Mode of Action of the Sesquiterpene Lactones Psilostachyin and Psilostachyin C on Trypanosoma cruzi

PUENTE V.; MARTINO V.S.; SULSEN V.P.; BATLLE A.; LOMBARDO M.E. CORRESPONDING AUTHORS; PAPADEMETRIO D.; FRANK F. M.

PLOS ONE

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2016 vol. 11 p. 1 - 14

1932-6203

Trypanosoma cruzi is the causative agent of Chagas? disease, which is a major endemicdisease in Latin America and is recognized by the WHO as one of the 17 neglected tropicaldiseases in the world. Psilostachyin and psilostachyin C, two sesquiterpene lactones isolatedfrom Ambrosia spp., have been demonstrated to have trypanocidal activity. Consideringboth the potential therapeutic targets present in the parasite, and the severalmechanisms of action proposed for sesquiterpene lactones, the aim of this work was tocharacterize the mode of action of psilostachyin and psilostachyin C on Trypanosoma cruziand to identify the possible targets for these molecules. Psilostachyin and psilostachyin Cwere isolated from Ambrosia tenuifolia and Ambrosia scabra, respectively. Interaction ofsesquiterpene lactones with hemin, the induction of oxidative stress, the inhibition of cruzipainand trypanothione reductase and their ability to inhibit sterol biosynthesis were evaluated.The induction of cell death by apoptosis was also evaluated by analyzingphosphatidylserine exposure detected using annexin-V/propidium iodide, decreased mitochondrialmembrane potential, assessed with Rhodamine 123 and nuclear DNA fragmentationevaluated by the TUNEL assay. Both STLs were capable of interacting with hemin.Psilostachyin increased about 5 times the generation of reactive oxygen species in Trypanosomacruzi after a 4h treatment, unlike psilostachyin C which induced an increase in reactiveoxygen species levels of only 1.5 times. Only psilostachyin C was able to inhibit thebiosynthesis of ergosterol, causing an accumulation of squalene. Both sesquiterpene lactonesinduced parasite death by apoptosis. Upon evaluating the combination of both compounds,and additive trypanocidal effect was observed. Despite their structural similarity,both sesquiterpene lactones exerted their anti-T. cruzi activity through interaction withdifferent targets. Psilostachyin accomplished its antiparasitic effect by interacting withhemin, while psilostachyin C interfered with sterol synthesis.