scholarly journals Histone Deacetylase Inhibitor, Trichostatin A, Synergistically Enhances Paclitaxel-Induced Cytotoxicity in Urothelial Carcinoma Cells by Suppressing the ERK Pathway

2019 ◽  
Vol 20 (5) ◽  
pp. 1162 ◽  
Author(s):  
Fu-Shun Hsu ◽  
June-Tai Wu ◽  
Jing-Yi Lin ◽  
Shao-Ping Yang ◽  
Kuan-Lin Kuo ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Erk Pathway ◽  
Antitumor Effects ◽  
Nude Mouse Model ◽  
Synergistic Cytotoxicity ◽  
Histone Deacetylase Inhibitor Trichostatin

Trichostatin A (TSA), an antifungal antibiotic derived from Streptomyces, inhibits mammalian histone deacetylases, and especially, selectively inhibits class I and II histone deacetylase (HDAC) families of enzymes. TSA reportedly elicits an antiproliferative response in multifarious tumors. This study investigated the antitumor effects of TSA alone and in combination with paclitaxel when applied to two high-grade urothelial carcinoma (UC) cell lines (BFTC-905 and BFTC-909). Fluorescence-activated cell sorting, flow cytometry, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium assay were used to assess TSA’s cytotoxicity and effects on apoptosis induction. TSA induced synergistic cytotoxicity, when combined with paclitaxel (combination index < 1), resulted in concomitant suppression of paclitaxel-induced activation of phospho-extracellular signal-regulated kinase (ERK) 1/2. A xenograft nude mouse model confirmed that TSA enhances the antitumor effects of paclitaxel. These findings demonstrate that the administration of TSA in combination with paclitaxel elicits a synergistic cytotoxic response. The results of this study indicate that the chemoresistance of UC could be circumvented by combining HDAC inhibitors to target the ERK pathway.

Histone deacetylase inhibitors suppress IFNα-induced up-regulation of promyelocytic leukemia protein

Blood ◽  
2006 ◽  
Vol 109 (4) ◽  
pp. 1373-1380 ◽  
Author(s):  
Jana Vlasáková ◽  
Zora Nováková ◽  
Lenka Rossmeislová ◽  
Michal Kahle ◽  
Pavel Hozák ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Transcriptional Activation ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Eukaryotic Cell ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Interferon Α

Abstract Promyelocytic leukemia nuclear bodies (PML NBs), the structural domains of the eukaryotic cell nucleus, play a role in cancer and apoptosis, and their involvement in antiviral mechanisms mediated by interferons (IFNs) is proposed. IFNs dramatically increase the transcription of the PML gene. In this study, we have shown that the response of 2 structural PML NB components, PML and Sp100, to interferon-α (IFNα) was suppressed in cells simultaneously treated with histone deacetylase (HDAC) inhibitors (trichostatin A, sodium butyrate, MS-275, SAHA, and valproic acid). Trichostatin A (TSA) blocked the increase of PML NB number and suppressed up-regulation of PML mRNA and protein levels in several human cell lines and in normal diploid skin fibroblasts. Moreover, IFNα induction of IRF-1 was also inhibited by TSA, although incompletely. Analysis of cellular fractions did not show any defects in cytoplasmic-nuclear transport of STAT2, a component of transcription factor ISGF3 responsible for IFNα/β-dependent gene transcription. Moreover, chromatin immunoprecipitation showed that after IFNα stimulation STAT2 binds to ISRE element of PML promoter even in the presence of TSA and thus excluded STAT2-dependent mechanism of TSA effect. These results indicate that the action of histone deacetylases is necessary for the full transcriptional activation of IFNα-stimulated genes.

Sign in / Sign up

Export Citation Format

Share Document