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Assays for Validating Histone Acetyltransferase Inhibitors
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Histone deacetylase inhibitors have a profound antigrowth activity in endometrial cancer cells

Noriyuki Takai1, Julian C Desmond, Takashi Kumagai

  • 1Division of Hematology/Oncology, Cedars-Sinai Medical Center/University of California at Los Angeles School of Medicine, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|February 12, 2004
PubMed
Abstract

Insights

Histone deacetylase inhibitors (HDACIs) effectively inhibit endometrial cancer cell growth and induce apoptosis in vitro and in vivo. These HDACIs show promise for treating endometrial cancers with minimal toxicity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Histone deacetylase inhibitors (HDACIs) are known to inhibit cancer cell proliferation, induce apoptosis, and cause cell cycle arrest.
  • Endometrial cancer remains a significant health concern, necessitating novel therapeutic strategies.

Purpose of the Study:

  • To investigate the antiproliferative effects of specific HDACIs, including suberoyl anilide bishydroxamine, valproic acid (VPA), trichostatin A, and sodium butyrate.
  • To evaluate the efficacy of HDACIs against six distinct endometrial cancer cell lines.
  • To assess the in vivo efficacy of VPA in inhibiting endometrial tumor growth in immunodeficient mice.

Main Methods:

  • Treatment of endometrial cancer cell lines with various HDACIs.
  • Assessment of cell growth, cell cycle progression, and apoptosis using clonogenic assays, cell cycle analysis, and terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assays.
  • Evaluation of gene expression changes related to malignant phenotype and analysis of histone acetylation via chromatin immunoprecipitation.
  • In vivo studies involving the administration of VPA to immunodeficient mice bearing human uterine tumors.

Main Results:

  • All tested endometrial cancer cell lines demonstrated sensitivity to the growth-inhibitory effects of HDACIs.
  • HDACI treatment led to a decrease in S phase cells and an increase in G(0)-G(1) and/or G(2)-M phase cells, indicating cell cycle arrest.
  • HDACIs induced apoptosis and altered the expression of key genes, including increased p21(Waf1), p27(Kip7), and E-cadherin, and decreased Bcl-2 and cyclin-D1/-D2.
  • Suberoylanilide bishydroxamine treatment significantly increased histone acetylation at the p21 promoter.
  • VPA demonstrated significant inhibition of human uterine tumor growth in mice without observable toxic side effects.

Conclusions:

  • HDACIs are effective in inhibiting endometrial cancer cell growth both in vitro and in vivo.
  • The observed effects include induction of apoptosis and cell cycle arrest, alongside favorable alterations in gene expression.
  • HDACIs exhibit a promising therapeutic potential for endometrial cancer treatment due to their efficacy and lack of significant toxicity.

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