Quinoline Derivative MC1626, a Putative GCN5 Histone Acetyltransferase (HAT) Inhibitor, Exhibits HAT-Independent Activity against
            <i>Toxoplasma gondii</i>

Smith, Aaron T.; Livingston, Meredith R.; Mai, Antonello; Filetici, Patrizia; Queener, Sherry F.; Sullivan, William J.

doi:10.1128/aac.01256-06

Cited by 31 publications

(11 citation statements)

References 20 publications

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“…These quinolines, represented by the prototype MC1626, inhibited HAT activity [48]. HAT inhibition in human HCQ * * * * colon cell lines was correlated with histone hypoacetylation and growth inhibition.…”

Section: Discussionmentioning

confidence: 99%

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Hydroxychloroquine, chloroquine, and all-trans retinoic acid regulate growth, survival, and histone acetylation in breast cancer cells

Rahim

Strobl

2009

Anti-Cancer Drugs

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The antimalarial drugs chloroquine (CQ) and hydroxychloroquine (HCQ) have potential applications in cancer treatment. The growth of MCF-7 and MDA-MB-231 human breast cancer cells in vitro was inhibited by CQ and HCQ and these cells were more sensitive than nontumorigenic MCF-10A breast epithelial cells. Furthermore, all-trans retinoic acid (ATRA) augmented the anticancer effects of CQ and HCQ as evidenced by significant reductions in Ki67-positive cancer cells and clonogenicity compared with cells treated with CQ or HCQ in the absence of ATRA. As an earlier study suggested that CQ, HCQ, and ATRA are breast cancer cell differentiation agents, these agents were screened in cell-free histone deacetylase (HDAC) and histone acetyltransferase (HAT) assays. ATRA, but not CQ or HCQ, inhibited HDAC activity in HeLa nuclear extracts. Growth inhibitory concentrations of HCQ and ATRA stimulated purified p300/CBP-associated factor, where CBP is the cAMP-response element binding protein, HAT activity. To investigate whether growth inhibitory concentrations of these agents influenced protein acetylation in cells, gel-purified histone H3 and histone H4 were analyzed using mass spectrometry. HCQ alone and HCQ+ATRA treatments altered the acetylation status in the N-terminal lysines of histones H3 and H4 compared with dimethyl sulfoxide (DMSO) controls. The results indicated that HCQ and ATRA regulate protein acetylation events in MCF-7 breast cancer cells, and identify a potential mechanism for their effects on breast cancer cell growth and differentiation.

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Section: Discussionmentioning

confidence: 99%

“…HAT has been identified as a potential target for antiproliferatives in yeast, nonbreast human tumor cell lines, and a protozoan parasite Toxoplasma gondii [45][46][47][48][49].…”

Section: Discussionmentioning

confidence: 99%

Hydroxychloroquine, chloroquine, and all-trans retinoic acid regulate growth, survival, and histone acetylation in breast cancer cells

Rahim

Strobl

2009

Anti-Cancer Drugs

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“…In contrast, there are no reports to date of a Toxoplasma KAT inhibitor despite genetic studies showing that KATs are essential for parasite viability (6)(7)(8)(9)(10)(11)(12)(13). The putative KAT inhibitor MC1626 has inhibitory activity against tachyzoites but most likely through an off-target effect (14). However, curcumin and anacardic acid have been reported to inhibit proliferation of the related parasite Plasmodium falciparum (the causative agent of malaria) through inhibition of its GCN5 KAT (15,16).…”

mentioning

confidence: 88%

Garcinol Inhibits GCN5-Mediated Lysine Acetyltransferase Activity and Prevents Replication of the Parasite Toxoplasma gondii

Jeffers

Gao

Checkley

et al. 2016

Antimicrob Agents Chemother

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Lysine acetylation is a critical posttranslational modification that influences protein activity, stability, and binding properties. The acetylation of histone proteins in particular is a well-characterized feature of gene expression regulation. In the protozoan parasite Toxoplasma gondii, a number of lysine acetyltransferases (KATs) contribute to gene expression and are essential for parasite viability. The natural product garcinol was recently reported to inhibit enzymatic activities of GCN5 and p300 family KATs in other species. Here we show that garcinol inhibits TgGCN5b, the only nuclear GCN5 family KAT known to be required for Toxoplasma tachyzoite replication. Treatment of tachyzoites with garcinol led to a reduction of global lysine acetylation, particularly on histone H3 and TgGCN5b itself. We also performed transcriptome sequencing (RNA-seq), which revealed increasing aberrant gene expression coincident with increasing concentrations of garcinol. The majority of the genes that were most significantly affected by garcinol were also associated with TgGCN5b in a previously reported chromatin immunoprecipitation assay with microarray technology (ChIP-chip) analysis. The dysregulated gene expression induced by garcinol significantly inhibits Toxoplasma tachyzoite replication, and the concentrations used exhibit no overt toxicity on human host cells. Garcinol also inhibits Plasmodium falciparum asexual replication with a 50% inhibitory concentration (IC 50 ) similar to that for Toxoplasma. Together, these data support that pharmacological inhibition of TgGCN5b leads to a catastrophic failure in gene expression control that prevents parasite replication.

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“…A reported GCN5 inhibitor MC1626 was found to be active against T. gondii, but not to inhibit the parasite GCN5. It seemed instead to target the apicoplast [74]. This underlines the possible off-target effects of HME inhibitors.…”

Section: -Inhibitors Of Hatsmentioning

confidence: 90%

Targeting Schistosome Histone Modifying Enzymes for Drug Development

Pierce

Dubois-Abdesselem²,

Lancelot³

et al. 2012

cpd

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The histone modifying enzymes (HME) represent particularly promising targets for the development of alternatives to praziquantel, the only currently available drug to combat schistosomiasis. The inhibition of these enzymes frequently arrests the cell cycle or induces apoptosis in cancer cells, but not in normal cells and numerous HME inhibitors are under investigation as potential anticancer agents. The recent resolution of the genome sequences of Schistosoma mansoni and Schistosoma japonicum has allowed us to identify all the schistosome genes encoding histone acetyltransferases, deacetylases, methyltransferases and demethylases. We have chosen a strategy using phylogenetic screening with inhibitors of HME classes, screening of individual HME targets by both high-throughput and reasoned (in silico docking using resolved crystal structures) approaches in a project funded by the European Community, named SEtTReND (Schistosome Epigenetics: Targets, Regulation, New Drugs). The initial focus is on the class I histone deacetylase (HDAC) 8 since the comparison of the catalytic site of the schistosome and human enzymes shows crucial differences, rendering possible the development of inhibitors specific for SmHDAC8. However, phenotypic screening shows that inhibitors of all HME classes tested were able to induce apoptosis and death in parasites in vitro, indicating that other enzymes may prove to be viable targets. SCHISTOSOMIASIS: IMPACT OF THE DISEASE AND THE NEED FOR NEW DRUGSThe impact of schistosomiasis on communities in endemic areas extends well beyond the classical signs of morbidity: Symmer's fibrosis leading to hepato-splenomegaly, ascites, oesophageal varices, and culminating in death. These overt and catastrophic symptoms affect only a relatively small percentage of infected individuals, even if absolute numbers of annual deaths (about 280 000) are high. However, more cryptic effects such as anaemia, undernutrition, diarrhoea and chronic pelvic or abdominal pain were consistently underevaluated until a meta-analysis of a large number of previous schistosomiasis morbidity studies by King et al.[1] allowed an objective assessment. This showed that the WHO's previously estimated disability weight for schistosomiasis of 0.5%, based essentially on mortality, should be markedly revised upwards to between 2 and 15% and that the years of life lost to schistosomiasis represented a relatively small proportion of the total of years lost to disability. This reassessment of the true disease burden represented by schistosomiasis has led to the realization of the importance of reinforcing control measures.In the continuing absence of an effective infection-preventing vaccine, the only viable strategy is the mass-treatment of populations in endemic areas using the currently available drug, praziquantel. Thus the Schistosomiasis Control Initiative in Africa [2] had dispensed more than 40 million praziquantel treatments in eight sub-Saharan countries by 2008. This ongoing programme will undoubtedly have a major impact, both on...

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Quinoline Derivative MC1626, a Putative GCN5 Histone Acetyltransferase (HAT) Inhibitor, Exhibits HAT-Independent Activity against Toxoplasma gondii

Cited by 31 publications

References 20 publications

Hydroxychloroquine, chloroquine, and all-trans retinoic acid regulate growth, survival, and histone acetylation in breast cancer cells

Hydroxychloroquine, chloroquine, and all-trans retinoic acid regulate growth, survival, and histone acetylation in breast cancer cells

Garcinol Inhibits GCN5-Mediated Lysine Acetyltransferase Activity and Prevents Replication of the Parasite Toxoplasma gondii

Targeting Schistosome Histone Modifying Enzymes for Drug Development

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