Evaluation of histone deacetylase inhibitors (HDACi) as therapeutic leads for human African trypanosomiasis (HAT)

Carrillo, Angela K.; Guiguemde, W. Armand; Guy, R. Kiplin

doi:10.1016/j.bmc.2014.12.066

Cited by 35 publications

(36 citation statements)

References 40 publications

(28 reference statements)

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“…Although, there is one report showing that resveratrol can inhibit the recombinant human zinc-dependent HDACs in vitro (Venturelli et al., 2013), the changes on histone acetylation observed here support the originally described action for resveratrol as a deacetylation activator [reviewed in Villalba and Alcaín, 2012 and in Hubbard and Sinclair, 2014]. Despite the reports on the anti-parasitic activity of HDAC inhibitors attenuating growth of Plasmodium , Toxoplasma , Leishmania , Trypanosoma brucei and other strains of T. cruzi (Andrews et al., 2012b, Carrillo et al., 2015, Engel et al., 2015, Murray et al., 2001, Veiga-Santos et al., 2014, Soares et al., 2012, Wang et al., 2015, Sereno et al., 2005), the inhibitors tested had little effect on CL Brener epimastigote growth (Fig. 1A), but blocked differentiation to metacyclic trypomastigotes (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, HDACi's originally targeted for cancer use are now being investigated as compound leads for parasitic diseases (Andrews et al., 2012b). For instance in a recent study, HDACis that are currently in clinical trials for oncology were evaluated for treatment of the human African trypanosomiasis (Carrillo et al., 2015). These inhibitors were found to block proliferation of blood-stage in culture; however, none were lethal to cultured parasites when tested at human tolerated doses.…”

Section: Introductionmentioning

confidence: 99%

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Comparative effects of histone deacetylases inhibitors and resveratrol on Trypanosoma cruzi replication, differentiation, infectivity and gene expression

Campo

2017

International Journal for Parasitology: Drugs and Drug Resistan

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Histone post-translational modification, mediated by histone acetyltransferases and deacetylases, is one of the most studied factors affecting gene expression. Recent data showing differential histone acetylation states during the Trypanosoma cruzi cell cycle suggest a role for epigenetics in the control of this process. As a starting point to study the role of histone deacetylases in the control of gene expression and the consequences of their inhibition and activation in the biology of T. cruzi, two inhibitors for different histone deacetylases: trichostatin A for class I/II and sirtinol for class III and the activator resveratrol for class III, were tested on proliferative and infective forms of this parasite. The two inhibitors tested caused histone hyperacetylation whereas resveratrol showed the opposite effect on both parasite forms, indicating that a biologically active in vivo level of these compounds was achieved. Histone deacetylase inhibitors caused life stage-specific effects, increasing trypomastigotes infectivity and blocking metacyclogenesis. Moreover, these inhibitors affected specific transcript levels, with sirtinol causing the most pronounced change. On the other hand, resveratrol showed strong anti-parasitic effects. This compound diminished epimastigotes growth, promoted metacyclogenesis, reduced in vitro infection and blocked differentiation and/or replication of intracellular amastigotes. In conclusion, the data presented here supports the notion that these compounds can modulate T. cruzi gene expression, differentiation, infection and histones deacetylase activity. Furthermore, among the compounds tested in this study, the results point to Resveratrol as promising trypanocidal drug candidate.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comparative effects of histone deacetylases inhibitors and resveratrol on Trypanosoma cruzi replication, differentiation, infectivity and gene expression

Campo

2017

International Journal for Parasitology: Drugs and Drug Resistan

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“…HDAC inhibitors have already shown promise for treatment of apicomplexan diseases, such as malaria (caused by Plasmodium spp.) or trypanosomiasis [90][91][92]. Structure-based studies on smHDAC8 inhibitors may be considered a model approach for speciesselective inhibitors in such diseases [24,87] and may also extend to, for example, fungi [93].…”

Section: Reviewmentioning

confidence: 99%

HDAC8: a multifaceted target for therapeutic interventions

Chakrabarti

Oehme

Witt

et al. 2015

Trends in Pharmacological Sciences

220

163

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Histone deacetylase 8 (HDAC8) is a class I histone deacetylase implicated as a therapeutic target in various diseases, including cancer, X-linked intellectual disability, and parasitic infections. It is a structurally well-characterized enzyme that also deacetylates nonhistone proteins. In cancer, HDAC8 is a major 'epigenetic player' that is linked to deregulated expression or interaction with transcription factors critical to tumorigenesis. In the parasite Schistosoma mansoni and in viral infections, HDAC8 is a novel target to subdue infection. The current challenge remains in the development of potent selective inhibitors that would specifically target HDAC8 with fewer adverse effects compared with pan-HDAC inhibitors. Here, we review HDAC8 as a drug target and discuss inhibitors with respect to their structural features and therapeutic interventions.

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“…41 T. brucei is known to express four HDAC homologues, two of which are believed to be essential to parasite viability, that may be inhibited by repurposed human HDAC inhibitors. 42, 43 In 2012, Kelly et al . reported an initial screening of representative HDAC inhibitors from a larger compound library, resulting in the discovery of belinostat ( 17 , Fig.…”

Section: Target Class Repurposingmentioning

confidence: 99%

Repurposing strategies for tropical disease drug discovery

Klug

Gelb

Pollastri

2016

Bioorganic & Medicinal Chemistry Letters

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Neglected tropical diseases (NTDs) and other diseases of the developing world, such as malaria, attract research investments that are disproportionately low compared to their impact on human health worldwide. Therefore, pragmatic methods for launching new drug discovery programs have emerged that repurpose existing chemical matter as new drugs or new starting points for optimization. In this Digest we describe applications of different repurposing approaches for NTDs, and provide a means by which these approaches may be differentiated from each other. These include drug repurposing, target repurposing, target class repurposing, and lead repurposing.

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Evaluation of histone deacetylase inhibitors (HDACi) as therapeutic leads for human African trypanosomiasis (HAT)

Cited by 35 publications

References 40 publications

Comparative effects of histone deacetylases inhibitors and resveratrol on Trypanosoma cruzi replication, differentiation, infectivity and gene expression

Comparative effects of histone deacetylases inhibitors and resveratrol on Trypanosoma cruzi replication, differentiation, infectivity and gene expression

HDAC8: a multifaceted target for therapeutic interventions

Repurposing strategies for tropical disease drug discovery

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