Cargando…
Topoisomerase IB poisons induce histone H2A phosphorylation as a response to DNA damage in Leishmania infantum
DNA topoisomerases are considered consolidated druggable targets against diseases produced by trypanosomatids. Several reports indicated that indenoisoquinolines, a family of non-camptothecinic based topoisomerase poisons, have a strong leishmanicidal effect both in vitro and in vivo in murine model...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796659/ https://www.ncbi.nlm.nih.gov/pubmed/31563118 http://dx.doi.org/10.1016/j.ijpddr.2019.09.005 |
_version_ | 1783459656935407616 |
---|---|
author | Gutiérrez-Corbo, Camino Álvarez-Velilla, Raquel Reguera, Rosa M. García-Estrada, Carlos Cushman, Mark Balaña-Fouce, Rafael Pérez-Pertejo, Yolanda |
author_facet | Gutiérrez-Corbo, Camino Álvarez-Velilla, Raquel Reguera, Rosa M. García-Estrada, Carlos Cushman, Mark Balaña-Fouce, Rafael Pérez-Pertejo, Yolanda |
author_sort | Gutiérrez-Corbo, Camino |
collection | PubMed |
description | DNA topoisomerases are considered consolidated druggable targets against diseases produced by trypanosomatids. Several reports indicated that indenoisoquinolines, a family of non-camptothecinic based topoisomerase poisons, have a strong leishmanicidal effect both in vitro and in vivo in murine models of visceral leishmaniasis. The antileishmanial effect of the indenoisoquinolines implies several mechanisms that include the stabilization of the cleavage complex, histone H2A phosphorylation and DNA fragmentation. A series of 20 compounds with the indenoisoquinoline scaffold and several substituents at positions N6, C3, C8 and C9, were tested both in promastigotes and in intramacrophage splenic amastigotes obtained from an experimental murine infection. The antileishmanial effect of most of these compounds was within the micromolar or submicromolar range. In addition, the introduction of an N atom in the indenoisoquinoline ring (7-azaindenoisoquinolines) produced the highest selectivity index along with strong DNA topoisomerase IB inhibition, histone H2A phosphorylation and DNA-topoisomerase IB complex stabilization. This report shows for the first time the effect of a series of synthetic indenoisoquinolines on histone H2A phosphorylation, which represents a primary signal of double stranded DNA break in genus Leishmania. |
format | Online Article Text |
id | pubmed-6796659 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-67966592019-10-22 Topoisomerase IB poisons induce histone H2A phosphorylation as a response to DNA damage in Leishmania infantum Gutiérrez-Corbo, Camino Álvarez-Velilla, Raquel Reguera, Rosa M. García-Estrada, Carlos Cushman, Mark Balaña-Fouce, Rafael Pérez-Pertejo, Yolanda Int J Parasitol Drugs Drug Resist Regular Article DNA topoisomerases are considered consolidated druggable targets against diseases produced by trypanosomatids. Several reports indicated that indenoisoquinolines, a family of non-camptothecinic based topoisomerase poisons, have a strong leishmanicidal effect both in vitro and in vivo in murine models of visceral leishmaniasis. The antileishmanial effect of the indenoisoquinolines implies several mechanisms that include the stabilization of the cleavage complex, histone H2A phosphorylation and DNA fragmentation. A series of 20 compounds with the indenoisoquinoline scaffold and several substituents at positions N6, C3, C8 and C9, were tested both in promastigotes and in intramacrophage splenic amastigotes obtained from an experimental murine infection. The antileishmanial effect of most of these compounds was within the micromolar or submicromolar range. In addition, the introduction of an N atom in the indenoisoquinoline ring (7-azaindenoisoquinolines) produced the highest selectivity index along with strong DNA topoisomerase IB inhibition, histone H2A phosphorylation and DNA-topoisomerase IB complex stabilization. This report shows for the first time the effect of a series of synthetic indenoisoquinolines on histone H2A phosphorylation, which represents a primary signal of double stranded DNA break in genus Leishmania. Elsevier 2019-09-20 /pmc/articles/PMC6796659/ /pubmed/31563118 http://dx.doi.org/10.1016/j.ijpddr.2019.09.005 Text en © 2019 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Regular Article Gutiérrez-Corbo, Camino Álvarez-Velilla, Raquel Reguera, Rosa M. García-Estrada, Carlos Cushman, Mark Balaña-Fouce, Rafael Pérez-Pertejo, Yolanda Topoisomerase IB poisons induce histone H2A phosphorylation as a response to DNA damage in Leishmania infantum |
title | Topoisomerase IB poisons induce histone H2A phosphorylation as a response to DNA damage in Leishmania infantum |
title_full | Topoisomerase IB poisons induce histone H2A phosphorylation as a response to DNA damage in Leishmania infantum |
title_fullStr | Topoisomerase IB poisons induce histone H2A phosphorylation as a response to DNA damage in Leishmania infantum |
title_full_unstemmed | Topoisomerase IB poisons induce histone H2A phosphorylation as a response to DNA damage in Leishmania infantum |
title_short | Topoisomerase IB poisons induce histone H2A phosphorylation as a response to DNA damage in Leishmania infantum |
title_sort | topoisomerase ib poisons induce histone h2a phosphorylation as a response to dna damage in leishmania infantum |
topic | Regular Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796659/ https://www.ncbi.nlm.nih.gov/pubmed/31563118 http://dx.doi.org/10.1016/j.ijpddr.2019.09.005 |
work_keys_str_mv | AT gutierrezcorbocamino topoisomeraseibpoisonsinducehistoneh2aphosphorylationasaresponsetodnadamageinleishmaniainfantum AT alvarezvelillaraquel topoisomeraseibpoisonsinducehistoneh2aphosphorylationasaresponsetodnadamageinleishmaniainfantum AT reguerarosam topoisomeraseibpoisonsinducehistoneh2aphosphorylationasaresponsetodnadamageinleishmaniainfantum AT garciaestradacarlos topoisomeraseibpoisonsinducehistoneh2aphosphorylationasaresponsetodnadamageinleishmaniainfantum AT cushmanmark topoisomeraseibpoisonsinducehistoneh2aphosphorylationasaresponsetodnadamageinleishmaniainfantum AT balanafoucerafael topoisomeraseibpoisonsinducehistoneh2aphosphorylationasaresponsetodnadamageinleishmaniainfantum AT perezpertejoyolanda topoisomeraseibpoisonsinducehistoneh2aphosphorylationasaresponsetodnadamageinleishmaniainfantum |