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Resistance mechanism development to the topoisomerase-I inhibitor Hoechst 33342 by Leishmania donovani

Published online by Cambridge University Press:  25 April 2005

J.-F. MARQUIS ,
I. HARDY  and
M. OLIVIER
J.-F. MARQUIS
Affiliation:
Centre for the Study of Host Resistance and the Research Institute of McGill University Health Centre, Departments of Experimental Medicine, Microbiology and Immunology, McGill University, Montréal, Québec, Canada, H3A 2B4 Centre de Recherche en Infectiologie du CHUQ, Département de Biologie Médicale, Université Laval, Sainte-Foy, Québec, Canada, G1V 4G2
I. HARDY
Affiliation:
Centre for the Study of Host Resistance and the Research Institute of McGill University Health Centre, Departments of Experimental Medicine, Microbiology and Immunology, McGill University, Montréal, Québec, Canada, H3A 2B4 Centre de Recherche en Infectiologie du CHUQ, Département de Biologie Médicale, Université Laval, Sainte-Foy, Québec, Canada, G1V 4G2
M. OLIVIER
Affiliation:
Centre for the Study of Host Resistance and the Research Institute of McGill University Health Centre, Departments of Experimental Medicine, Microbiology and Immunology, McGill University, Montréal, Québec, Canada, H3A 2B4
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Abstract

The bisbenzimidazole compound Hoechst 33342 (Ho342) has been identified as a specific Topoisomerase-I (Topo-I) inhibitor in mammalian cells. More recently, we have reported the ability of Ho342 to target L. donovani Topo-I, leading to parasite growth inhibition in vitro by mechanisms involving DNA breakage and apoptosis-like phenomenon. As the Ho342 lead molecule (2,5′-Bi-1H-benzimidazole) can be used as a starting structure for derivative compounds more effective against Leishmania, defining the Ho342 resistance mechanism(s) in Leishmania represents an important strategic tool. In the present study, we selected resistant parasites to Ho342 (LdRHo.300). While we observed an increase of the Topo-I gene expression correlated by a higher Topo-I DNA relaxation activity, the Topo-I genes (LdTOP1A and LdTOP1B) sequencing did not reveal any mutation for the resistant parasites. Moreover, our results on Ho342 cellular accumulation suggested the presence of a potential energy-dependent Ho342 transporter in the wild-type parasite, and that an alteration of this transporter has occurred in LdRHo.300, leading to an altered drug accumulation. Collectively, Ho342 resistance characterization provided results supporting that the resistance developed by LdRHo.300 involves complex mechanisms, most likely dominated by an altered drug accumulation, providing new insight in the Ho342 resistance mechanisms.

Keywords

Hoechst 33342MGBLsLeishmaniaTopoisomerase-Idrug resistance
Type
Research Article
Information
Parasitology , Volume 131 , Issue 2 , August 2005 , pp. 197 - 206
Copyright
2005 Cambridge University Press

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