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Bee venom protects hepatocytes from tumor necrosis factor-α and actinomycin D

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Abstract

Honeybee (Apis mellifera) venom (BV) has a broad array of therapeutic applications in traditional medicine to treat variety of diseases. It is also known that BV possesses anti-inflammatory and anticancer effect and that it can inhibit proliferation and induces apoptosis in cancer cells, but there is no evidence of information regarding anti-apoptosis of BV on hepatocytes. In the present study, we investigated the anti-apoptotic effect of BV on tumor necrosis factor (TNF)-α with actinomycin (Act) D induces apoptosis in hepatocytes. TNF-α/Act D-treated hepatocytes were exposed to different low concentration (1, 10 and 100 ng/mL) of BV. Our results showed statistically significant inhibition in DNA damage caused by BV treatment compared to corresponding TNF-α/Act D-treated hepatocytes. BV suppressed TNF-α/Act Dtreated activation of bcl-2 family and caspase family, which resulted in inhibition of cytochrome c release and PARP cleavage. These results demonstrate that low concentration BV possess a potent suppressive effect on anti-apoptotic responses of TNF-α/Act D-treated hepatocytes and suggest that these compounds may contribute substantial therapeutic potential for the treatment of liver diseases.

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References

  • Billingham, M. E., Morley, J., Hanson, J. M., Shipolini, R. A., and Vernon, C. A., Letter: An anti-inflammatory peptide from bee venom. Nature, 245, 163–164 (1973).

    Article  CAS  PubMed  Google Scholar 

  • Budihardjo, I., Oliver, H., Lutter, M., Luo, X., and Wang, X., Biochemical pathways of caspase activation during apoptosis. Annu. Rev. Cell Dev. Biol., 15, 269–290 (1999).

    Article  CAS  PubMed  Google Scholar 

  • Cursio, R., Gugenheim, J., Ricci, J. E., Crenesse, D., Rostagno, P., Maulon, L., Saint-Paul, M. C., Ferrua, B., Mouiel, J., and Auberger, P., Caspase inhibition protects from liver injury following ischemia and reperfusion in rats. Transpl. Int., 13Suppl 1, S568–S572 (2000).

    Article  PubMed  Google Scholar 

  • Ding, W. X. and Yin, X. M., Dissection of the multiple mechanisms of TNF-alpha-induced apoptosis in liver injury. J. Cell. Mol. Med., 8, 445–454 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Earnshaw, W. C., Martins, L. M., and Kaufmann, S. H., Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu. Rev. Biochem., 68, 383–424 (1999).

    Article  CAS  PubMed  Google Scholar 

  • Gajski, G. and Garaj-Vrhovac, V., 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 (2009).

    Article  CAS  PubMed  Google Scholar 

  • Garaj-Vrhovac, V. and Gajski, G., 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 (2009).

    PubMed  Google Scholar 

  • Han, S., Lee, K., Yeo, J., Kweon, H., Woo, S., Lee, M., Baek, H., Kim, S., and Park, K., Effect of honey bee venom on microglial cells nitric oxide and tumor necrosis factoralpha production stimulated by LPS. J. Ethnopharmacol., 111, 176–181 (2007).

    Article  CAS  PubMed  Google Scholar 

  • Higuchi, H., Adachi, M., Miura, S., Gores, G. J., and Ishii, H., The mitochondrial permeability transition contributes to acute ethanol-induced apoptosis in rat hepatocytes. Hepatology, 34, 320–328 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Hong, S. J., Rim, G. S., Yang, H. I., Yin, C. S., Koh, H. G., Jang, M. H., Kim, C. J., Choe, B. K., and Chung, J. H., Bee venom induces apoptosis through caspase-3 activation in synovial fibroblasts of patients with rheumatoid arthritis. Toxicon, 46, 39–45 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Hu, H., Chen, D., Li, Y., and Zhang, X., 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. J. Pharm. Pharmacol., 58, 83–89 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Jacobson, M. D., Weil, M., and Raff, M. C., Programmed cell death in animal development. Cell, 88, 347–354 (1997).

    Article  CAS  PubMed  Google Scholar 

  • Jang, M. H., Shin, M. C., Lim, S., Han, S. M., Park, H. J., Shin, I., Lee, J. S., Kim, K. A., Kim, E. H., and Kim, C. J., 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 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Jones, R. A., Johnson, V. L., Buck, N. R., Dobrota, M., Hinton, R. H., Chow, S. C., and Kass, G. E., Fas-mediated apoptosis in mouse hepatocytes involves the processing and activation of caspases. Hepatology, 27, 1632–1642 (1998).

    Article  CAS  PubMed  Google Scholar 

  • Kammerer, R., Chvatchko, Y., Kettner, A., Dufour, N., Corradin, G., and Spertini, F., Modulation of T-cell response to phospholipase A2 and phospholipase A2-derived peptides by conventional bee venom immunotherapy. J. Allergy Clin. Immunol., 100, 96–103 (1997).

    Article  CAS  PubMed  Google Scholar 

  • Kim, T. H., Zhao, Y., Barber, M. J., Kuharsky, D. K., and Yin, X. M., Bid-induced cytochrome c release is mediated by a pathway independent of mitochondrial permeability transition pore and Bax. J. Biol. Chem., 275, 39474–39481 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Kwon, Y. B., Lee, H. J., Han, H. J., Mar, W. C., Kang, S. K., Yoon, O. B., Beitz, A. J., and Lee, J. H., The water-soluble fraction of bee venom produces antinociceptive and anti-inflammatory effects on rheumatoid arthritis in rats. Life Sci., 71, 191–204 (2002).

    Article  CAS  PubMed  Google Scholar 

  • Kwon, Y. B., Lee, J. D., Lee, H. J., Han, H. J., Mar, W. C., Kang, S. K., Beitz, A. J., and Lee, J. H., Bee venom injection into an acupuncture point reduces arthritis associated edema and nociceptive responses. Pain, 90, 271–280 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Lariviere, W. R. and Melzack, R., The bee venom test: a new tonic-pain test. Pain, 66, 271–277 (1996).

    Article  CAS  PubMed  Google Scholar 

  • Lee, Y. J., Kang, S. J., Kim, B. M., Kim, Y. J., Woo, H. D., and Chung, H. W., Cytotoxicity of honeybee (Apis mellifera) venom in normal human lymphocytes and HL-60 cells. Chem. Biol. Interact., 169, 189–197 (2007).

    Article  CAS  PubMed  Google Scholar 

  • Leist, M., Gantner, F., Bohlinger, I., Germann, P. G., Tiegs, G., and Wendel, A., Murine hepatocyte apoptosis induced in vitro and in vivo by TNF-alpha requires transcriptional arrest. J. Immunol., 153, 1778–1788 (1994).

    CAS  PubMed  Google Scholar 

  • Li, J., Yang, S., and Billiar, T. R., Cyclic nucleotides suppress tumor necrosis factor alpha-mediated apoptosis by inhibiting caspase activation and cytochrome c release in primary hepatocytes via a mechanism independent of Akt activation. J. Biol. Chem., 275, 13026–13034 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Liao, J. H., Chen, J. S., Chai, M. Q., Zhao, S., and Song, J. G., The involvement of p38 MAPK in transforming growth factor beta1-induced apoptosis in murine hepatocytes. Cell Res., 11, 89–94 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Lindahl, T., Satoh, M. S., Poirier, G. G., and Klungland, A., Post-translational modification of poly(ADP-ribose) polymerase induced by DNA strand breaks. Trends Biochem. Sci., 20, 405–411 (1995).

    Article  CAS  PubMed  Google Scholar 

  • Liu, X., Chen, D., Xie, L., and Zhang, R., 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 (2002).

    Article  CAS  PubMed  Google Scholar 

  • Matsumaru, K., Ji, C., and Kaplowitz, N., Mechanisms for sensitization to TNF-induced apoptosis by acute glutathione depletion in murine hepatocytes. Hepatology, 37, 1425–1434 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Micheau, O. and Tschopp, J., Induction of TNF receptor Imediated apoptosis via two sequential signaling complexes. Cell, 114, 181–190 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Miyashita, T., Krajewski, S., Krajewska, M., Wang, H. G., Lin, H. K., Liebermann, D. A., Hoffman, B., and Reed, J. C., Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene, 9, 1799–1805 (1994).

    CAS  PubMed  Google Scholar 

  • Moon, D. O., Park, S. Y., Heo, M. S., Kim, K. C., Park, C., Ko, W. S., Choi, Y. H., and Kim, G. Y., Key regulators in bee venom-induced apoptosis are Bcl-2 and caspase-3 in human leukemic U937 cells through downregulation of ERK and Akt. Int. Immunopharmacol., 6, 1796–1807 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Musallam, L., Ethier, C., Haddad, P. S., and Bilodeau, M., EGF mediates protection against Fas-induced apoptosis by depleting and oxidizing intracellular GSH stocks. J. Cell. Physiol., 198, 62–72 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Nam, K. W., Je, K. H., Lee, J. H., Han, H. J., Lee, H. J., Kang, S. K., and Mar, W., 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. Arch. Pharm. Res., 26, 383–388 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Nam, S., Ko, E., Park, S. K., Ko, S., Jun, C. Y., Shin, M. K., Hong, M. C., and Bae, H., Bee venom modulates murine Th1/Th2 lineage development. Int. Immunopharmacol., 5, 1406–1414 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Orsolic, N., Sver, L., Verstovsek, S., Terzic, S., and Basic, I., Inhibition of mammary carcinoma cell proliferation in vitro and tumor growth in vivo by bee venom. Toxicon, 41, 861–870 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Perez-Paya, E., Houghten, R. A., and Blondelle, S. E., The role of amphipathicity in the folding, self-association and biological activity of multiple subunit small proteins. J. Biol. Chem., 270, 1048–1056 (1995).

    Article  CAS  PubMed  Google Scholar 

  • Stennicke, H. R., Jurgensmeier, J. M., Shin, H., Deveraux, Q., Wolf, B. B., Yang, X., Zhou, Q., Ellerby, H. M., Ellerby, L. M., Bredesen, D., Green, D. R., Reed, J. C., Froelich, C. J., and Salvesen, G. S., Pro-caspase-3 is a major physiologic target of caspase-8. J. Biol. Chem., 273, 27084–27090 (1998).

    Article  CAS  PubMed  Google Scholar 

  • Stennicke, H. R. and Salvesen, G. S., Properties of the caspases. Biochim. Biophys. Acta, 1387, 17–31 (1998).

    CAS  PubMed  Google Scholar 

  • Tarn, C., Bilodeau, M. L., Hullinger, R. L., and Andrisani, O. M., Differential immediate early gene expression in conditional hepatitis B virus pX-transforming versus nontransforming hepatocyte cell lines. J. Biol. Chem., 274, 2327–2336 (1999).

    Article  CAS  PubMed  Google Scholar 

  • Wolter, K. G., Hsu, Y. T., Smith, C. L., Nechushtan, A., Xi, X. G., and Youle, R. J., Movement of Bax from the cytosol to mitochondria during apoptosis. J. Cell Biol., 139, 1281–1292 (1997).

    Article  CAS  PubMed  Google Scholar 

  • Yin, C. S., Lee, H. J., Hong, S. J., Chung, J. H., and Koh, H. G., Microarray analysis of gene expression in chondrosarcoma cells treated with bee venom. Toxicon, 45, 81–91 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Yin, X. M., Signal transduction mediated by Bid, a pro-death Bcl-2 family proteins, connects the death receptor and mitochondria apoptosis pathways. Cell Res., 10, 161–167 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Yoon, S. Y., Kwon, Y. B., Kim, H. W., Roh, D. H., Seo, H. S., Han, H. J., Lee, H. J., Beitz, A. J., Hwang, S. W., and Lee, J. H., Peripheral bee venom’s anti-inflammatory effect involves activation of the coeruleospinal pathway and sympathetic preganglionic neurons. Neurosci. Res., 59, 51–59 (2007).

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Kwan-Kyu Park.

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Park, JH., Kim, KH., Kim, SJ. et al. Bee venom protects hepatocytes from tumor necrosis factor-α and actinomycin D. Arch. Pharm. Res. 33, 215–223 (2010). https://doi.org/10.1007/s12272-010-0205-6

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  • DOI: https://doi.org/10.1007/s12272-010-0205-6

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