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Natural sesquiterpene lactones induce programmed cell death in Trypanosoma cruzi: a new therapeutic target?
Phytomedicine. 2014 Sep 25; 21(11):1411-8.P

Abstract

BACKGROUND

Chagas disease or American Trypanosomiasis is caused by the flagellated protozoan parasite Trypanosoma cruzi (T. cruzi) and is recognized by the WHO as one of the world's 17 neglected tropical diseases. Only two drugs (Benznidazol, Bz and Nifurtimox, Nx) are currently accepted for treatment, however they cause severe adverse effects and their efficacy is still controversial. It is then important to explore for new drugs.

PURPOSE

Programmed cell death (PCD) in parasites offers interesting new therapeutic targets. The aim of this work was to evaluate the induction of PCD in T. cruzi by two natural sesquiterpene lactones (STLs), dehydroleucodine (DhL) and helenalin (Hln) as compared with the two conventional drugs, Bz and Nx.

MATERIAL AND METHODS

Hln and DhL were isolated from aerial parts of Gaillardia megapotamica and Artemisia douglassiana Besser, respectively. Purity of compounds (greater than 95%) was confirmed by (13)C-nuclear magnetic resonance, melting point analysis, and optical rotation. Induction of PCD in T. cruzi epimastigotes and trypomastigotes by DhL, Hln, Bz and Nx was assayed by phosphatidylserine exposure at the parasite surface and by detection of DNA fragmentation using the TUNEL assay. Trypanocidal activity of natural and synthetic compounds was assayed by measuring parasite viability using the MTT method.

RESULTS

The two natural STLs, DhL and Hln, induce programmed cell death in both, the replicative epimastigote form and the infective trypomastigote form of T. cruzi. Interestingly, the two conventional antichagasic drugs (Bz and Nx) do not induce programmed cell death. A combination of DhL and either Bz or Nx showed an increased effect of natural compounds and synthetic drugs on the decrease of parasite viability.

CONCLUSION

DhL and Hln induce programmed cell death in T. cruzi replicative epimastigote and infective trypomastigote forms, which is a different mechanism of action than the conventional drugs to kill the parasite. Therefore DhL and Hln may offer an interesting option for the treatment of Chagas disease, alone or in combination with conventional drugs.

Authors+Show Affiliations

Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.Programa de Anatomía y Biología del Desarrollo, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.Laboratorio de Salud de Ecosistemas, Escuela de Medicina Veterinaria, Facultad de Ecología y Recursos Naturales, Universidad Andrés Bello, Santiago, Chile.Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Chile.Instituto de Histología y Embriología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina.Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile. Electronic address: ngalanti@med.uchile.cl.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25022207

Citation

Jimenez, V, et al. "Natural Sesquiterpene Lactones Induce Programmed Cell Death in Trypanosoma Cruzi: a New Therapeutic Target?" Phytomedicine : International Journal of Phytotherapy and Phytopharmacology, vol. 21, no. 11, 2014, pp. 1411-8.
Jimenez V, Kemmerling U, Paredes R, et al. Natural sesquiterpene lactones induce programmed cell death in Trypanosoma cruzi: a new therapeutic target? Phytomedicine. 2014;21(11):1411-8.
Jimenez, V., Kemmerling, U., Paredes, R., Maya, J. D., Sosa, M. A., & Galanti, N. (2014). Natural sesquiterpene lactones induce programmed cell death in Trypanosoma cruzi: a new therapeutic target? Phytomedicine : International Journal of Phytotherapy and Phytopharmacology, 21(11), 1411-8. https://doi.org/10.1016/j.phymed.2014.06.005
Jimenez V, et al. Natural Sesquiterpene Lactones Induce Programmed Cell Death in Trypanosoma Cruzi: a New Therapeutic Target. Phytomedicine. 2014 Sep 25;21(11):1411-8. PubMed PMID: 25022207.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Natural sesquiterpene lactones induce programmed cell death in Trypanosoma cruzi: a new therapeutic target? AU - Jimenez,V, AU - Kemmerling,U, AU - Paredes,R, AU - Maya,J D, AU - Sosa,M A, AU - Galanti,N, Y1 - 2014/07/08/ PY - 2014/03/04/received PY - 2014/06/04/revised PY - 2014/06/11/accepted PY - 2014/7/16/entrez PY - 2014/7/16/pubmed PY - 2015/3/31/medline KW - Chagas disease KW - Programmed cell death KW - Sesquiterpene lactones KW - Trypanosoma cruzi SP - 1411 EP - 8 JF - Phytomedicine : international journal of phytotherapy and phytopharmacology JO - Phytomedicine VL - 21 IS - 11 N2 - BACKGROUND: Chagas disease or American Trypanosomiasis is caused by the flagellated protozoan parasite Trypanosoma cruzi (T. cruzi) and is recognized by the WHO as one of the world's 17 neglected tropical diseases. Only two drugs (Benznidazol, Bz and Nifurtimox, Nx) are currently accepted for treatment, however they cause severe adverse effects and their efficacy is still controversial. It is then important to explore for new drugs. PURPOSE: Programmed cell death (PCD) in parasites offers interesting new therapeutic targets. The aim of this work was to evaluate the induction of PCD in T. cruzi by two natural sesquiterpene lactones (STLs), dehydroleucodine (DhL) and helenalin (Hln) as compared with the two conventional drugs, Bz and Nx. MATERIAL AND METHODS: Hln and DhL were isolated from aerial parts of Gaillardia megapotamica and Artemisia douglassiana Besser, respectively. Purity of compounds (greater than 95%) was confirmed by (13)C-nuclear magnetic resonance, melting point analysis, and optical rotation. Induction of PCD in T. cruzi epimastigotes and trypomastigotes by DhL, Hln, Bz and Nx was assayed by phosphatidylserine exposure at the parasite surface and by detection of DNA fragmentation using the TUNEL assay. Trypanocidal activity of natural and synthetic compounds was assayed by measuring parasite viability using the MTT method. RESULTS: The two natural STLs, DhL and Hln, induce programmed cell death in both, the replicative epimastigote form and the infective trypomastigote form of T. cruzi. Interestingly, the two conventional antichagasic drugs (Bz and Nx) do not induce programmed cell death. A combination of DhL and either Bz or Nx showed an increased effect of natural compounds and synthetic drugs on the decrease of parasite viability. CONCLUSION: DhL and Hln induce programmed cell death in T. cruzi replicative epimastigote and infective trypomastigote forms, which is a different mechanism of action than the conventional drugs to kill the parasite. Therefore DhL and Hln may offer an interesting option for the treatment of Chagas disease, alone or in combination with conventional drugs. SN - 1618-095X UR - https://www.unboundmedicine.com/medline/citation/25022207/Natural_sesquiterpene_lactones_induce_programmed_cell_death_in_Trypanosoma_cruzi:_a_new_therapeutic_target L2 - https://linkinghub.elsevier.com/retrieve/pii/S0944-7113(14)00254-2 DB - PRIME DP - Unbound Medicine ER -