title: Inhibition of NAD+-dependent histone deacetylases (sirtuins) causes growth arrest and activates both apoptosis and autophagy in the pathogenic protozoan Trypanosoma cruzi.
abstract: Chagas disease, which is caused by the parasite Trypanosoma cruzi, affects approximately 7-8 million people in Latin America. The drugs available to treat this disease are ineffective against chronic phase disease and are associated with toxic side effects. Therefore, the development of new compounds that can kill T. cruzi at low concentrations is critically important. Herein, we report the effects of a novel 3-arylideneindolin-2-one that inhibits sirtuins, which are highly conserved proteins that are involved in a variety of physiological processes. The compound KH-TFMDI was tested against the epimastigote, trypomastigote and amastigote forms of T. cruzi, and its effects were evaluated using flow cytometry, light and electron microscopy. KH-TFMDI inhibited the replication of T. cruzi intracellular amastigotes with an IC50 of 0.5 ± 0.2 μM, which is significantly lower than the IC50 of benznidazole. The compound also lysed the highly infectious bloodstream trypomastigotes (BST) with LC50 values of 0.8 ± 0.3 μM at 4 °C and 2.5 ± 1.1 μM at 37 °C. KH-TFMDI inhibited cytokinesis and induced several morphological changes in the parasite, leading to its death by apoptosis and autophagy. This study highlights sirtuins as a potential new target for Chagas disease therapy.
authors.affiliation: Laboratório de Ultraestrutura Celular Hertha Meyer, CCS, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Bloco G, Ilha do Fundão, Rio de Janeiro, CEP 21941-902, Brazil.
authors.forename: Phercyles
authors.initials: P
authors.lastname: Veiga-Santos
authors.affiliation: Laboratório de Ultraestrutura Celular Hertha Meyer, CCS, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Bloco G, Ilha do Fundão, Rio de Janeiro, CEP 21941-902, Brazil.
authors.forename: Lissa Catherine
authors.initials: LC
authors.lastname: Reignault
authors.affiliation: Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-University of Munich, Butenandtstrasse 5-13, 81377 Munich, Germany.
authors.forename: Kilian
authors.initials: K
authors.lastname: Huber
authors.affiliation: Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-University of Munich, Butenandtstrasse 5-13, 81377 Munich, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Bracher
authors.affiliation: Laboratório de Ultraestrutura Celular Hertha Meyer, CCS, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Bloco G, Ilha do Fundão, Rio de Janeiro, CEP 21941-902, Brazil.
authors.forename: Wanderley
authors.initials: W
authors.lastname: De Souza
authors.affiliation: Laboratório de Ultraestrutura Celular Hertha Meyer, CCS, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Bloco G, Ilha do Fundão, Rio de Janeiro, CEP 21941-902, Brazil.
authors.forename: Tecia Maria Ulisses
authors.initials: TM
authors.lastname: De Carvalho
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D014355:Chagas Disease / Q000188:drug therapy* / Q000469:parasitology; D056545:Group III Histone Deacetylases / Q000037:antagonists & inhibitors*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D037761:Sirtuins / Q000037:antagonists & inhibitors; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology / Q000648:ultrastructure
chemical_list: D007211:Indoles; D014344:Trypanocidal Agents; D056545:Group III Histone Deacetylases; D037761:Sirtuins