Preclinical antitumor activity of ST7612AA1: a novel second generation oral histone deacetylase (HDAC) inhibitor
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE62460 | GEO | 2015/03/18
SECONDARY ACCESSION(S): PRJNA264171
REPOSITORIES: GEO
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Project description: Not available
| S-EPMC4467398 | biostudies-literature
Project description:Epithelioid Sarcoma (ES) is a rare neoplasm uniquely comprised of cells exhibiting both mesenchymal and epithelial features. Having propensity for local and distant recurrence, it can pose a diagnostic dilemma secondary to pathologic complexity. Patients have dismal prognosis due to lack of effective therapy. HDAC inhibitors exhibit marked anti-tumor effects in various malignancies. Our studies demonstrate that pan-HDAC inhibitors constitute potentially novel therapeutics versus ES. Human ES cells (VAESBJ, HS-ES, Epi544) were studied in vitro to evaluate the effects of HDACi. Gene array analysis was used to identify the impact of HDACi on ES gene expression in three cell lines.
2015-11-03 | E-GEOD-66800 | biostudies-arrayexpress
Project description:HDAC inhibitors (HDACi) belong to a new group of chemotherapeutics that are increasingly used to treat B-cell-derived malignancies. Such malignancies regularly carry mutational signatures that conform to off-target induction of uracil by the AID/APOBEC family of cytidine deaminases, or downstream processing of uracil. . HDACi suppress thymidylate synthase increasing the cellular dUTP/dTTP ratio and leading to increased pressure on uracil repair machinery due to misincorporated uracil lesions. To investigate potential effect upon other enzymes involved in genomic uracil induction and processing, Jurkat (T-cell lymphoma) and SUDHL5 (B-cell lymphoma) cells were treated with pan-HDACi SAHA prior to SILAC based MS/MS investigation. HDACi treatment mediated significant differential expression of xx and xx proteins in Jurkat and SUDHL5, respectively, and had a substantial impact upon enzymes involved in in pyrimidine metabolism. Surprisingly, uracil N-glycosylase, UNG, was strongly downregulated by HDACi treatment. Further analysis in HEK and HeLa cells revealed that HDACis induce specific loss of the nuclear isoform UNG2 independent of transcription and cell-cycle alterations. More than 80% of UNG2 is degraded proteasomally after 24 hours treatment with SAHA, MS275, Valproate or Na-butyrate, indicating a universal ability of HDACis to mediate loss of UNG2. Targeted MS/MS analysis in HEK cells against a panel of proteins involved in DNA repair, translesion synthesis and nucleotide metabolism, revealed that UNG2 was the most pronounced differentially expressed among these after HDACi treatment. 48 hour treatment lead to a 30-40% increase in uracil lesions in the nuclear genome of HeLa and HEK cells and MS275 treatment in murine CH12F3 cell line mediated robust UNG2-loss accompanied by reduced class switch recombination. Furthermore, our analysis identified the PCNA-associated factor PAF15 among the downregulated proteins. PAF15 is overexpressed in many cancers and suppress TLS by inducing double monoubiquitinylation of PCNA and recruitment of the replicative polymerases. In summary, our findings demonstrate that HDAC inhibition affects the levels of proteins involved in DNA base excision repair, translesion synthesis and pyrimidine metabolism. These findings are important for a wide range of clinical applications of HDACi, such as in rheumatology, HIV-, and cancer treatment.
2020-04-14 | PXD008293 | Pride
Project description:Histone acetylation, which is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), plays a crucial role in the control of gene expression. HDAC inhibitors (HDACi) have shown potential in cancer therapy; however, the specific roles of HDACs in early embryos remain unclear. Moreover, although some pan-HDACi have been used to maintain cellular undifferentiated states in early embryos, the specific mechanisms underlying their effects remain unknown. Thus, there remains a significant knowledge gap regarding the application of selective HDACi in early embryos. To address this gap, we treated early embryos with two selective HDACi (MGCD0103 and T247). Subsequently, we collected and analyzed their transcriptome data at different developmental stages. Our findings unveiled a significant effect of HDACi treatment during the crucial 2-cell stage of zygotes, leading to a delay in embryonic development after T247 and an arrest at 2-cell stage after MGCD0103 administration. Furthermore, we elucidated the regulatory targets underlying this arrested embryonic development, which pinpointed the G2/M phase as the potential period of embryonic development arrest caused by MGCD0103. Moreover, our investigation provided a comprehensive profile of the biological processes that are affected by HDACi, with their main effects being predominantly localized in four aspects of zygotic gene activation (ZGA): RNA splicing, cell cycle regulation, autophagy, and transcription factor regulation. By exploring the transcriptional regulation and epigenetic features of the genes affected by HDACi, we made inferences regarding the potential main pathways via which HDACs affect gene expression in early embryos. Notably, Hdac7 exhibited a distinct response, highlighting its potential as a key player in early embryonic development. Our study conducted a comprehensive analysis of the effects of HDACi on early embryonic development at the transcriptional level. The results demonstrated that HDACi significantly affected ZGA in embryos, elucidated the distinct actions of various selective HDACi, and identified specific biological pathways and mechanisms via which these inhibitors modulated early embryonic development.
2024-01-18 | GSE238124 | GEO
Project description:Epithelioid Sarcoma (ES) is a rare neoplasm uniquely comprised of cells exhibiting both mesenchymal and epithelial features. Having propensity for local and distant recurrence, it can pose a diagnostic dilemma secondary to pathologic complexity. Patients have dismal prognosis due to lack of effective therapy. HDAC inhibitors exhibit marked anti-tumor effects in various malignancies. Our studies demonstrate that pan-HDAC inhibitors constitute potentially novel therapeutics versus ES. Human ES cells (VAESBJ, HS-ES, Epi544) were studied in vitro to evaluate the effects of HDACi.
2015-11-03 | GSE66800 | GEO
Project description:Histone deacetylase inhibitors are a class of drug which rapidly induce hyperacetylation of histone proteins. Here, we aimed to study the association between HDACi-induced histone acetylation and changes in gene expression. To study the early responses to HDACi treatment we treated cells with three different concentrations of two HDACi, sodium valproate (VPA) and suberoylanilide hydroxamic acid over a short timecourse.
2015-08-31 | GSE65297 | GEO
Project description:We investigated the response of acute myeloid cells (AML) expressing MLL-AF9 fusion gene to the pan-HDACi panobinostat (LBH589), and found that low conentrations of panobinostat lead to MLL-AF9 cell toxicity and rapid changes in gene expression. Human hematopoietic stem/progenitor cells (HSPC) expressing MLL-AF9 fusion protein (Wei et al, Cancer Cell 2008) were cultured with 30 nM panobinostat during 6 and 24 hours. The different gene expression between cells treated and untreated was studied by gene expression analysis. Three independent HSPC-MA9 clones were used, for each two replicates of cells after culture with 30 nM panobinostat for 6 and 24 hours and one untreated were used. A total of 16 samples were analyzed.
2015-03-01 | E-GEOD-54218 | biostudies-arrayexpress
Project description:Dual bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first and second bromodomains across BRD2, BRD3, BRD4 and BRDt only displayed modest activity as monotherapy in clinical trials. Thrombocytopenia, closely followed by symptoms characteristic of GI toxicity, have presented as dose limiting adverse events that may prevented escalation to higher dose levels for more robust efficacy. ABBV-744 is a highly selective inhibitor for the second bromodomain (BD2) of the four BET family proteins. In contrast to the broad antiproliferative activities observed with DbBi, ABBV-744 displayed significant antiproliferative activities largely but not exclusively in cancer cell lines derived from AML and androgen receptor (AR) positive prostate cancer. Studies in AML xenograft models demonstrated anti-tumor efficacy for ABBV-744 that was comparable to the pan-BET inhibitor ABBV-075 but with improved tolerability. Enhanced anti-tumor efficacy was also observed with the combination of ABBV-744 and the Bcl-2 inhibitor, venetoclax (ABT-199) compared to monotherapies of either agent alone. These results collectively support the clinical evaluation of ABBV-744 in AML (Clinical Trials.gov identifier: NCT03360006).
2021-01-31 | GSE144326 | GEO
Project description:We investigated the response of acute myeloid cells (AML) expressing MLL-AF9 fusion gene to the pan-HDACi panobinostat (LBH589), and found that low conentrations of panobinostat lead to MLL-AF9 cell toxicity and rapid changes in gene expression. Human hematopoietic stem/progenitor cells (HSPC) expressing MLL-AF9 fusion protein (Wei et al, Cancer Cell 2008) were cultured with 30 nM panobinostat during 6 and 24 hours. The different gene expression between cells treated and untreated was studied by gene expression analysis.
2015-03-01 | GSE54218 | GEO
Project description:S78454 (Abexinostat, PCI-24781) is a pan histone deacetylase inhibitor (HDACi) that demonstrates efficacy in malignancy treatment. Like other HDACi, this drug induces a profound thrombocytopenia, whose mechanism is partially understood. We have tested its effect at doses reached in patients plasma on in vitro megakaryopoiesis derived from human CD34+ cells. When added at day 0 in culture, S78454 inhibited CFU-MK growth, megakaryocyte (MK) proliferation and differentiation. This effect only required a short incubation period. When added later on (day 8), the compound induced a dose-dependent decrease (up to 10-fold) in proplatelet formation. Decreased proliferation was due to induction of apoptosis and was not related to a defect in TPO/MPL/JAK2 signaling. MK gene profiling revealed a silencing in the expression of DNA repair genes with a marked RAD51 decrease at protein level. Double DNA strand breaks were increased as attested by elevated gH2AX phosphorylation level. Consequently, ATM was phosphorylated leading to p53 stabilization and increased BAX and p21 expression. The use of a p53 shRNA rescued apoptosis, but only partially the defect in proplatelet formation. These results suggest that HDACi induces a thrombocytopenia by a p53 dependent mechanism along MK differentiation and a p53 independent mechanism for proplatelet formation.
2013-06-30 | E-MTAB-1180 | biostudies-arrayexpress