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KH-TFMDI, a novel sirtuin inhibitor, alters the cytoskeleton and mitochondrial metabolism promoting cell death in Leishmania amazonensis.
- Source :
-
Apoptosis : an international journal on programmed cell death [Apoptosis] 2017 Sep; Vol. 22 (9), pp. 1169-1188. - Publication Year :
- 2017
-
Abstract
- Treatment of leishmaniasis involves the use of antimonials, miltefosine, amphotericin B or pentamidine. However, the side effects of these drugs and the reports of drug-resistant parasites demonstrate the need for new treatments that are safer and more efficacious. Histone deacetylase inhibitors are a new class of compounds with potential to treat leishmaniasis. Herein, we evaluated the effects of KH-TFMDI, a novel histone deacetylase inhibitor, on Leishmania amazonensis promastigotes and intracellular amastigotes. The IC <subscript>50</subscript> values of this compound for promastigotes and intracellular amastigotes were 1.976 and 1.148 μM, respectively, after 72 h of treatment. Microscopic analyses revealed that promastigotes became elongated and thinner in response to KH-TFMDI, indicating changes in cytoskeleton organization. Immunofluorescence microscopy, western blotting and flow cytometry using an anti-acetylated tubulin antibody revealed an increase in the expression of acetylated tubulin. Furthermore, transmission electron microscopy revealed several ultrastructural changes, such as (a) mitochondrial swelling, followed by the formation of many vesicles inside the matrix; (b) presence of lipid bodies randomly distributed through the cytoplasm; (c) abnormal chromatin condensation; and (d) formation of blebs on the plasma membrane. Physiological studies for mitochondrial function, flow cytometry with propidium iodide and TUNEL assay confirmed the alterations in the mitochondrial metabolism, cell cycle, and DNA fragmentation, respectively, which could result to cell death by mechanisms related to apoptosis-like. All these together indicate that histone deacetylases are promising targets for the development of new drugs to treat Leishmania, and KH-TFMDI is a promising drug candidate that should be tested in vivo.
- Subjects :
- Animals
Antiparasitic Agents pharmacology
Antiparasitic Agents toxicity
Apoptosis drug effects
Benzylidene Compounds toxicity
Cell Cycle Checkpoints drug effects
Cell Survival drug effects
Cytoskeleton metabolism
Histone Deacetylase Inhibitors toxicity
Indoles toxicity
Inhibitory Concentration 50
Leishmania cytology
Leishmania growth & development
Leishmania ultrastructure
Leishmaniasis drug therapy
Leishmaniasis parasitology
Lipid Droplets drug effects
Lipid Droplets metabolism
Microtubules drug effects
Microtubules metabolism
Oxidative Stress drug effects
Benzylidene Compounds pharmacology
Cell Death drug effects
Cytoskeleton drug effects
Histone Deacetylase Inhibitors pharmacology
Indoles pharmacology
Leishmania drug effects
Mitochondria drug effects
Sirtuins antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1573-675X
- Volume :
- 22
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Apoptosis : an international journal on programmed cell death
- Publication Type :
- Academic Journal
- Accession number :
- 28685254
- Full Text :
- https://doi.org/10.1007/s10495-017-1397-8