Hostname: page-component-cd9895bd7-jkksz Total loading time: 0 Render date: 2024-12-29T12:28:27.794Z Has data issue: false hasContentIssue false
  • English
  • Français

Apis mellifera venom induces different cell death pathways in Trypanosoma cruzi

Published online by Cambridge University Press:  19 July 2012

CAMILA M. ADADE ,
GABRIELA S. F. CHAGAS  and
THAÏS SOUTO-PADRÓN
CAMILA M. ADADE
Affiliation:
Laboratório de Biologia Celular e Ultraestrutura, Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes, Centro de Ciências da Saúde, bloco I and Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagens, Universidade Federal do Rio de Janeiro, Ilha do Fundão, Rio de Janeiro, RJ 21941-590, Brazil
GABRIELA S. F. CHAGAS
Affiliation:
Laboratório de Biologia Celular e Ultraestrutura, Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes, Centro de Ciências da Saúde, bloco I and Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagens, Universidade Federal do Rio de Janeiro, Ilha do Fundão, Rio de Janeiro, RJ 21941-590, Brazil
THAÏS SOUTO-PADRÓN*
Affiliation:
Laboratório de Biologia Celular e Ultraestrutura, Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes, Centro de Ciências da Saúde, bloco I and Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagens, Universidade Federal do Rio de Janeiro, Ilha do Fundão, Rio de Janeiro, RJ 21941-590, Brazil
*
*Corresponding author: Tel: +55 (21) 2562 6738. Fax: +55 (21) 2560 8344. E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Summary

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

Keywords

Apis melliferaTrypanosoma cruziChagas disease chemotherapyprogrammed cell deathautophagyapoptosis
Type
Research Article
Information
Parasitology , Volume 139 , Issue 11 , September 2012 , pp. 1444 - 1461
Copyright
Copyright © Cambridge University Press 2012

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Adade, C. M., Cons, B. L., Melo, P. A. and Souto-Padrón, T. (2011). Effect of Crotalus viridis viridis snake venom on the ultrastructure and intracellular survival of Trypanosoma cruzi. Parasitology 138, 46–58. doi: 10.1017/S0031182010000958.CrossRefGoogle ScholarPubMed
Alberola, J., Rodríguez, A., Francino, O., Roura, X., Rivas, L. and Andreu, D. (2004). Safety and efficacy of antimicrobial peptides against naturally acquired leishmaniasis. Antimicrobial Agents and Chemotherapy 48, 641–643. doi: 10.1128/AAC.48.2.641-643.2004.CrossRefGoogle ScholarPubMed
Altmann, K. H. (2001). Microtubule-stabilizing agents: a growing class of important anticancer drugs. Current Opinion in Chemical Biology 5, 424–431. doi: 10.1016/S1367-5931(00)00225-8.CrossRefGoogle ScholarPubMed
Alvarez, V. E., Kosec, G., Sant Anna, C., Turk, V., Cazzulo, J. J., Turk, B. (2008). Blocking autophagy to prevent parasite differentiation: a possible new strategy for fighting parasitic infections? Autophagy. 4, 361–363. doi: 10.1074/jbc.M708474200.CrossRefGoogle ScholarPubMed
Arnoult, D., Tatischeff, I., Estaquier, J., Girard, M., Sureau, F., Tissier, J. P., Grodet, A., Dellinger, M., Traincard, F., Kahn, A., Ameisen, J. C. and Petit, P. X. (2001). On the evolutionary conservation of the cell death pathway: mitochondrial release of an apoptosis-inducing factor during Dictyostelium discoideum cell death. Molecular Biology of the Cell 12, 3016–3030.CrossRefGoogle ScholarPubMed
Azambuja, P., Mello, C. B., D'Escoffier, L. N. and Garcia, E. S. (1989). In vitro cytotoxicity of Rhodnius prolixus hemolytic factor and melittin towards different trypanosomatids. Brazilian Journal of Medical and Biological Research 22, 597–599.Google ScholarPubMed
Bechinger, B. (1997). Structure and functions of channel-forming peptides: magainins, cecropins, melittin and alamethicin. The Journal of Membrane Biology 156, 197–211. doi: 10.1007/s002329900201.CrossRefGoogle ScholarPubMed
Bera, A., Singh, S., Nagaraj, R. and Vaidya, T. (2003). Induction of autophagic cell death in Leishmania donovani by antimicrobial peptides. Molecular and Biochemical Parasitology 127, 23–35. doi: 10.1016/S0166-685(02)00300-6.CrossRefGoogle ScholarPubMed
Berridge, M. V., Herst, P. M. and Tan, A. S. (2005). Tetrazolium dyes as tools in cell biology: new insights into their cellular reduction. Biotechnology Annual Review 11, 127–152. doi: 10.1016/S1387-2656(05)11004-7.CrossRefGoogle ScholarPubMed
Besteiro, S., Williams, R. A., Morrison, L. S., Coombs, G. H. and Mottram, J. C. (2006). Endosome sorting and autophagy are essential for differentiation and virulence of Leishmania major. The Journal of Biological Chemistry 281, 11384–11396. doi: 10.1074/jbc.M512307200.CrossRefGoogle ScholarPubMed
Blondelle, S.E. and Houghten, R. A. (1991). Hemolytic and antimicrobial activities of twenty-four individual omission analogues of melittin. Biochemistry 30, 4671–4678. doi: 10.1021/bi00233a006.CrossRefGoogle ScholarPubMed
Boutrin, M.-C. F., Foster, H. A. and Pentreath, V. W. (2008). The effects of bee (Apis mellifera) venom phospholipase A2 on Trypanosoma brucei brucei and enterobacteria. Experimental Parasitology 119, 246–251. doi: 10.1016/j.exppara.2008.02.002.CrossRefGoogle ScholarPubMed
Brand, G. D., Leite, J. R., De Sa Mandel, S. M., Mesquita, D. A., Silva, L. P., Prates, M. V., Barbosa, E. A., Vinecky, F., Martins, G. R., Galasso, J. H., Kuchelhaus, S. A., Sampaio, R. N., Furtado, J. R., Andrade, A. C. and Bloch, C. (2006). Novel dermaseptins from Phyllomedusa hypochondrialis (Amphibia). Biochemical and Biophysical Research Communications 347, 739–746. doi: 10.1016/j.bbrc.2006.06.168.CrossRefGoogle ScholarPubMed
Chen, Y. N., Li, K. C., Li, Z., Shang, G. W., Liu, D. N., Lu, Z. M., Zhang, J. W., Ji, Y. H., Gao, G. D. and Chen, J. (2006). Effects of bee venom peptidergic components on rat pain-related behaviors and inflammation. Neuroscience 138, 631–640. doi: 10.1016/j.neuroscience.2005.11.022.CrossRefGoogle ScholarPubMed
Chicharro, C., Granata, C., Lozano, R., Andreu, D. and Rivas, L. (2001). N-terminal fatty acid substitution increases the leishmanicidal activity of CA(1–7)M(2–9), a cecropin-melittin hybrid peptide. Antimicrobial Agents and Chemotherapy 45, 2441–2449. doi: 10.1128/AAC.45.9.2441-2449.2001.CrossRefGoogle Scholar
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. and Jan, C. R. (2007). Phospholipase A2-independent Ca2+ entry and subsequent apoptosis induced by melittin in human MG63 osteosarcoma cells. Life Sciences 80, 364–369. doi: 10.1016/j.lfs.2006.09.024.CrossRefGoogle ScholarPubMed
Ciscotto, P., Machado de Avila, R. A., Coelho, E. A. F., Oliveira, J., Diniz, C. G., Farías, L. M., Carvalho, M. A. R., Maria, W. S., Sanchez, E. F., Borges, A. and Chávez-Olórtegui, C. (2009). Antigenic, microbicidal and antiparasitic properties of an L -amino acid oxidase isolated from Bothrops jararaca snake venom. Toxicon 53, 330–341. doi: 10.1016/j.toxicon.2008.12.004.CrossRefGoogle Scholar
De Souza, E. M., Menna-Barreto, R., Araújo-Jorge, T. C., Kumar, A., Hu, Q., Boykin, D. W. and Soeiro, M. N. (2006). Antiparasitic activity of aromatic diamidines is related to apoptosis-like death in Trypanosoma cruzi. Parasitology 133, 75–79. doi: 10.1017/S0031182006000084.CrossRefGoogle ScholarPubMed
Debrabant, A. and Nakhasi, H. (2003). Programmed cell death in trypanosomatids: is it an altruistic mechanism for survival of the fittest? Kinetoplastid Biology and Disease 2, 7. doi: 10.1186/1475-9292-2-7.CrossRefGoogle ScholarPubMed
Delgado, M., Anderson, P., Garcia-Salcedo, J. A., Caro, M. and Gonzalez-Rey, E. (2009). Neuropeptides kill African trypanosomes by targeting intracellular compartments and inducing autophagic-like cell death. Cell Death and Differentiation 16, 406–416. doi: 10.1038/cdd.2008.161.CrossRefGoogle ScholarPubMed
Deolindo, P., Teixeira-Ferreira, A. S., DaMatta, R. A. and Alves, E. W. (2010). L-amino acid oxidase activity present in fractions of Bothrops jararaca venom is responsible for the induction of programmed cell death in Trypanosoma cruzi. Toxicon 56, 944–955. doi: 10.1016/j.toxicon.2010.06.019.CrossRefGoogle ScholarPubMed
Deolindo, P., Teixeira-Ferreira, A. S., Melo, E. J. T., Arnholdt, A. C. V., De Souza, W., Alves, E. W. and DaMatta, R. A. (2005). Programmed cell death in Trypanosoma cruzi induced by Bothrops jararaca venom. Memórias do Instituto Oswaldo Cruz 100, 33–38. doi: 10.1590/S0074-02762005000100006.CrossRefGoogle ScholarPubMed
Díaz-Achirica, P., Ubach, J., Guinea, A., Andreu, D. and Rivas, L. (1998). The plasma membrane of Leishmania donovani promastigotes is the main target for CA(1–8)M(1–18), a synthetic cecropin A-melittin hybrid peptide. The Biochemical Journal 330, 453–460.CrossRefGoogle Scholar
Duszenko, M., Figarella, K., Macleod, E. T. and Welburn, S. C. (2006). Death of a trypanosome: a selfish altruism. Trends in Parasitology 22, 536–542. doi: 10.1016/j.pt.2006.08.010.CrossRefGoogle ScholarPubMed
Duszenko, M., Ginger, M. L., Brennand, A., Gualdrón-López, M., Colombo, M. I., Coombs, G. H., Coppens, I., Jayabalasingham, B., Langsley, G., De Castro, S. L., Menna-Barreto, R., Mottram, J. C., Navarro, M., Rigden, D. J., Romano, P. S., Stoka, V., Turk, B. and Michels, P. A. (2011). Autophagy in protists. Autophagy 7, 127–158. doi: 10.4161/auto.7.2.13310.CrossRefGoogle ScholarPubMed
Fernandez-Gomez, R., Zerrouk, H., Sebti, F., Loyens, M., Benslimane, A. and Ouaissi, M. A. (1994). Growth inhibition of Trypanosoma cruzi and Leishmania donovani infantum by different snake venoms: Preliminary identification of proteins from Cerastes cerastes venom wich interact with the parasites. Toxicon 32, 875–882. doi: 10.1016/0041-0101(94)90366-2.CrossRefGoogle Scholar
Fieck, A., Hurwitz, I., Kang, A. S. and Durvasula, R. (2010). Trypanosoma cruzi: synergistic cytotoxicity of multiple amphipathic anti-microbial peptides to T. cruzi and potential bacterial hosts. Experimental Parasitology 125, 342–347. doi: 10.1016/j.exppara.2010.02.016.CrossRefGoogle Scholar
Fox, J. W. and Serrano, S. M. (2007). Approaching the golden age of natural product pharmaceuticals from venom libraries: an overview of toxins and toxin-derivatives currently involved in therapeutic or diagnostic applications. Current Pharmaceutical Design 13, 2927–2934.CrossRefGoogle ScholarPubMed
Golstein, P. and Kroemer, G. (2005). Redundant cell death mechanisms as relics and backups. Cell Death and Differentiation 12, 1490–1496. doi: 10.1038/sj.cdd.4401607.CrossRefGoogle ScholarPubMed
Gonçalves, A. R., Soares, M. J., De Souza, W., DaMatta, R. A. and Alves, E. W. (2002). Ultrastructural alterations and growth inhibition of Trypanosoma cruzi and Leishmania major induced by Bothrops jararaca venom. Parasitology Research 88, 598–602. doi: 10.1007/s00436-002-0626-3.Google ScholarPubMed
Gordeeva, A. V., Labas, Y. A. and Zvyagilskaya, R. A. (2004). Apoptosis in unicellular organisms: mechanisms and evolution. Biochemistry 69, 1055–1066. doi: 10.1023/B:BIRY.0000046879.54211.ab.Google ScholarPubMed
Guillaume, C., Deregnaucourt, C., Clavey, V. and Schrével, J. (2004). Anti-Plasmodium properties of group IA, IB, IIA and III secreted phospholipases A2 are serum-dependent. Toxicon 43, 311–318. doi: 10.1016/j.toxicon.2004.01.006.CrossRefGoogle ScholarPubMed
Guimarães, C. A. and Linden, R. (2004). Programmed cell deaths. Apoptosis and alternative deathstyles. European Journal of Biochemistry 271, 1638–1650. doi: 10.1111/j.1432-1033.2004.04084.x.Google Scholar
Habermann, E. (1972). Bee and wasp venoms. Science 177, 314–322.CrossRefGoogle ScholarPubMed
Holle, L., Song, W., Holle, E., Wei, Y., Li, J., Wagner, T. E. and Yu, X. (2009). In vitro- and in vivo-targeted tumor lysis by an MMP2 cleavable melittin-LAP fusion protein. International Journal of Oncology 35, 829–835. doi: 10.3892/ijo_00000396.Google ScholarPubMed
Huh, J. E., Baek, Y. H., Lee, M. H., Choi, D. Y., Park, D. S. and 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, 98–110. doi: 10.1016/j.canlet.2009.11.013.CrossRefGoogle ScholarPubMed
Kaczanowski, S., Sajid, M. and Reece, S.E. (2011). Evolution of apoptosis-like programmed cell death in unicellular protozoan parasites. Parasites & Vectors 4, 44. doi: 10.1186/1756-3305-4-44.CrossRefGoogle ScholarPubMed
Kiel, J. A. (2010). Autophagy in unicellular eukaryotes. Philosophical Transactions of the Royal Society of London, Series B i 365, 819–830. doi: 10.1098/rstb.2009.0237.CrossRefGoogle ScholarPubMed
Kirkpatrick, P. (2002). Antibacterial drugs: stitching together naturally. Nature Reviews Drug Discovery 1, 748. doi: 10.1038/nrd921.CrossRefGoogle Scholar
Kroemer, G., Galluzzi, L., Vandenabeele, P., Abrams, J., Alnemri, E. S., Baehrecke, E. H., Blagosklonny, M. V., El-Deiry, W. S., Golstein, P., Green, D. R., Hengartner, M., Knight, R. A., Kumar, S., Lipton, S. A., Malorni, W., Nuñez, G., Peter, M. E., Tschopp, J., Yuan, J., Piacentini, M., Zhivotovsky, B. and Melino, G. (2009). Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death and Differentiation 16, 3–11. doi: 10.1038/cdd.2008.150.CrossRefGoogle 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. (2002). The water-soluble fraction of bee venom produces antinociceptive and anti-inflammatory effects on rheumatoid arthritis in rats. Life Sciences 71, 191–204. doi: 10.1016/S0024-3205(02)01617-X.CrossRefGoogle ScholarPubMed
Lee, N., Bertholet, S., Debrabant, A., Muller, J., Duncan, R. and Nakhasi, H. L. (2002). Programmed cell death in the unicellular protozoan parasite Leishmania. Cell Death and Differentiation 9, 53–64. doi: 10.1038/sj/cdd/4400952.CrossRefGoogle ScholarPubMed
Levine, B. and Yuan, J. (2005). Autophagy in cell death: an innocent convict? The Journal of Clinical Investigation 115, 2679–2688. doi: 10.1172/JCI26390.CrossRefGoogle ScholarPubMed
Lewis, R. J. and Garcia, M. L. (2003). Therapeutic potential of venom peptides. Nature Reviews Drug Discovery 2,790–802. doi: 10.1038/nrd1197.CrossRefGoogle ScholarPubMed
Li, B., Gu, W., Zhang, C., Huang, X. Q., Han, K. Q. and Ling, C. Q. (2006). Growth arrest and apoptosis of the human hepatocellular carcinoma cell line BEL-7402 induced by melittin. Onkologie 29, 367–371. doi: 10.1159/000094711.Google ScholarPubMed
Lüder, C. G., Gross, U. and Lopes, M. F. (2001). Intracellular protozoan parasites and apoptosis: diverse strategies to modulate parasite-host interactions. Trends in Parasitology 17, 480–486. doi: 10.1016/S1471-4922(01)02016-5.CrossRefGoogle ScholarPubMed
Luque-Ortega, J. R., Saugar, J. M., Chiva, C., Andreu, D. and Rivas, L. (2003). Identification of new leishmanicidal peptide lead structures by automated real-time monitoring of changes in intracellular ATP. The Biochemical Journal 375, 221–230. doi: 10.1042/BJ20030544.CrossRefGoogle ScholarPubMed
Meijer, W. H., van der Klei, I. J., Veenhuis, M. and Kiel, J. A. (2007). ATG genes involved in non-selective autophagy are conserved from yeast to man, but the selective Cvt and pexophagy pathways also require organism-specific genes. Autophagy 3, 106–116.CrossRefGoogle Scholar
Menna-Barreto, R. F. S., Corrêa, J. R., Cascabulho, C. M., Fernandes, M. C., Pinto, A. V., Soares, M. J. and De Castro, S. L. (2009 a). Naphthoimidazoles promote different death phenotypes in Trypanosoma cruzi. Parasitology 136, 499–510. doi: 10.1017/S0031182009005745.CrossRefGoogle ScholarPubMed
Menna-Barreto, R. F. S., Salomão, K., Dantas, A. P., Santa-Rita, R. M., Soares, M. J., Barbosa, H. S. and De Castro, S. L. (2009 b). Different cell death pathways induced by drugs in Trypanosoma cruzi: An ultrastructural study. Micron 40, 157–168. doi: 10.1016/j.micron.2008.08.003.CrossRefGoogle ScholarPubMed
Moncayo, A. and Silveira, A. C. (2009). Current epidemiological trends for Chagas disease in LatinAmerica and future challenges in epidemiology, surveillance and health policy. Memórias do Instituto Oswaldo Cruz 104, 17–30. doi: 10.1590/S0074-02762009000900005.CrossRefGoogle Scholar
Monte Neto, R. L., Sousa, L. M., Dias, C. S., Barbosa Filho, J. M., Oliveira, M. R. and Figueiredo, R. C. (2011). Morphological and physiological changes in Leishmania promastigotes induced by yangambin, a lignan obtained from Ocotea duckei. Experimental Parasitology 127, 215–221. doi: 10.1016/j.exppara.2010.07.020.CrossRefGoogle ScholarPubMed
Moreira, L. A., Ito, J., Ghosh, A., Devenport, M., Zieler, H., Abraham, E. G., Crisanti, A., Nolan, T., Catteruccia, F. and Jacobs-Lorena, M. (2002). Bee venom phospholipase inhibits malaria parasite development in transgenic mosquitoes. The Journal of Biological Chemistry 277, 40839–40843. doi: 10.1074/jbc.M206647200.CrossRefGoogle ScholarPubMed
Nguewa, P. A., Fuertes, M. A., Valladares, B., Alonso, C. and Pérez, J. M. (2004). Programmed cell death in trypanosomatids: a way to maximize their biological fitness? Trends in Parasitology 20, 375–380. doi: 10.1016/j.pt.2004.05.006.CrossRefGoogle ScholarPubMed
Papo, N. and Shai, Y. (2003). Can we predict biological activity of antimicrobial peptides from their interactions with model phospholipid membranes? Peptides 24, 1693–1703. doi: 10.1016/j.peptides.2003.09.013.CrossRefGoogle ScholarPubMed
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. and 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, 3504–3515. doi: 10.1002/art.20626.CrossRefGoogle Scholar
Park, M. H., Choi, M. S., Kwak, D. H., Oh, K. W., Yoon do, Y., Han, S. B., Song, H. S., Song, M. J. and Hong, J. T. (2011). Anti-cancer effect of bee venom in prostate cancer cells through activation of caspase pathway via inactivation of NF-κB. Prostate 71, 801–812. doi: 10.1002/pros.21296.CrossRefGoogle ScholarPubMed
Passero, L. F. D., Tomokane, T. Y., Corbett, C. E. P., Laurenti, M. D. and Toyama, M. H. (2007). Comparative studies of the anti-leishmanial activity of three Crotalus durissus ssp. venoms. Parasitology Research 101, 1365–1371. doi: 10.1007/s00436-007-0653-1.CrossRefGoogle ScholarPubMed
Pérez-Cordero, J. J., Lozano, J. M., Cortés, J. and Delgado, G. (2011). Leishmanicidal activity of synthetic antimicrobial peptides in an infection model with human dendritic cells. Peptides 32, 683–690. doi: 10.1016/j.peptides.2011.01.011.CrossRefGoogle Scholar
Putz, T., Ramoner, R., Gander, H., Rahm, A., Bartsch, G., Bernardo, K., Ramsay, S. and 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 and Immunotherapy 56, 627–640. doi: 10.1007/s00262-006-0220-0.CrossRefGoogle ScholarPubMed
Putz, T., Ramoner, R., Gander, H., Rahm, A., Bartsch, G. and Thurnher, M. (2006). Antitumor action and immune activation through cooperation of bee venom secretory phospholipase A2 and phosphatidylinositol-(3,4)-bisphosphate. Cancer Immunology and Immunotherapy 55, 1374–1383. Doi: 10.1007/s00262-006-0143-9.CrossRefGoogle ScholarPubMed
Raghuraman, H. and Chattopadhyay, A. (2007). Melittin: a membrane-active peptide with diverse functions. Bioscience Reports 27, 189–223. doi: 10.1007/s10540-006-9030-z.CrossRefGoogle ScholarPubMed
Rassi, A. Jr, Rassi, A. and Marin-Neto, J. A. (2009). Chagas heart disease: pathophysiologic mechanisms, prognostic factors and risk stratification. Memórias do Instituto Oswaldo Cruz 104, 152–158. doi: 10.1590/S0074-02762009000900021.CrossRefGoogle ScholarPubMed
Sandes, J. M., Borges, A. R., Junior, C. G., Silva, F. P., Carvalho, G. A., Rocha, G. B., Vasconcellos, M. L. and Figueiredo, R. C. (2010). 3-Hydroxy-2-methylene-3-(4-nitrophenylpropanenitrile): A new highly active compound against epimastigote and trypomastigote form of Trypanosoma cruzi. Bioorganic Chemistry 38, 190–195. doi: 10.1016/j.bioorg.2010.06.003.CrossRefGoogle ScholarPubMed
Schurigt, U., Schad, C., Glowa, C., Baum, U., Thomale, K., Schnitzer, J. K., Schultheis, M., Schaschke, N., Schirmeister, T. and Moll, H. (2010). Aziridine-2,3-dicarboxylate-based cysteine cathepsin inhibitors induce cell death in Leishmania major associated with accumulation of debris in autophagy-related lysosome-like vacuoles. Antimicrobial Agents and Chemotherapy 54, 5028–5041. doi: 10.1128/AAC.00327-10.CrossRefGoogle ScholarPubMed
Sloviter, R. S. (2002). Apoptosis: a guide for the perplexed. Trends in Pharmacological Sciences 23, 19–24. doi: 10.1016/S0165-6147(00)01867-8.CrossRefGoogle ScholarPubMed
Son, D. J., Lee, J. W., Lee, Y. H., Song, H. S., Lee, C. K. and 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, 246–270. doi: 10.1016/j.pharmthera.2007.04.004.CrossRefGoogle ScholarPubMed
Tempone, A. G., Andrade, H. F., Spencer, P. J., Lourenço, C. O., Rogero, J. R. and Nascimento, N. (2001). Bothrops moojeni venom kills Leishmania spp. with hydrogen peroxide generated by its L-amino acid oxidase. Biochemical and Biophysical Research Communications 280, 620–624. doi: 10.1006/bbrc.2000.4175.CrossRefGoogle ScholarPubMed
Tempone, A. G., Sartorelli, P., Mady, C. and Fernandes, F. (2007). Natural products to anti-trypanosomal drugs: an overview of new drug prototypes for American Trypanosomiasis. Cardiovascular & Hematological Agents in Medicinal Chemistry 5, 222–235. doi: 10.2174/187152507781058726.CrossRefGoogle ScholarPubMed
Toyama, M. H., Toyama, D. O., Passero, L. F., Laurenti, M. D., Corbett, C. E., Tomokane, T. Y., Fonseca, F. V., Antunes, E., Joazeiro, P. P., Beriam, L. O., Martins, M. A., Monteiro, H. S. and Fonteles, M. C. (2006). Isolation of a new L-amino acid oxidase from Crotalus durissus cascavella venom. Toxicon 47, 47–57. doi: 10.1016/j.toxicon.2005.09.008.CrossRefGoogle ScholarPubMed
Tsujimoto, Y. and Shimizu, S. (2005). Another way to die: autophagic programmed cell death. Cell Death and Differentiation 12, 1528–1534. doi: 10.1038/sj.cdd.4401777.CrossRefGoogle ScholarPubMed
Urbina, J. A. and Docampo, R. (2003). Specific chemotherapy of Chagas disease: controversies and advances. Trends in Parasitology 19, 495–501. doi: 10.1016/j.pt.2003.09.001.CrossRefGoogle ScholarPubMed
Wanderley, J. L., Moreira, M. E., Benjamin, A., Bonomo, A. C. and Barcinski, M. A. (2006). Mimicry of apoptotic cells by exposing phosphatidylserine participates in the establishment of amastigotes of Leishmania (L) amazonensis in mammalian hosts. Journal of Immunology 176, 1834–1839.CrossRefGoogle ScholarPubMed
Wanderley, J. L., Pinto da Silva, L. H., Deolindo, P., Soong, L., Borges, V. M., Prates, D. B., de Souza, A. P., Barral, A., Balanco, J. M., do Nascimento, M. T., Saraiva, E. M. and Barcinski, M. A. (2009). Cooperation between apoptotic and viable metacyclics enhances the pathogenesis of Leishmaniasis. PLoS One 4, e5733. doi: 10.1371/journal.pone.0005733.CrossRefGoogle ScholarPubMed
Wang, C., Chen, T., Zhang, N., Yang, M., Li, B., Lü, X., Cao, X. and Ling, C. (2009). Melittin, a major component of bee venom, sensitizes human hepatocellular carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by activating CaMKII-TAK1-JNK/p38 and inhibiting IkappaBalpha kinase-NFkappaB. The Journal of Biological Chemistry 284, 3804–3813. doi: 10.1074/jbc.M807191200.CrossRefGoogle Scholar
Zieler, H., Keister, D. B., Dvorak, J. A. and Ribeiro, M. C. (2001). A snake venom phospholipase A2 blocks malaria parasite development in the mosquito midgut by inhibiting ookinete association with the midgut surface. The Journal of Experimental Biology 204, 4157–4167.CrossRefGoogle ScholarPubMed