2024-03-28T17:47:41Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/976452020-06-01T07:46:46Zcom_10261_79com_10261_1col_10261_332
DIGITAL.CSIC
author
Prada, Christopher F.
author
Álvarez-Velilla, Raquel
author
Balaña-Fouce, Rafael
author
Prieto-Sánchez, Carlos
author
Calvo-Álvarez, Estefanía
author
Escudero-Martínez, José Miguel
author
Requena, José María
author
Ordóñez, César
author
Desideri, Alessandro
author
Pérez-Pertejo, Yolanda
author
Reguera, Rosa M.
2014-06-03T10:29:51Z
2014-06-03T10:29:51Z
2013
Biochemical Pharmacology 85: 1433- 1440 (2013)
http://hdl.handle.net/10261/97645
10.1016/j.bcp.2013.02.024
The aim of this work is the in vitro and ex vivo assessment of the leishmanicidal activity of camptothecin and three analogues used in cancer therapy: topotecan (Hycantim®), gimatecan (ST1481) and the pro-drug irinotecan (Camptosar®) as well as its active metabolite SN-38 against Leishmania infantum. The activity of camptothecin and its derivatives was studied on extracellular L. infantum infrared-emitting promastigotes and on an ex vivo murine model of infected splenocytes with L. infantum fluorescent amastigotes. In situ formation of SDS/KCl precipitable DNA-protein complexes in Leishmania promastigotes indicated that these drugs are DNA topoisomerase IB poisons. The inhibitory potency of camptothecin derivatives on recombinant L. infantum topoisomerase IB was assessed in vitro showing that gimatecan is the most active compound preventing the relaxation of supercoiled DNA at submicromolar concentrations. Cleavage equilibrium assays in Leishmania topoisomerase IB show that gimatecan changes the equilibrium towards cleavage at much lower concentrations than the other camptothecin derivatives and that this effect persists over time. Gimatecan and camptothecin were the most powerful compounds preventing cell growth of free-living L. infantum promastigotes within the same concentration range. All these compounds killed L. infantum splenocyte-infecting amastigotes within the nanomolar range. The amastigote form showed higher sensitivity to topoisomerase IB poisons (with high therapeutic selectivity indexes) than free-living promastigotes. All the compounds assayed poisoned L. infantum DNA topoisomerase IB leading to a strong leishmanicidal effect. Camptothecin derivatives are suitable for reducing the parasitic burden of ex vivo infected splenocytes. The selectivity index of gimatecan makes it a promising drug against this neglected disease. © 2013 Elsevier Inc.
eng
closedAccess
Camptothecin
Splenic explants
Leishmania spp.
DNA topoisomerase IB
Gimatecan
Gimatecan and other camptothecin derivatives poison Leishmania DNA-topoisomerase IB leading to a strong leishmanicidal effect
artículo
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