Histone Deacetylase Inhibitors: Latest Developments, Trends and Prospects

Moradei, Oscar; Maroun, Christiane R.; Paquin, Isabelle; Vaisburg, A. F.

doi:10.2174/1568011054866946

Cited by 80 publications

(45 citation statements)

References 64 publications

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“…Given that HIV undergoes early and late reverse transcription in astrocytes and yet is well documented to be restricted in productive HIV replication (22), we evaluated the status of histone modification of the HIV LTR in untreated astrocytes. Several histones wrap around the DNA, and when deacetylated they lead to chromatin condensation and are associated with inactive genes (29,34,52). However, once the histones are acetylated, the chromatin structure is modified, becoming accessible to replication enzymes.…”

Section: Resultsmentioning

confidence: 99%

Human Immunodeficiency Virus-Restricted Replication in Astrocytes and the Ability of Gamma Interferon To Modulate This Restriction Are Regulated by a Downstream Effector of the Wnt Signaling Pathway

Carroll-Anzinger¹,

Kumar²,

Adarichev

et al. 2007

J Virol

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Astrocyte dysregulation correlates with the severity and the rate of human immunodeficiency virus (HIV)-associated dementia (HAD) progression, highlighting a pivotal role for astrocytes in HIV neuropathogenesis. Yet, astrocytes limit HIV, indicating that they posses an intrinsic molecular mechanism to restrict HIV replication. We previously established that this restriction can be partly overcome by priming astrocytes with gamma interferon (IFN-␥), which is elevated in the cerebral spinal fluid of HAD patients. We evaluated the mechanism of restrictive HIV replication in astrocytes and how IFN-␥ priming modulates this restriction. We demonstrate that the downstream effector of Wnt signaling, T-cell factor 4 (TCF-4), is part of a transcriptional complex that is immunoprecipitated with HIV TAR-containing region in untreated astrocytes but not in IFN-␥-treated cells. Blocking TCF-4 activity with a dominant-negative mutant enhanced HIV replication by threefold in both the astrocytoma cell line U87MG and primary fetal astrocytes. Using a TCF-4 reporter plasmid, we directly demonstrate that Wnt signaling is active in human astrocytes and is markedly reduced by IFN-␥ treatment. Collectively, these data implicate TCF-4 in repressing HIV replication and the ability of IFN-␥ to regulate this restriction by inhibiting TCF-4. Given that TCF-4 is the downstream effector of Wnt signaling, harnessing Wnt signaling as an intrinsic molecular mechanism to limit HIV replication may emerge as a powerful tool to regulate HIV replication within and outside of the brain.

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Section: Resultsmentioning

confidence: 99%

Human Immunodeficiency Virus-Restricted Replication in Astrocytes and the Ability of Gamma Interferon To Modulate This Restriction Are Regulated by a Downstream Effector of the Wnt Signaling Pathway

Carroll-Anzinger¹,

Kumar²,

Adarichev

et al. 2007

J Virol

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“…Although current panHDACi are relatively well tolerated, they have been associated with numerous side effects such as cardiac arrhythmia, bone marrow depression, clotting disorders, diarrhea, fatigue, and electrolyte disturbances in phase I and II studies (48). It is expected that compounds that specifically inhibit the subset of enzymatic isoforms required to obtain a desired clinical outcome will substantially broaden the therapeutic window of HDACi (49).…”

Section: Discussionmentioning

confidence: 99%

Genetic dissection of histone deacetylase requirement in tumor cells

Haberland

Johnson

Mokalled

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

100

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Histone deacetylase inhibitors (HDACi) represent a new group of drugs currently being tested in a wide variety of clinical applications. They are especially effective in preclinical models of cancer where they show antiproliferative action in many different types of cancer cells. Recently, the first HDACi was approved for the treatment of cutaneous T cell lymphomas. Most HDACi currently in clinical development act by unspecifically interfering with the enzymatic activity of all class I HDACs (HDAC1, 2, 3, and 8), and it is widely believed that the development of isoform-specific HDACi could lead to better therapeutic efficacy. The contribution of the individual class I HDACs to different disease states, however, has so far not been fully elucidated. Here, we use a genetic approach to dissect the involvement of the different class I HDACs in tumor cells. We show that deletion of a single HDAC is not sufficient to induce cell death, but that HDAC1 and 2 play redundant and essential roles in tumor cell survival. Their deletion leads to nuclear bridging, nuclear fragmentation, and mitotic catastrophe, mirroring the effects of HDACi on cancer cells. These findings suggest that pharmacological inhibition of HDAC1 and 2 may be sufficient for anticancer activity, providing an experimental framework for the development of isoform-specific HDAC inhibitors.cancer ͉ mitotic catastrophe ͉ HDAC inhibitor ͉ acetylation ͉ tumorigenesis

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“…Here, we demonstrate only modest antiproliferative activity (IC 50 of 8 to 20 M) against P. falciparum in vitro for compounds known to be specific inhibitors of hHDAC enzymes of class I (MS-275), class II (2664-12), and class III (sirtinol) ( Table 1). MS-275 selectively inhibits hHDAC-1 (26), and compound 2664-12 is a thiolate analogue of an hHDAC-6-selective substrate and is a 40-fold-more-potent inhibitor of hHDAC-6 than hHDAC-1 or hHDAC-4 in enzyme assays (34), while sirtinol is a selective inhibitor of class III mammalian HDACs (15). One of our objectives was to rationally select HDAC inhibitors that might more potently inhibit PfHDACs.…”

Section: Effect Of Inhibitors Of Hhdacs On P Falciparum Growth In VImentioning

confidence: 99%

“…e Mammalian cell toxicity was tested against neonatal foreskin fibroblast cells for TSA (26), SBHA (2), and sirtinol (our unpublished results); against Vero cells for SAHA (24); and against WI-38 lung fibroblasts and breast fibroblasts for MS-275 (37).…”

Section: Effect Of Inhibitors Of Hhdacs On P Falciparum Growth In VImentioning

confidence: 99%

Potent Antimalarial Activity of Histone Deacetylase Inhibitor Analogues

Andrews

Tran

Lucke

et al. 2008

Antimicrob Agents Chemother

111

121

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The malaria parasite Plasmodium falciparum has at least five putative histone deacetylase (HDAC) enzymes, which have been proposed as new antimalarial drug targets and may play roles in regulating gene transcription, like the better-known and more intensively studied human HDACs (hHDACs). Fourteen new compounds derived from L-cysteine or 2-aminosuberic acid were designed to inhibit P. falciparum HDAC-1 (PfHDAC-1) based on homology modeling with human class I and class II HDAC enzymes. The compounds displayed highly potent antiproliferative activity against drug-resistant (Dd2) or drug sensitive (3D7) strains of P. falciparum in vitro (50% inhibitory concentration of 13 to 334 nM). Unlike known hHDAC inhibitors, some of these new compounds were significantly more toxic to P. falciparum parasites than to mammalian cells. The compounds inhibited P. falciparum growth in erythrocytes at both the early and late stages of the parasite's life cycle and caused altered histone acetylation patterns (hyperacetylation), which is a marker of HDAC inhibition in mammalian cells. These results support PfHDAC enzymes as being promising targets for new antimalarial drugs.

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Histone Deacetylase Inhibitors: Latest Developments, Trends and Prospects

Cited by 80 publications

References 64 publications

Human Immunodeficiency Virus-Restricted Replication in Astrocytes and the Ability of Gamma Interferon To Modulate This Restriction Are Regulated by a Downstream Effector of the Wnt Signaling Pathway

Human Immunodeficiency Virus-Restricted Replication in Astrocytes and the Ability of Gamma Interferon To Modulate This Restriction Are Regulated by a Downstream Effector of the Wnt Signaling Pathway

Genetic dissection of histone deacetylase requirement in tumor cells

Potent Antimalarial Activity of Histone Deacetylase Inhibitor Analogues

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