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Gimatecan and other camptothecin derivatives poison Leishmania DNA-topoisomerase IB leading to a strong leishmanicidal effect.
Biochem Pharmacol. 2013 May 15; 85(10):1433-40.BP

Abstract

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.

Authors+Show Affiliations

Departamento de Ciencias Biomédicas, Universidad de León, Campus de Vegazana s/n, 24071 León, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23466420

Citation

Prada, Christopher F., et al. "Gimatecan and Other Camptothecin Derivatives Poison Leishmania DNA-topoisomerase IB Leading to a Strong Leishmanicidal Effect." Biochemical Pharmacology, vol. 85, no. 10, 2013, pp. 1433-40.
Prada CF, Alvarez-Velilla R, Balaña-Fouce R, et al. Gimatecan and other camptothecin derivatives poison Leishmania DNA-topoisomerase IB leading to a strong leishmanicidal effect. Biochem Pharmacol. 2013;85(10):1433-40.
Prada, C. F., Alvarez-Velilla, R., Balaña-Fouce, R., Prieto, C., Calvo-Álvarez, E., Escudero-Martínez, J. M., Requena, J. M., Ordóñez, C., Desideri, A., Pérez-Pertejo, Y., & Reguera, R. M. (2013). Gimatecan and other camptothecin derivatives poison Leishmania DNA-topoisomerase IB leading to a strong leishmanicidal effect. Biochemical Pharmacology, 85(10), 1433-40. https://doi.org/10.1016/j.bcp.2013.02.024
Prada CF, et al. Gimatecan and Other Camptothecin Derivatives Poison Leishmania DNA-topoisomerase IB Leading to a Strong Leishmanicidal Effect. Biochem Pharmacol. 2013 May 15;85(10):1433-40. PubMed PMID: 23466420.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Gimatecan and other camptothecin derivatives poison Leishmania DNA-topoisomerase IB leading to a strong leishmanicidal effect. AU - Prada,Christopher F, AU - Alvarez-Velilla,Raquel, AU - Balaña-Fouce,Rafael, AU - Prieto,Carlos, AU - Calvo-Álvarez,Estefania, AU - Escudero-Martínez,Jose Miguel, AU - Requena,José María, AU - Ordóñez,César, AU - Desideri,Alessandro, AU - Pérez-Pertejo,Yolanda, AU - Reguera,Rosa M, Y1 - 2013/03/01/ PY - 2012/12/14/received PY - 2013/02/22/revised PY - 2013/02/22/accepted PY - 2013/3/8/entrez PY - 2013/3/8/pubmed PY - 2013/6/15/medline SP - 1433 EP - 40 JF - Biochemical pharmacology JO - Biochem. Pharmacol. VL - 85 IS - 10 N2 - 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. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/23466420/Gimatecan_and_other_camptothecin_derivatives_poison_Leishmania_DNA_topoisomerase_IB_leading_to_a_strong_leishmanicidal_effect_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(13)00147-0 DB - PRIME DP - Unbound Medicine ER -