Inhibition of NAD+-dependent histone deacetylases (sirtuins) causes growth arrest and activates both apoptosis and autophagy in the pathogenic protozoanTrypanosoma cruzi
VEIGA-SANTOS P., REIGNAULT LC., HUBER K., BRACHER F., DE SOUZA W., DE CARVALHO TMU.
SUMMARYChagas disease, which is caused by the parasiteTrypanosoma 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 killT. cruziat 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 ofT. cruzi, and its effects were evaluated using flow cytometry, light and electron microscopy. KH-TFMDI inhibited the replication ofT. cruziintracellular amastigotes with an IC50of 0·5±0·2 μm, which is significantly lower than the IC50of benznidazole. The compound also lysed the highly infectious bloodstream trypomastigotes (BST) with LC50values of 0·8±0·3 μmat 4 °C and 2·5±1·1 μmat 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.