Histone deacetylase inhibitor trichostatin A inhibits the growth of bladder cancer cells through induction of p21WAF1 and G1 cell cycle arrest.
ABSTRACT To investigate whether Trichostatin A (TSA) possesses antitumor activity against human bladder cancer cells, and if any, its mechanism.
A human bladder cancer cell line, BIU-87, was treated with different concentrations of TSA. After treatment, cell growth was measured by MTT assay. Cell apoptosis and cell cycle changes were examined by means of flow cytometry (FCM). Apoptosis was confirmed by apoptotic ladder formation assay. mRNA expression of p21WAF1 and p53 was assessed by differential reverse transcription-polymerase chain reaction.
Trichostatin A significantly inhibited the proliferation of bladder cancer cell at nanomolar concentrations in a time- and dose-dependent fashion. TSA treatment caused cell cycle arrest at the G1 phase and increased apoptotic cell death as shown by FCM and DNA fragmentation analysis, accompanied by increased p21WAF1 mRNA expression. In addition, TSA treatment did not alter p53 mRNA expression.
Our results indicate that TSA is able to inhibit bladder cancer cell growth in vitro, possibly through p21WAF1 mediated cell cycle arrest and apoptotic cell death. This study suggests that TSA may be a potential therapeutic agent for the treatment of bladder cancer.
Article: Histone deacetylase inhibitors and a functional potent inhibitory effect on human uterine contractility.[show abstract] [hide abstract]
ABSTRACT: This study was undertaken to investigate the effects of 3 histone deacetylase inhibitors on human uterine contractility. Biopsy specimens of human myometrium were obtained at elective cesarean section (n = 18). Dissected myometrial strips suspended under isometric conditions, undergoing spontaneous, and oxytocin-induced contractions, were subjected to cumulative additions of 3 histone deacetylase inhibitors: trichostatin A, suberic bishydroxamate (1 nmol/L-10 micromol/L) and valproic acid (100 nmol/L--1 mmol/L). Control experiments were run simultaneously. Integrals of contractile activity were measured by using the PowerLab hardware unit and Chart v3.6 software. Data were analyzed by using 1-way analysis of variance, followed by post hoc analysis. All 3 histone deacetylase inhibitor compounds exerted a potent and cumulative inhibitory effect on spontaneous (n = 18) and oxytocin-induced (n =18) contractility. The mean maximal inhibition values for the 3 compounds were as follows: trichostatin A, 46-54% (P < .05); valproic acid, 35-36% (P < .05); and suberic bishydroxamate, 53-65% (P < .05). The histone deacetylase inhibitors trichostatin A, valproic acid, and suberic bishydroxamate exerted a potent inhibitory effect on human uterine contractions. This raises the possibility that this new class of compounds may have tocolytic potential, in addition to their current clinical indications. We speculate that this inhibitory effect may be linked, at least in part, to the ability of histone deacetylase inhibitors to induce the expression of genes involved in maintaining myometrial quiescence via epigenetic mechanisms but may also potentially involve nonepigenetic pathways.American journal of obstetrics and gynecology 05/2008; 199(2):167.e1-7. · 3.28 Impact Factor
Article: Toxicogenomic activity of gemcitabine in two TP53-mutated bladder cancer cell lines: special focus on cell cycle-related genes[show abstract] [hide abstract]
ABSTRACT: Because of its lower toxicity and good tolera-bility and response, gemcitabine has been described as one of the most highly promising drugs for urinary bladder cancer therapy. Its phosphorylated active-dFdCTP metab-olite can incorporate into DNA, causing replication blockage. Additionally, it is known that mutations in the TP53 gene are related to the high recurrence rate of these neoplasias. Based on these premises, we investigated the effects of gemcitabine on the expression of the cell cycle-related genes in two different TP53-mutated bladder tran-sitional carcinoma cell lines–5637 (from a moderate-grade tumor with a TP53 allele carrying two mutations) and T24 (from an invasive tumor with a TP53 allele encoding an in-frame deletion). Cell viability and morphology analyses (phase-contrast photomicrographs), Nuclear Division Index and pathway-specific quantitative RT-PCR gene arrays were performed. Treatment with gemcitabine led to the following results: (1) a significant decrease of viable T24 cells after treatment at the highest concentration (3.12 lM) tested; (2) scattered, elongated and vacuolated 5637 and T24 cells; (3) a cytostatic effect in both cell lines; and (4) significant upregulation of the BRCA1, and CHEK1 genes. Gemcitabine had distinct toxicogenomic effects in the bladder transi-tional carcinoma cell lines with two different TP53 muta-tions. However, independent of the type of mutation and tumor grade, gemcitabine induced cell cycle arrest; upregulation of DNA repair-related genes, G1/S transition, apoptosis and activation of transcription factors, mainly by upregulation of the CCNE1, CDKN1A and GADD45A genes.Plant Molecular Biology Reporter 10/2012; 1(1):1. · 2.45 Impact Factor
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ABSTRACT: NDRG2, a member of the N-Myc downstream-regulated gene family, was shown to be a putative tumor suppressor gene in glioblastoma and other cancers. Through a bioinformatic analysis, we found that NDRG2 protein contains an acyl carrier domain. In the current study, we therefore hypothesized that NDRG2 may play an important role in the regulation of histone acetylation. Treatment of U251 and U87 glioma cells with trichostatin A, an inhibitor of histone deacetylase, upregulated the expression of NDRG2 and acetylated forms of histones H3 and H4, reduced tumor cell viability and arrested the cell cycle at the G1/G0 phase. Overexpression of NDRG2 by transfecting glioma cells with adenovirus containing the NDRG2 gene upregulated the levels of acetylated forms of H3 and H4 whereas inhibition of NDRG2 expression by siRNA-mediated knockdown downregulated the level of histone acetylation. Furthermore, NDRG2 siRNA significantly reduced the level of histone acetylation induced by trichostatin A. Taken together, these data demonstrate that NDRG2 can regulate the level of histone acetylation to control glioma cell growth.Journal of Neuro-Oncology 09/2011; 106(3):485-92. · 3.21 Impact Factor