Epigenetic and molecular mechanisms underlying the antileukemic activity of the histone deacetylase inhibitor belinostat in human acute promyelocytic leukemia cells

Savickienė, Jūratė; Treigytė, Gražina; Valiulienė, Giedrė; Stirblytė, Ieva; Navakauskienė, Rūta

doi:10.1097/cad.0000000000000122

Cited by 33 publications

(27 citation statements)

References 40 publications

(45 reference statements)

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“…A preclinical study of belinostat in three hepatocellular carcinoma cell lines (PLC/PRF/5, Hep3B and HepG2) showed that it can inhibit cell growth in a dose dependent manner and induce histone acetylation in all three cell lines [ 63 ]. Antileukemia activity of this compound as a single drug and in combination with all- trans -retinoic acid was characterized in promyelocytic leukemia HL-60 and NB4 cell lines, where belinostat can exert dose-dependent growth inhibitory or proapoptotic effects promoting cell cycle arrest at the G0/G1 or the S transition phase [ 64 ].…”

Section: Fda Approved Drugsmentioning

confidence: 99%

Histone Deacetylase Inhibitors in Clinical Studies as Templates for New Anticancer Agents

et al. 2015

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Histone dacetylases (HDACs) are a group of enzymes that remove acetyl groups from histones and regulate expression of tumor suppressor genes. They are implicated in many human diseases, especially cancer, making them a promising therapeutic target for treatment of the latter by developing a wide variety of inhibitors. HDAC inhibitors interfere with HDAC activity and regulate biological events, such as cell cycle, differentiation and apoptosis in cancer cells. As a result, HDAC inhibitor-based therapies have gained much attention for cancer treatment. To date, the FDA has approved three HDAC inhibitors for cutaneous/peripheral T-cell lymphoma and many more HDAC inhibitors are in different stages of clinical development for the treatment of hematological malignancies as well as solid tumors. In the intensifying efforts to discover new, hopefully more therapeutically efficacious HDAC inhibitors, molecular modeling-based rational drug design has played an important role in identifying potential inhibitors that vary in molecular structures and properties. In this review, we summarize four major structural classes of HDAC inhibitors that are in clinical trials and different computer modeling tools available for their structural modifications as a guide to discover additional HDAC inhibitors with greater therapeutic utility.

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Section: Fda Approved Drugsmentioning

confidence: 99%

Histone Deacetylase Inhibitors in Clinical Studies as Templates for New Anticancer Agents

et al. 2015

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“…In addition, ChIP results indicated the obvious increase in hyperacetylated histone H4 association with p27 promoter region. It was demonstrated earlier 22 , that belinostat up-regulates NB4 cells p27 protein levels as well. Taken this data together, it is plausible not to underestimate the role of p27 activation in belinostat-mediated antileukaemic effect.…”

Section: Discussionmentioning

confidence: 78%

“…In addition, our group previously indicated 22 that, although belinostat promotes APL granulocytic differentiation, as a single agent it has no effect on NB4 cells C/EBPα and C/EBPε genes expression or genes coding for transcription factors that drive granulocytic differentiation 47 , 48 . In this study, using ChIP, we aimed to determine histone H4 hyperacetylation level in C/EBPα and C/EBPε promoter regions.…”

Section: Discussionmentioning

confidence: 99%

Belinostat, a potent HDACi, exerts antileukaemic effect in human acute promyelocytic leukaemia cells via chromatin remodelling

Valiulienė

Stirblytė

Cicenaite

et al. 2015

J Cellular Molecular Medi

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Epigenetic changes play a significant role in leukaemia pathogenesis, therefore histone deacetylases (HDACis) are widely accepted as an attractive strategy for acute promyelocytic leukaemia (APL) treatment. Belinostat (Bel, PXD101), a hydroxamate-type HDACi, has proved to be a promising cure in clinical trials for solid tumours and haematological malignancies. However, insight into molecular effects of Bel on APL, is still lacking. In this study, we investigated the effect of Bel alone and in combination with differentiation inducer retinoic acid (RA) on human promyelocytic leukaemia NB4 and HL-60 cells. We found that treatment with Bel, depending on the dosage used, inhibits cell proliferation, whereas in combination with RA enhances and accelerates granulocytic leukaemia cell differentiation. We also evaluated the effect of used treatments with Bel and RA on certain epigenetic modifiers (HDAC1, HDAC2, PCAF) as well as cell cycle regulators (p27) gene expression and protein level modulation. We showed that Bel in combination with RA up-regulates basal histone H4 hyperacetylation level more strongly compared to Bel or RA alone. Furthermore, chromatin immunoprecipitation assay indicated that Bel induces the accumulation of hyperacetylated histone H4 at the p27 promoter region. Mass spectrometry analysis revealed that in control NB4 cells, hyperacetylated histone H4 is mainly found in association with proteins involved in DNA replication and transcription, whereas after Bel treatment it is found with proteins implicated in pro-apoptotic processes, in defence against oxidative stress and tumour suppression. Summarizing, our study provides some novel insights into the molecular mechanisms of HDACi Bel action on APL cells.

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“…These observations fueled a lot of investigations on the anticancer properties of AF and its analogues, and on the underlying molecular mechanisms [ 2 , 3 , 4 , 5 ]. In recent years, new knowledge regarding the molecular mechanisms involved in leukemia cells growth has shifted the focus of antileukemic drug development to agents acting on specific molecular targets and pathways that regulate signal transduction, epigenetic alterations, cell death, and cell cycle progression [ 6 , 7 , 8 , 9 ]. In this regard, the ubiquitin-proteasome system seems to be a particularly attractive target [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Antiproliferative Properties of a Few Auranofin-Related Gold(I) and Silver(I) Complexes in Leukemia Cells and their Interferences with the Ubiquitin Proteasome System

et al. 2020

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A group of triethylphosphine gold(I) and silver(I) complexes, structurally related to auranofin, were prepared and investigated as potential anticancer drug candidates. The antiproliferative properties of these metal compounds were assessed against two leukemia cell lines, i.e., CCRF-CEM and its multidrug-resistant counterpart, CEM/ADR5000. Interestingly, potent cytotoxic effects were disclosed for both series of compounds against leukemia cells, with IC50 values generally falling in the low-micromolar range, the gold derivatives being on the whole more effective than the silver analogues. Some initial structure-function relationships were drawn. Subsequently, the ability of the study compounds to inhibit the three main catalytic activities of the proteasome was investigated. Different patterns of enzyme inhibition emerged for the various metal complexes. Notably, gold compounds were able to inhibit effectively both the trypsin-like and chymotrypsin-like proteasome activities, being less effective toward the caspase-like catalytic activity. In most cases, a significant selectivity of the study compounds toward the proteasome proteolytic activities was detected when compared to other proteases. The implications of the obtained results are discussed.

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Epigenetic and molecular mechanisms underlying the antileukemic activity of the histone deacetylase inhibitor belinostat in human acute promyelocytic leukemia cells

Cited by 33 publications

References 40 publications

Histone Deacetylase Inhibitors in Clinical Studies as Templates for New Anticancer Agents

Histone Deacetylase Inhibitors in Clinical Studies as Templates for New Anticancer Agents

Belinostat, a potent HDACi, exerts antileukaemic effect in human acute promyelocytic leukaemia cells via chromatin remodelling

Antiproliferative Properties of a Few Auranofin-Related Gold(I) and Silver(I) Complexes in Leukemia Cells and their Interferences with the Ubiquitin Proteasome System

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