Induction of apoptosis-like cell death by pentamidine and doxorubicin through differential inhibition of topoisomerase II in arsenite-resistant L. donovani

Singh, Gaganmeet; Dey, Chinmoy Sankar

doi:10.1016/j.actatropica.2007.06.004

Cited by 43 publications

(31 citation statements)

References 45 publications

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“…However, while diamidines are excellent minor groove DNA binders, this interaction itself cannot fully explain their biological activity. Recent reports suggest that their association with DNA is an initial step and that it is followed by topological changes that lead to molecule instability and destruction and/or modification of DNA-protein interactions; this, in turn leads to replication errors, DNA degradation and eventual parasite death (Singh & Dey 2007, Wilson et al 2008. Interestingly, recent unpublished results from our group from the screening of 21 dicationic molecules against T. cruzi showed that while all compounds were localised to a greater extent within the kinetoplast than in the nucleus, no correlation could be found between compound activity and the level of kDNA accumulation (A Daliry et al, unpublished observations, CF Silva et al, unpublished observations).…”

Section: Diamidines and Related Compoundsmentioning

confidence: 99%

Experimental chemotherapy for Chagas disease: 15 years of research contributions from in vivo and in vitro studies

Soeiro

Dantas

Daliry

et al. 2009

Mem. Inst. Oswaldo Cruz

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Section: Diamidines and Related Compoundsmentioning

confidence: 99%

Experimental chemotherapy for Chagas disease: 15 years of research contributions from in vivo and in vitro studies

Soeiro

Dantas

Daliry

et al. 2009

Mem. Inst. Oswaldo Cruz

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“…DOX has been shown to induce apoptosis in the Leishmania parasite (Singh and Dey, 2007;Luanpitpong et al, 2012) and, recently, was found to activate immune functions of macrophages and NK cells (Hussner et al, 2012). Immunointervention with antimonials, amphotericin B and DOX is known to improve VL (Murray et al, 2003a;Mukherjee et al, 2004), but toxicity remains a major concern.…”

Section: Introductionmentioning

confidence: 99%

Coating doxorubicin‐loaded nanocapsules with alginate enhances therapeutic efficacy against Leishmania in hamsters by inducing Th1‐type immune responses

Kansal

Tandon

Verma

et al. 2014

British J Pharmacology

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BACKGROUND AND PURPOSEThe aim of the present study was to evaluate the immunomodulatory and chemotherapeutic potential of alginate-(SA) coated nanocapsule (NCs) loaded with doxorubicin (SA-NCs-DOX) against visceral leishmaniasis in comparison with nano-emulsions containing doxorubicin (NE-DOX). EXPERIMENTAL APPROACHNE-DOX was prepared using low-energy emulsification methods. Stepwise addition of protamine sulphate and SA in a layer-by-layer manner was used to form SA-NCs-DOX. SA-NCs-DOX, NE-DOX and Free DOX were compared for their cytotoxicity against Leishmania donovani-infected macrophages in vitro and generation of T-cell responses in infected hamsters in vivo. KEY RESULTSSize and ζ potential of the NE-DOX and SA-NCs-DOX formulations were 310 ± 2.1 nm and (−)32.6 ± 2.1 mV, 342 ± 4.1 nm and (−)29.3 ± 1.2 mV respectively. SA-NCs-DOX was better (1.5 times) taken up by J774A.1 macrophages compared with NE-DOX. SA-NCs -DOX showed greater efficacy than NE-DOX against intramacrophagic amastigotes. SA-NCs-DOX treatment exhibited enhanced apoptotic efficiency than NE-DOX and free DOX as evident by cell cycle analysis, decrease in mitochondrial membrane potential, ROS and NO production. T-cell responses, when assessed through lymphoproliferative responses, NO production along with enhanced levels of iNOS, TNF-α, IFN-γ and IL-12 were found to be up-regulated after SA-NCs-DOX, compared with responses to NE-DOX in vivo. Parasitic burden was decreased in Leishmania-infected hamsters treated with SA-NCs-DOX, compared with NE-DOX. CONCLUSIONS AND IMPLICATIONSOur results provide insights into the development of an alternative approach to improved management of leishmaniasis through a combination of chemotherapy with stimulation of the innate immune system.

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“…rhodesiense affecting parasite motility and infectivity to mice (Williamson and Scott-Finnigan 1978 ). Moreover, doxorubicin has been shown to be highly active in an in vivo model of visceral leishmaniasis (Sett et al 1992 ), its mechanism of action being the inhibition of leishmanial topoisomerase II (Singh and Dey 2007 ). Another set of topoisomerase II poisons, the fl uoroquinolones like KB5426, ofl oxacin and ciprofl oxacin have been shown to have activity against T .…”

Section: Topoisomerasesmentioning

confidence: 99%

Selection of Molecular Targets for Drug Development Against Trypanosomatids

Smirlis

Soares

2013

Subcellular Biochemistry

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Trypanosomatid parasites are a group of flagellated protozoa that includes the genera Leishmania and Trypanosoma, which are the causative agents of diseases (leishmaniases, sleeping sickness and Chagas disease) that cause considerable morbidity and mortality, affecting more than 27 million people worldwide. Today no effective vaccines for the prevention of these diseases exist, whereas current chemotherapy is ineffective, mainly due to toxic side effects of current drugs and to the emergence of drug resistance and lack of cost effectiveness. For these reasons, rational drug design and the search of good candidate drug targets is of prime importance. The search for drug targets requires a multidisciplinary approach. To this end, the completion of the genome project of many trypanosomatid species gives a vast amount of new information that can be exploited for the identification of good drug candidates with a prediction of "druggability" and divergence from mammalian host proteins. In addition, an important aspect in the search for good drug targets is the "target identification" and evaluation in a biological pathway, as well as the essentiality of the gene in the mammalian stage of the parasite, which is provided by basic research and genetic and proteomic approaches. In this chapter we will discuss how these bioinformatic tools and experimental evaluations can be integrated for the selection of candidate drug targets, and give examples of metabolic and signaling pathways in the parasitic protozoa that can be exploited for rational drug design.

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Induction of apoptosis-like cell death by pentamidine and doxorubicin through differential inhibition of topoisomerase II in arsenite-resistant L. donovani

Cited by 43 publications

References 45 publications

Experimental chemotherapy for Chagas disease: 15 years of research contributions from in vivo and in vitro studies

Experimental chemotherapy for Chagas disease: 15 years of research contributions from in vivo and in vitro studies

Coating doxorubicin‐loaded nanocapsules with alginate enhances therapeutic efficacy against Leishmania in hamsters by inducing Th1‐type immune responses

Selection of Molecular Targets for Drug Development Against Trypanosomatids

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