The novel histone deacetylase inhibitor BML-210 exerts growth inhibitory, proapoptotic and differentiation stimulating effects on the human leukemia cell lines (original) (raw)
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Annals of The New York Academy of Sciences, 2006
FK228 (depsipeptide) is a novel histone deacetylase inhibitor (HDACI) that has shown therapeutical efficacy in clinical trials for malignant lymphoma. In this article, we examined in vitro effects of FK228 on human leukemia cell lines, NB4 and HL-60. FK228 alone (0.2-1 ng/mL) inhibited leukemia cell growth in a dose-dependent manner and induced death by apoptosis. FK228 had selective differentiating effects on two cell lines when used for 6 h before induction of granulocytic differentiation by retinoic acid (RA) or in combination with RA. These effects were accompanied by a time-and dose-dependent histone H4 hyper-acetylation or histone H3 dephosphorylation and alterations in DNA binding of NF-B in association with cell death and differentiation. Pifithrin-␣ (PFT), an inhibitor of p53 transcriptional activity, protected only NB4 cells with functional p53 from FK228-induced apoptosis and did not interfere with antiproliferative activity in p53-negative HL-60 cells. In NB4 cells, PFT inhibited p53 binding to the p21 (Waf1/Cip1) promotor and induced DNA binding of NF-B leading to enhanced cell survival. Thus, beneficial effects of FK228 on human promyelocytic leukemia may be exerted through the induction of differentiation or apoptosis via histone modification and selective involvement of transcription factors, such as NF-B and p53.
Haematologica, 2004
Chromatin structure and thereby transcription is controlled by the level of acetylation of histones, which is determined by the balance between histone acetyl transferase (HAT) activity and histone deacetylase (HDAC) activity. HDAC inhibitors are a class of compounds able to regulate gene expression by modulating chromatin structure. There are two major classes of HDAC inhibitors: the hydroxamic acid derivatives such as trichostatin A (TSA) or SAHA, and the butyrates such as phenyl-butyrate. HDAC inhibitors interfere with differentiation, proliferation and apoptosis in tumor cells. Here, we investigated the activity of a new hydroxamic acid derivative, LAQ824, on lymphoblastic cells. Four different pre-B lymphoblastic cell lines: Sup-B15 and TMD-5, both t(9;22) positive, SEM, t(4;11) positive, and NALM-6 cells were exposed to the hydroxamic acid derivatives, LAQ824 and TSA. Histone hyperacetylation, apoptosis, cell cycle and related pathways were assessed by flow cytometry and Weste...
Apoptotic effects of the novel histone deacetylase inhibi tor BML210 on HeLa cells
2008
Histone deacetylase inhibitors (HDACI) have been shown to inhibit cancer cell proliferation, induce cell cycle arrest, and stimulate apoptosis. To date, the key apoptotic proteins and pathways necessary for the anti-tumor activities of HDACI remain ill-defined, and the specific genes regulated by HDACI to mediate these effects have not been fully dissected. We have asked how novel HDACIs induce apoptosis, and how tumour cells can circumvent HDACI-mediated cell death. In the present study, we have investigated the antiproliferative effects of the novel HDACI, BML-210, and its combination with retinoic acid (RA) on human cervical cancer cells (HeLa). Cell cycle analysis indicated that HeLa cell treatment with BML-210 alone (10 µM) and in its 5 µM combination with 1 µM Ra decreased the proportion of cells in g 2 /M phase, increased in g 0 /g 1 and caused accumulation in subg1 indicating the cells undergoing apoptosis. These changes occurred concomitantly with the increased level of some proteins related to the malignant phenotype. We observed the activation of caspases 3, 8, 9 and an increase of the transcription factor NF-κB in the HeLa cell nucleus at 24 h of treatment with BML-210 or RA alone and in combination. Electrophoretic mobility shift assay (EMSA) experiments revealed an enhanced binding activity of NF-κB and the transcription factor p53 to the p21 promoter immediately after treatment with BML-210. In conclusion, these results suggest that BML-210 and its combination with RA are effective in inhibiting growth and inducing apoptosis in HeLa cells in vitro. The findings imply that BML-210 may prove particularly effective in cancer therapy.
Histone deacetylase inhibitors: A new perspective for the treatment of leukemia
Leukemia Research, 2010
Histone deacetylase inhibitors (HDIs) promote or enhance several different anticancer mechanisms and therefore are in evidence as potential antileukemia agents. Studies on leukemia have provided examples for their functional implications in cancer development and progression, as well as their relevance for therapeutic targeting. A number of HDIs have been tested in clinical trials and have been proven safe with significant clinical activity. The use of HDIs in association with other molecules, such as classical chemotherapeutic drugs and DNA demethylating agents, has been implied as a promising treatment alternative for leukemia patients in the future. Here we describe the histone deacetylase inhibitors that have been tested in clinical trials for the treatment of leukemia and lymphoma. We conclude that further clinical trials involving a broader number of HDIs used either alone or in combination with other agents are needed to consolidate the use of these epigenetic modulators on leukemia therapy.
Induction of apoptosis in B-CLL cells by selected histone deacetylase inhibitors
2011
Histone modifications influence the chromatin structure, changing the patterns of gene expression. Histone deacetylases (HDACs) comprise a group of enzymes governing acetylation status of N-terminal lysine residues of four core histones. Acetylation, the result of histone deacetylases inhibition, leads to cell cycle arrest and differentiation or apoptosis in neoplastic cells. The aim of the study was to induce apoptosis in B-cell chronic lymphocytic leukemia cells in vitro using histone deacetylase inhibitors. B-CLL cells isolated from peripheral blood of 30 patients were examined after 24 hour culture with histone deacetylase inhibitors: phenylbutyric acid and sodium butyrate. Control B-CLL cells were cultured either with dexamethasone (positive control of apoptosis) or media alone (negative control of apoptosis). Normal cells were also examined in this study: 6 specimens of B-lymphocytes isolated from tonsils and 6 specimens of peripheral blood lymphocytes isolated from healthy bl...
Biologija, 2005
The acute promyelocytic leukemia cell line NB4 can differentiate to granulocytes in response to retinoic acid (RA) or to monocytes / macrophages in response to 1.25 dihydroxyvitamin D 3 (1.25 D 3) and phorbol esters. We have examined changes in protein levels during granulocytic differentiation of NB4 cells treated with RA alone or in combination with the histone deacetylase inhibitor (HDACI), Bml-210. By MALDI-TOF MS analysis we identified proteins that displayed significant changes in the expression level with indicated treatments. One of the identified proteins whose expression levels underwent significant changes is β-dystrobrevin, a splice isoform of α-dystrobrevin. We further demonstrated changes in the expression of α-dystrobrevin in total soluble and insoluble protein fractions of NB4 cells treated with RA or Bml-210 alone or in combination. We found increased levels of αdystrobrevin in the insoluble fraction of NB4 cells exposed to RA or in combination with Bml-210 for 24-48 h. The current results indicate an association between the increased level of dystrobrevin expression and induction of differentiation by RA. In the present work we also characterised some proteins that are present in proliferating leukemia cells and may be involved in the differentiation process in response to RA and combination of RA with HDAC inhibitor. Our results suggest that HDACI Bml-210 may be a promising agent in leukemia therapy.
Clinical immunology Induction of apoptosis in B-CLL cells by selected histone deacetylase inhibitors
Central European Journal of Immunology, 2011
Histone deacetylase inhibitors constitute a heterogenous group including short chain fatty acids [5], phenylbutyric acid [6, 7], benzamides etc., which have the ability of restoring acetylation of histone tails. This ability is essential in neoplastic cells, in which deacetylation is one of features of malignant phenotype [8]. Acetylation, the result of histone deacetylases inhibition, leads to cell cycle arrest and differentiation or apoptosis [9]. The aim of the study was to induce apoptosis in B-cell chronic lymphocytic leukemia cells in vitro using histone deacetylase inhibitors: phenylbutyric acid and sodium butyrate. Expression of P21 and HDAC1 gene as well as histone H3 and H4 acetylation status were assesed.