancer cells and xenografts through luteinizing hormone receptors. Prostate, 46, 116–126.PubMedCrossRefGoogle Scholar
  124. 124.
    Hansel, W., Leuschner, C., Gawronska, B., & Enright, F. M. (2001). Targeted destruction of prostate cancer cells and xenografts by lytic peptide-LH. Reproductive Biology, 1, 20–32.PubMedGoogle Scholar
  125. 125.
    Sancar, A., Lindsey-Boltz, L. A., Unsal-Kacmaz, K., & Linn, S. (2004). Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annual Review of Biochemistry, 73, 39–85.PubMedCrossRefGoogle Scholar
  126. 126.
    Hait, W. N., Cadman, E., Benz, C., Cole, J., & Weiss, B. (1983). Inhibition of cyclic nucleotide phosphodiesterase and calmodulin. Proceedings of the American Association for Cancer Research, 2, 5–9.Google Scholar
  127. 127.
    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 Chemotherapy and Pharmacology, 14, 202–205.PubMedCrossRefGoogle Scholar
  128. 128.
    Hait, W. N., & Lee, G. L. (1985). Characteristics of the cytotoxic effects of the phenothiazine class of calmodulin antagonists. Biochemical Pharmacology, 34(22), 3973–3978.PubMedCrossRefGoogle Scholar
  129. 129.
    Okumara, K., Kato, T., Ito, J., & Tanaka, R. (1982). Inhibition by calmodulin antagonists of glioblast DNA synthesis and morphological changes induced by glial maturation factor. Developmental Brain Reserch, 255, 661–665.Google Scholar
  130. 130.
    Means, A. R., Chafouleas, J. A., Lagace, L., Lai, E., & Stein, J. P. (1982). Multiple roles for calmodulin in the regulation of eukarryotic cell metabolism. In Gene regulation (pp. 307–326). New York: Academic.Google Scholar
  131. 131.
    Chafouleas, J. G., Bolton, W. E., Hidaka, H., Boyd, A. E., & Means, A. R. (1982). Calmodulin and the cell cycle: involvement in regulation of cell cycle progression. Cell, 28, 41–50.PubMedCrossRefGoogle Scholar
  132. 132.
    Gamapathi, R., & Grabowski, D. (1983). Enhancement of sensitivity to adriamyc in resistant P388 leukemia by the calmodulin inhibitor, trifluoperazine. Cancer Reserch, 43, 3696–3699.Google Scholar
  133. 133.
    Rahmanzadeh, R., Rai, P., Celli, J. P., Rizvi, I., Baron-Lühr, B., Gerdes, J., & Hasan, T. (2010). Ki-67 as a molecular target for therapy in an in vitro three-dimensional model for ovarian cancer. Cancer Reserch, 70(22), 9234–9242.CrossRefGoogle Scholar
  134. 134.
    Bullwinkel, J., Baron-Lühr, B., Lüdemann, A., Wohlenberg, C., Gerdes, J., & Scholzen, T. (2006). Ki-67 protein is associated with ribosomal RNA transcription in quiescent and proliferating cells. Journal of Cell Physiology, 206(3), 624–635.CrossRefGoogle Scholar
  135. 135.
    Yang, Z. L., Ke, Y. Q., Xu, R. X., & Peng, P. (2007). Melittin inhibits proliferation and induces apoptosis of malignant human glioma cells. Nan Fang Yi Ke Da Xue Xue Bao, 27(11), 1775–1777.PubMedGoogle Scholar
  136. 136.
    Balk, S. D., Polimeni, P. I., Hoon, B. S., Lestourgeon, D. N., & Mitchell, R. S. (1979). Proliferation of Rous sarcoma virus-infected, but not of normal chicken fibroblasts in a medium of reduced calcium and magnesium concentration. The Proceedings of the National Academy of Sciences USA, 76, 3913–3916.CrossRefGoogle Scholar
  137. 137.
    Whitfield, J. F., Boynton, A. L., Macmanus, J. P., Sicorska, M., & Tsang, B. K. (1979). The regulation of cell proliferation by calcium and cyclic AMP. Molecular and Cellular Biochemistry, 27, 155–179.PubMedCrossRefGoogle Scholar
  138. 138.
    Zhao, M., Brunk, U. T., & Eaton, J. W. (2001). Delayed oxidant-induced cell death involves activation of phospholipase A2. FEBS Letters, 509(3), 399–404.PubMedCrossRefGoogle Scholar
  139. 139.
    Li, B., Li, L. Y., Luo, X., & Wang, X. (2001). Endonuclease G is an apoptotic DNase when released from mitochondria. Nature, 412, 95–99.PubMedCrossRefGoogle Scholar
  140. 140.
    Miramar, M. D., Costantini, P., Ravagnan, L., Saraiva, L. M., Haouzi, D., Brothers, G., Penninger, J. M., Peleato, M. L., Kroemer, G., & Susin, S. A. (2001). NADH oxidase activity of mitochondrial apoptosis-inducing factor. Journal of Biological Chemistry, 276(19), 16391–16398.PubMedCrossRefGoogle Scholar
  141. 141.
    Kroemer, G., & Martin, S. J. (2005). Caspase-independent cell death. Nature Medicine, 11(7), 725–730.PubMedCrossRefGoogle Scholar
  142. 142.
    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. (2008). The role of mitochondria in bee venom-induced apoptosis in human breast cancer MCF7 cells. Vivo, 22(2), 237–245.Google Scholar
  143. 143.
    Ip, SW., Wei, HC., Lin, JP., Kuo, HM., Liu, KC., Hsu, SC., Yang, JS., Mei-Dueyang, Chiu, TH., Han, SM., Chung, JG (2008a) Bee venom induced cell cycle arrest and apoptosis in human cervical epidermoid carcinoma Ca Ski cells. Anticancer Research, 28(2A), 833–842.Google Scholar
  144. 144.
    Moon, D. O., Park, S. Y., Choi, Y. H., Kim, N. D., Lee, C., & Kim, G. Y. (2008). Melittin induces Bcl-2 and caspase-3-dependent apoptosis through downregulation of Akt phosphorylation in human leukemic U937 cells. Toxicon, 51(1), 112–120.PubMedCrossRefGoogle Scholar
  145. 145.
    Wang, C., Chen, T., Zhang, N., Yang, M., Li, B., Lu, X., Cao, X., & Ling, C. (2009). Melittin, a major component of Bee Venom, sensitizes human hepatocellular carcinoma cells to TRAIL-induced apoptosis by activating CaMKII-TAK1-JNK/p38 and inhibiting IKK-NFkappa B. Journal of Biological Chemistry, 284(6), 3804–3813.PubMedCrossRefGoogle Scholar
  146. 146.
    Grisotto, L. S., Mendes, G. E., Castro, I., Baptista, M. A., Alves, V. A., Yu, L., & Burdmann, E. A. (2006). Mechanisms of bee venom-induced acute renal failure. Toxicon, 48(1), 44–54.PubMedCrossRefGoogle Scholar
  147. 147.
    Putz, T., Ramoner, R., Gander, H., Rahm, A., Bartsch, G., Bernardo, K., Ramsay, S., & Thurnher, M. (2007). Bee venom secretory phospholipase A2 and phosphatidylinositol-homologues cooperatively disrupt membrane integrity, abrogate signal transduction and inhibit proliferation of renal cancer cells. Cancer Immunology, Immunotherapy, 56(5), 627–640.PubMedCrossRefGoogle Scholar
  148. 148.
    Andreae, S., Buisson, S., & Triebel, F. (2003). MHC class II signal transduction in human dendritic cells induced by a natural ligand, the LAG-3 protein (CD223). Blood, 102, 2130–2137.PubMedCrossRefGoogle Scholar
  149. 149.
    Appel, S., Rupf, A., Weck, M. M., Schoor, O., Brummendorf, T. H., Weinschenk, T., Grunebach, F., & Brossart, P. (2005). Effects of imatinib on monocyte-derived dendritic cells are mediated by inhibition of nuclear factor-kappaB and Akt signaling pathways. Clinical Cancer Reserch, 11, 1928–1940.CrossRefGoogle Scholar
  150. 150.
    Del Prete, A., Vermi, W., Dander, E., Otero, K., Barberis, L., Luini, W., Bernasconi, S., Sironi, M., Santoro, A., Garlanda, C., Facchetti, F., Wymann, M. P., Vecchi, A., Hirsch, E., Mantovani, A., & Sozzani, S. (2004). Defective dendritic cell migration and activation of adaptive immunity in I3Kgamma-deficient mice. EMBO Journal, 23, 3505–3515.PubMedCrossRefGoogle Scholar
  151. 151.
    Payrastre, B., Missy, K., Giuriato, S., Bodin, S., Plantavid, M., & Gratacap, M. (2001). Phosphoinositides: key players in cell signalling, in time and space. Cellular Signalling, 13, 377–387.PubMedCrossRefGoogle Scholar
  152. 152.
    Toker, A. (2002). Phosphoinositides and signal transduction. Cellular and Molecular Life Science, 59, 761–779.CrossRefGoogle Scholar
  153. 153.
    Gille, H., & Downward, J. (1999). Multiple ras effector pathways contribute to G(1) cell cycle progression. Journal of Biological Chemistry, 274, 22033–22040.PubMedCrossRefGoogle Scholar
  154. 154.
    Kennedy, S. G., Wagner, A. J., Conzen, S. D., Jordan, J., Bellacosa, A., Tsichlis, P. N., & Hay, N. (1997). The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal. Genes & Development, 11, 701–713.CrossRefGoogle Scholar
  155. 155.
    Park, J. H., Kim, K. H., Kim, S. J., Lee, W. R., Lee, K. G., & Park, K. K. (2010). Bee venom protects hepatocytes from tumor necrosis factor-alpha and actinomycin D.Archives. Pharmacological Reserch, 33(2), 215–223.Google Scholar
  156. 156.
    Wang, W., & El-Deiry, W. S. (2008). Restoration of p53 to limit tumor growth. Current Opinion in Oncology, 20(1), 90–96.PubMedCrossRefGoogle Scholar
  157. 157.
    Wiman, K. G. (2010). Pharmacological reactivation of mutant p53: from protein structure to the cancer patient. Oncogene, 29(30), 4245–4252.PubMedCrossRefGoogle Scholar
  158. 158.
    Vousden, K. H., & Lane, D. P. (2007). p53 in health and disease. Nature Reviews Molecular Cell Biology, 8, 275–283.PubMedCrossRefGoogle Scholar
  159. 159.
    Shangary, S., Qin, D., McEachern, D., Liu, M., Miller, R. S., Qiu, S., Nikolovska-Coleska, Z., Ding, K., Wang, G., Chen, J., Bernard, D., Zhang, J., Lu, Y., Gu, Q., Shah, R. B., Pienta, K. J., Ling, X., Kang, S., Guo, M., Sun, Y., Yang, D., & Wang, S. (2008). Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. The Proceedings of the National Academy of Sciences USA, 105, 3933–3938.CrossRefGoogle Scholar
  160. 160.
    Li, C., Pazgier, M., Liu, M., Lu, W. Y., & Lu, W. (2009). Apamin as a template for structure-based rational design of potent peptide activators of p53. Angewandte Chemie International Edition in English, 48(46), 8712–8715.CrossRefGoogle Scholar
  161. 161.
    Stocker, M. (2004). Ca(2+)-activated K+ channels: molecular determinants and function of the SK family. Nature Reviews Neuroscience, 5, 758–770.PubMedCrossRefGoogle Scholar
  162. 162.
    Bykov, V. J., Issaeva, N., Shilov, A., Hultcrantz, M., Pugacheva, E., Chumakov, P., Bergman, J., Wiman, K. G., & Selivanova, G. (2002). Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nature Medicine, 8(3), 282–288.PubMedCrossRefGoogle Scholar
  163. 163.
    Tongyoo, A. (2010). Targeted therapy: novel agents against cancer. Journal of the Medical Association of Thailand, 93(Suppl 7), S311–S323. Review.PubMedGoogle Scholar
  164. 164.
    Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144(5), 646–674. Review.PubMedCrossRefGoogle Scholar
  165. 165.
    Song CC, Lu X, Cheng BB, DU J, Li B, Ling CQ. (2007) Effects of melittin on growth and angiogenesis of human hepatocellular carcinoma BEL-7402 cell xenografts in nude mice. Ai Zheng, 26(12), 1315–1322.Google Scholar
  166. 166.
    Weng, C. J., Chau, C. F., Yen, G. C., Liao, J. W., Chen, D. H., & Chen, K. D. (2009). Inhibitory effects of ganoderma lucidum on tumorigenesis and metastasis of human hepatoma cells in cells and animal models. Journal of Agricultural and Food Chemistry, 57(11), 5049–5057.PubMedCrossRefGoogle Scholar
  167. 167.
    Kato, Y., Yamashita, T., & Ishikawa, M. (2002). Relationship between expression of matrix metalloproteinase-2 and matrix metalloproteinase-9 and invasion ability of cervical cancer cells. Oncology Reports, 9(3), 565–569.PubMedGoogle Scholar
  168. 168.
    Liotta, L. A., & Stetler-Stevenson, W. G. (1991). Tumor invasion and metastasis: an imbalance of positive and negative regulation. Cancer Research, 51(18 Suppl)), 5054s–5059s. Review.PubMedGoogle Scholar
  169. 169.
    Rahman, K. M., Sarkar, F. H., Banerjee, S., Wang, Z., Liao, D. J., Hong, X., & Sarkar, N. H. (2006). Therapeutic intervention of experimental breast cancer bone metastasis by indole-3-carbinol in SCID-human mouse model. Molecular Cancer Therapeutics, 5(11), 2747–2756.PubMedCrossRefGoogle Scholar
  170. 170.
    Nabeshima, K., Inoue, T., Shimao, Y., & Sameshima, T. (2002). Matrix metalloproteinases in tumor invasion: role for cell migration. Pathology International, 52(4), 255–264. Review.PubMedCrossRefGoogle Scholar
  171. 171.
    Bhoopathi, P., Chetty, C., Kunigal, S., Vanamala, S. K., Rao, J. S., & Lakka, S. S. (2008). Blockade of tumor growth due to matrix metalloproteinase-9 inhibition is mediated by sequential activation of beta1-integrin, ERK, and NF-kappaB. Journal of Biological Chemistry, 283(3), 1545–1552.PubMedCrossRefGoogle Scholar
  172. 172.
    Hamedani, M., Mirshafiey, A., Vatanpour, H., Khorramizadeh, M., Saadat, F., Berahmeh, A., & Hadji-Ghasemi, F. (2005). In vitro assessment of bee venom effects on matrix metalloproteinase activity and interferon production. Iranian Journal of Allergy, Asthma, and Immunology, 4(1), 9–14.PubMedGoogle Scholar
  173. 173.
    Hamedani, M., Vatanpour, H., Saadat, F., Reza Khorramizaheh, M., & Mirshafiey, A. (2005). Bee venom, immunostimulant or immunosuppressor? Insight into the effect on matrix metalloproteinases and interferons. Immunopharmacology and Immunotoxicology, 27(4), 671–681.PubMedCrossRefGoogle Scholar
  174. 174.
    Nam, S., Ko, E., Park, S. K., Ko, S., Jun, C. Y., Shin, M. K., Hong, M. C., & Bae, H. (2005). Bee venom modulates murine Th1/Th2 lineage development. International Immunopharmacology, 5(9), 1406–1414.PubMedCrossRefGoogle Scholar
  175. 175.
    Leitinger, N. (2003). Oxidized phospholipids as modulators of inflammation in atherosclerosis. Current Opinion in Lipidology, 14, 421–430.PubMedCrossRefGoogle Scholar
  176. 176.
    Banchereau, J., & Steinman, R. M. (1998). Dendritic cells and the control of immunity. Nature, 392, 245–252.PubMedCrossRefGoogle Scholar
  177. 177.
    Matzinger, P. (2002). The danger model: a renewed sense of self. Science, 296, 301–305.PubMedCrossRefGoogle Scholar
  178. 178.
    Hartman Hartman, D. A., Tomchek, L. A., Lugay, J. R., Lewin, A. C., Chau, T. T., & Carlson, R. P. (1991). Comparison of antiinflammatory and antiallergic drugs in the melittin- and D49 PLA2-induced mouse paw edema models. Agents and Actions, 34(1–2), 84–88.CrossRefGoogle Scholar
  179. 179.
    Lariviere, W. R., & Melzack, R. (1996). The bee venom test: a new tonic-pain test. Pain, 66(2–3), 271–277.PubMedCrossRefGoogle Scholar
  180. 180.
    Schneider, H., & Urbanek, R. (1984). Humoral and cellular immune response of the rat to immunization with bee venom. Clinical and Experimental Immunology, 57, 449–453.PubMedGoogle Scholar
  181. 181.
    Magnan, A., Marin, V., Mely, L., Birnbaum, J., Romanet, S., Bongrand, P., & Vervloet, D. (2001). Venom immunotherapy induces monocyte activation. Clinical and Experimental Allergy, 31(8), 1303–1309.PubMedCrossRefGoogle Scholar
  182. 182.
    Ribardo, D. A., Kuhl, K. R., Peterson, J. W., & Chopra, A. K. (2002). Role of melitin- like region within phospholipase A2-activating protein in biological function. Toxicon, 40, 519–526.PubMedCrossRefGoogle Scholar
  183. 183.
    Rekka, E., Kourounakis, L., & Kourounakis, P. (1990). Antioxidant activity of interleukin production affected by honeybee venom. Arzneimittel-Forschung, 40, 912–913.PubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Animal Physiology, Faculty of ScienceUniversity of ZagrebZagrebCroatia

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