Stage-specific antileishmanial activity of an inhibitor of SIR2 histone deacetylase.
Silent information regulator 2 (SIR2) proteins are NAD-dependant deacetylases found in organisms ranging from bacteria to human. In eukaryotes, these proteins are involved in many biological processes including transcriptional repression, metabolism, ageing, or apoptosis. Here, we have shown that Sirtinol, a commercially available inhibitor of SIR2 deacetylases, significantly inhibits the in vitro proliferation of Leishmania infantum axenic amastigotes in a dose-dependent manner. This activity is stage specific since sirtinol did not affect the in vitro growth of parasite promastigotes. Growth arrest in amastigotes is associated with genomic DNA fragmentation, a process reminiscent of apoptosis. Interestingly parasites carrying extra copies of the LmSIR2 gene were less susceptible to the sirtinol mediated cell death. Altogether, these results constitute novel evidences that Leishmania SIR2 proteins play a role in the control of the parasite apoptotic phenomenon.
Vergnes
Baptiste
B
IRD UR008 Pathogénie des Trypanosomatidés, Institut de Recherche pour le Développement, Centre IRD de Montpellier, 911 Av. Agropolis, BP 64501, 34394 Montpellier Cedex 5, France.
Vanhille
Laurent
L
Ouaissi
Ali
A
Sereno
Denis
D
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D053938:DNA Fragmentation / Q000187:drug effects; D016054:DNA, Protozoan / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D018314:Leishmania infantum / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D007898:Leishmaniasis, Visceral / Q000469:parasitology; D008969:Molecular Sequence Data; D009284:Naphthols / Q000494:pharmacology*; D016415:Sequence Alignment; D037761:Sirtuins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism
D001549:Benzamides; D016054:DNA, Protozoan; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D009284:Naphthols; C439060:sirtinol; D037761:Sirtuins; D006655:Histone Deacetylases