Will broad-spectrum histone deacetylase inhibitors be superseded by more specific compounds?

Karagiannis, Tom C.; El‐Osta, Assam

doi:10.1038/sj.leu.2404464

Cited by 94 publications

(73 citation statements)

References 63 publications

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“…In the 30-year period following the discovery of chemical inhibitors of HDACs (Riggs et al, 1977;Vidali et al, 1978), such pharmacological compounds have transited from the laboratory bench to the treatment of cancer patients (reviewed by Johnstone, 2002;Karagiannis and El-Osta, 2007). Although early trials have used broad-spectrum inhibitors, selective targeting of specific deacetylases may provide a better alternative.…”

Section: Hdac3 As An Attractive Therapeutic Targetmentioning

confidence: 99%

HDAC3: taking the SMRT-N-CoRrect road to repression

2007

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Known histone deacetylases (HDACs) are divided into different classes, and HDAC3 belongs to Class I. Through forming multiprotein complexes with the corepressors SMRT and N-CoR, HDAC3 regulates the transcription of a plethora of genes. A growing list of nonhistone substrates extends the role of HDAC3 beyond transcriptional repression. Here, we review data on the composition, regulation and mechanism of action of the SMRT/ N-CoR-HDAC3 complexes and provide several examples of nontranscriptional functions, to illustrate the wide variety of physiological processes affected by this deacetylase. Furthermore, we discuss the implication of HDAC3 in cancer, focusing on leukemia. We conclude with some thoughts about the potential therapeutic efficacies of HDAC3 activity modulation.

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Section: Hdac3 As An Attractive Therapeutic Targetmentioning

confidence: 99%

HDAC3: taking the SMRT-N-CoRrect road to repression

2007

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“…13,14 However, several factors, including the similarity between their catalytic sites, the difficulty in obtaining purified active proteins and until recently, lack of X-ray crystal structures, have hampered the search for potent isoform-specific inhibitors, and this in turn has slowed down the progress in delineating the biology of the individual HDAC isoforms in cancer. 15,16 Knockdown experiments of selective HDAC isoforms have revealed that HDAC8 is essential for cell survival. 17 HDAC8 is a 49 kDa HDAC isoform with deacetylase activity in vitro that is expressed in multiple tissue types and tumor cell lines.…”

Section: Introductionmentioning

confidence: 99%

A novel histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 induces apoptosis in T-cell lymphomas

et al. 2008

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We have developed a potent, histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 with 4200-fold selectivity over the other HDAC isoforms. PCI-34051 induces caspase-dependent apoptosis in cell lines derived from T-cell lymphomas or leukemias, but not in other hematopoietic or solid tumor lines. Unlike broad-spectrum HDAC inhibitors, PCI-34051 does not cause detectable histone or tubulin acetylation. Cells defective in T-cell receptor signaling were still sensitive to PCI-34051-induced apoptosis, whereas a phospholipase C-c1 (PLCc1)-defective line was resistant. Jurkat cells showed a dosedependent decrease in PCI-34051-induced apoptosis upon treatment with a PLC inhibitor U73122, but not with an inactive analog. We found that rapid intracellular calcium mobilization from endoplasmic reticulum (ER) and later cytochrome c release from mitochondria are essential for the apoptotic mechanism. The rapid Ca 2 þ flux was dependent on PCI-34051 concentration, and was blocked by the PLC inhibitor U73122. Further, apoptosis was blocked by Ca 2 þ chelators (BAPTA) and enhanced by Ca 2 þ effectors (thapsigargin), supporting this model. These studies show that HDAC8-selective inhibitors have a unique mechanism of action involving PLCc1 activation and calcium-induced apoptosis, and could offer benefits including a greater therapeutic index for treating T-cell malignancies.

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“…As the efficacy and safety data from human cancer trials with nonselective HDAC inhibitors emerge, the question remains as to whether it will be advantageous to develop isotype-selective inhibitors to improve the therapeutic index over non-selective inhibitors (39). Additionally, research continues to define which specific HDAC isotype(s) are better targets for human cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo

Fournel¹,

Bonfils²,

Hou³

et al. 2008

Molecular Cancer Therapeutics

312

241

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Nonselective inhibitors of human histone deacetylases (HDAC) are known to have antitumor activity in mice in vivo, and several of them are under clinical investigation. The first of these, Vorinostat (SAHA), has been approved for treatment of cutaneous T-cell lymphoma. Questions remain concerning which HDAC isotype(s) are the best to target for anticancer activity and whether increased efficacy and safety will result with an isotypeselective HDAC inhibitor. We have developed an isotypeselective HDAC inhibitor, MGCD0103, which potently targets human HDAC1 but also has inhibitory activity against HDAC2, HDAC3, and HDAC11 in vitro. In intact cells, MGCD0103 inhibited only a fraction of the total HDAC activity and showed long-lasting inhibitory activity even upon drug removal. MGCD0103 induced hyperacetylation of histones, selectively induced apoptosis, and caused cell cycle blockade in various human cancer cell lines in a dose-dependent manner. MGCD0103 exhibited potent and selective antiproliferative activities against a broad spectrum of human cancer cell lines in vitro, and HDAC inhibitory activity was required for these effects. In vivo, MGCD0103 significantly inhibited growth of human tumor xenografts in nude mice in a dose-dependent manner and the antitumor activity correlated with induction of histone acetylation in tumors. Our findings suggest that the isotype-selective HDAC inhibition by MGCD0103 is sufficient for antitumor activity in vivo and that further clinical investigation is warranted. [Mol Cancer Ther 2008;7(4):759 -68]

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Will broad-spectrum histone deacetylase inhibitors be superseded by more specific compounds?

Cited by 94 publications

References 63 publications

HDAC3: taking the SMRT-N-CoRrect road to repression

HDAC3: taking the SMRT-N-CoRrect road to repression

A novel histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 induces apoptosis in T-cell lymphomas

MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo

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