Histone Deacetylase Enzymes as Potential Drug Targets in Cancer and Parasitic Diseases

The elucidation of the mechanisms of transcriptional activation and repression in eukaryotic cells has shed light on the important role of acetylation-deacetylation of histones mediated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. Another group belonging to the large family of sirtuins (silent information regulators (SIRs)) has an (nicotinamide adenine dinucleotide) NAD(+)-dependent HDAC activity. Several inhibitors of HDACs (HDIs) have been shown to exert antitumor effects. Interestingly, some of the HDIs exerted a broad spectrum of antiprotozoal activity. The purpose of this review is to analyze some of the current data related to the deacetylase enzymes as a possible target for drug development in cancer and parasitic diseases with special reference to protozoan infections. Given the structural differences among members of this family of enzymes, development of specific inhibitors will not only allow selective therapeutic intervention, but may also provide a powerful tool for functional study of these enzymes

Immunology and Molecular Biology of Protozoan Infections

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Apoptosis-like death in trypanosomatids: search for putative pathways and genes involved

Members of the Trypanosomatidae family comprises species that are causative of important human diseases such as Chagas'disease, Leishmaniasis and sleeping sickness. A wealth of evidence has accumulated that illustrates the ability of these unicellular organisms to undergo, with or without induction (stress conditions), a cell death with some features resembling apoptosis-like phenomenon. However, despite the apparent phenotypic similarities between the apoptosis-like death of kinetoplastids and mammalian nucleated cell programmed cell death (PCD), the pathways seem to differ significantly. This review analyses some of the current data related to the cell death in trypanosomatids. Special attention is given to members of conserved protein families demonstrating remarkable diversity and plasticity of function [i.e. elongation factor-1 subunits α and γ ; and the Silent Information Regulator (SIR2)-related gene, showed to be associated with resistance to apoptosis-like death in Leishmania]. The elucidation of the molecular events which tightly regulated the processes of growth arrest, differentiation and death of Trypanosoma cruzi, Leishmania spp and African trypanosomes, might allow not only to define a more comprehensive view of the cell death machinery in term of evolutionary origin but may also be useful to identify new target molecules for chemotherapeutic drug development and therapeutic intervention

Host Cell Phenotypic Variability Induced by Trypanosomatid-Parasite-Released Immunomodulatory Factors: Physiopathological Implications

The parasitic protozoa Trypanosoma cruzi and Leishmania sp release a variety of molecules into their mammalian hosts (ESA: excretory-secretory products). The effects of these ESA on the host cell function may participate in the establishment of a successful infection, in which the parasite persists for a sufficient period of time to complete its life cycle. A number of regulatory components or processes originating from the parasite that control or regulate the metabolism and the growth of host cell have been identified. The purpose of the present review is to analyze some of the current data related to the parasite ESA that interfere with the host cell physiology. Special attention is given to members of conserved protein families demonstrating remarkable diversity and plasticity of function (ie, glutathione S-transferases and related molecules; members of the trans-sialidase and mucin family; and members of the ribosomal protein family). The identification of parasite target molecules and the elucidation of their mode of action toward the host cell represents a step forward in efforts aimed at an immunotherapeutic or pharmacological control of parasitic infection

Leishmania amastigotes as targets for drug screening

Direct drug screening against the mammalian stage of Leishmania has been hampered by cost and the time consuming effort required to accomplish it. The ability to derive transgenic Leishmania expressing reporter genes opened up new possibilities for the development of drug screening tests. Further developments to standardize and gather multiple informations could now be envisionned. We will discuss on such available methodologies that could improve sensitivity, reliability, versatility and the rapidity, of the screen based on intracellular model

Experimental study of the function of the excreted/secreted Leishmania LmSIR2 protein by heterologous expression in eukaryotic cell line

BACKGROUND: In yeast and Caenorhabditis elegans, Silent Information Regulator (SIR2) proteins have been shown to be involved in ageing regulation. In Leishmania, the LmSIR2rp was originally isolated from the excreted/secreted material of the Leishmania parasites. Among the function(s) of this protein in Leishmania biology, we have documented its implication in parasite survival, and in particular in Leishmania amastigotes. In this paper we question the role of the excreted/secreted form of the protein. In particular we wonder if the Leishmania Sir2 homologue is involved in some aspect of its biological function(s), in various components and pathways, which could promote the host cell survival. To test this hypothesis we have mimicked an intracellular release of the protein through constitutive expression in mouse L929 fibrosarcoma cells. RESULTS: Our results demonstrate that the LmSIR2 protein was properly expressed by fibroblasts and that LmSIR2 is localized both in the cytoplasm and the nucleus of all the transformed cell clones. Unexpectedly, we found that cells expressing LmSIR2 presents reduced saturation cell density ranging from 40% to 60% and expressed an acidic (pH6.0) β-galactosidase activity, which is known to be a senescence biomarker. As a consequence, we observed that LmSIR2 positive fibroblasts were more permissive towards Leihmania infection. CONCLUSIONS: LmSIR2 is able to substantially interfere with the host cell physiology. Thus, it is tempting to speculate that these modifications could help Leishmania to survive for a long period in a cell with reduced capacity to multiply or respond to immunologic stimuli. The potential implications of our finding during the in vivo infection process are discussed

Sera from Trypanosoma b. gambiense infected patients cross-react with a Trypanosoma cruzi recombinant protein

In previous studies, we and others have shown utility of a 24-kDa #Trypanosoma cruzi recombinant antigen (rTc24) for serological diagnosis of Chagas' disease. Also, this molecule has been proved useful to evaluate cure of chagasic patients who submit to specific treatment. However, in all the studies done so far, the 24-kDa protein was used as a fusion with a Gluthatione-S-transferase (GST) of #Schistosoma japonicum, therefore, parallel assays to determine the anti-GST responses of all sera were required to deduce the GST noise in serological tests. Here, we show the subcloning by polymerase chain reaction of the cDNA encoding the #T. cruzi$ 24-kDa antigen in a vector system (pQE) allowing us to obtain Tc24 recombinant protein as a single molecule. The highly reactivity of chagasic sera from Colombia, Ecuador, Brazil and Bolivia in ELISA against the recombinant antigen is confirmed. However, sera from patients infected with African trypanosomes recognize rTc24 in ELISA and blot. The relevance of these findings in the context of Chagas' disease diagnosis and/or the relationship with African trypanosomes is analyzed. (Résumé d'auteur

Trypanosoma cruzi-induced host immune system dysfunction: a rationale for parasite immunosuppressive factor(s) encoding gene targeting

An intense suppression of T cell proliferation to mitogens and to antigens is observed in a large number of parasitic infections. The impairment of T cell proliferation also occurred during the acute phase of Chagas' disease, caused by the intracellular protozoan parasite Trypanosoma cruzi. A wealth of evidence has accumulated that illustrates the ability of T. cruzi released molecules to influence directly a variety of diverse immunological functions. In this paper, we review the data concerning the immunoregulatory effects of T. cruzi Tc24 (a B cell activator antigen) and Tc52 (an immunosuppressive protein) released molecules on the host immune system. The gene targeting approach developed to further explore the biological function(s) of Tc52 molecule, revealed interesting unexpected functional properties. Indeed, in addition to its immunusuppressive activity a direct or indirect involvement of Tc52 gene product alone or in combination with other cellular components in T. cruzi differentiation control mechanisms have been evidenced. Moreover, targeted Tc52 replacement allowed the obtention of parasite mutants exhibiting low virulence in vitro and in vivo. Thus, the generation of a complete deficiency state of virulence factors by gene targeting should provide a means to assess the importance of these factors in the pathophysiological processes and disease progression. It is hoped that such approaches might allow rational design of tools to control T. cruzi infections

Rationale for Possible Targeting of Histone Deacetylase Signaling in Cancer Diseases with a Special Reference to Pancreatic Cancer

There is ongoing interest to identify signaling pathways and genes that play a key role in carcinogenesis and the development of resistance to antitumoral drugs. Given that histone deacetylases (HDACs) interact with various partners through complex molecular mechanims leading to the control of gene expression, they have captured the attention of a large number of researchers. As a family of transcriptional corepressors, they have emerged as important regulators of cell differentiation, cell cycle progression, and apoptosis. Several HDAC inhibitors (HDACis) have been shown to efficiently protect against the growth of tumor cells in vitro as well as in vivo. The pancreatic cancer which represents one of the most aggressive cancer still suffers from inefficient therapy. Recent data, although using in vitro tumor cell cultures and in vivo chimeric mouse model, have shown that some of the HDACi do express antipancreatic tumor activity. This provides hope that some of the HDACi could be potential efficient anti-pancreatic cancer drugs. The purpose of this review is to analyze some of the current data of HDACi as possible targets of drug development and to provide some insight into the current problems with pancreatic cancer and points of interest for further study of HDACi as potential molecules for pancreatic cancer adjuvant therapy

Les abcès orbitaires: à propos de 7 cas

L’abcès orbitaire correspond à une infection collectée bien limitée située dans l’orbite, généralement due  à une cellulite orbitaire. Nous rapportons notre expérience à propos de 7 cas d’abcès orbitaires opérés  dans le service d’ORL est de chirurgie cervico-faciale de l’hôpital 20 aout de Casablanca entre juin 2007 et juin 2008. L’âge moyen est de 11 ans avec des extrêmes de 5 et 22 ans. On note une prédominance  masculine avec un sex-ratio de 3. On retrouve une exophtalmie inflammatoire, avec tuméfaction  palpébrale et une porte d’entrée sinusienne chez tous nos patients. L’ophtalmoplégie est notée dans 5  cas, la baisse de l’acuité visuelle dans 4 cas, et la cécité dans 2 cas. La tomodensitométrie a été réalisée chez tous nos patients. Elle a permit de confirmer l’abcès et sa localisation : interne (4 cas), supéro- interne (2 cas), et inférieure (1 cas). L’imagerie par résonnance magnétique a été faite dans 3 cas, et a permis de préciser les limites de l’infection. Le traitement médical a été instauré d’emblée, associant  une triple antibiothérapie par voie parentérale. Le traitement chirurgical a été réalisé chez 5 patients  devant la non amélioration clinique. Un drainage externe a été pratiqué et la cure de la sinusite était différée. On note une évolution défavorable dans 3 cas: cécité par névrite optique (2 cas) et  ophtalmoplégie (1 cas). Elle a été favorable dans les autres cas. En conclusion, l’abcès orbitaire est une affection rare et grave du sujet jeune, engageant le pronostic visuel voire même le pronostic vital, et  constitue de ce fait une urgence ophtalmologique et ORL. Le traitement se base sur une  poly-antibiothérapie avec des drainages de la collection le plus rapidement possible. La prévention passe par un diagnostic et un traitement appropriés des sinusites.Key words: Abcès orbitaire, diagnostic, traitement