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Histone deacetylase inhibitors profoundly decrease proliferation of human lymphoid cancer cell lines

Sakura Sakajiri1, Takashi Kumagai, Norihiko Kawamata

  • 1Division of Hematology/Oncology, Cedars Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA 90048, USA.

Experimental Hematology
|January 22, 2005
PubMed

Insights

Histone deacetylase inhibitors (HDACIs) show promise for treating human lymphoid cancers by restoring tumor suppressor gene expression and inhibiting cancer cell proliferation. Both suberoylanilide hydroxamic acid (SAHA) and valproic acid demonstrated significant antiproliferative effects in vitro and in vivo.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Tumor suppressor gene silencing via DNA methylation and histone deacetylase (HDAC) recruitment is common in human cancers.
  • HDAC inhibitors (HDACIs) can reverse this silencing, restoring gene expression and inhibiting cancer cell growth.

Purpose of the Study:

  • To investigate the in vitro antiproliferative effects of HDACIs suberoylanilide hydroxamic acid (SAHA) and valproic acid on human lymphoid cancer cell lines.
  • To evaluate the efficacy and safety of SAHA in a preclinical mouse model of mantle cell lymphoma.

Main Methods:

  • Treatment of 14 human lymphoid cancer cell lines with SAHA and valproic acid.
  • Cell cycle analysis (G1 and G2-M arrest), apoptosis assays, and Western blotting for cell cycle regulatory proteins (cyclin D1, D2, p53, p21, p27).
  • Chromatin immunoprecipitation (ChIP) assay to assess histone acetylation at the p21 promoter.
  • In vivo efficacy study of SAHA in nude mice bearing mantle cell lymphoma xenografts.

Main Results:

  • All 14 lymphoid cancer cell lines were sensitive to the antiproliferative effects of HDACIs.
  • SAHA induced G1 or G2-M cell cycle arrest and apoptosis, downregulating cyclin D1/D2 and upregulating p53/p21/p27.
  • SAHA treatment increased histone acetylation at the p21 promoter, indicating restored gene accessibility.
  • SAHA significantly inhibited tumor growth in a mantle cell lymphoma mouse model with no major toxic side effects.

Conclusions:

  • HDAC inhibitors, particularly SAHA, exhibit potent in vitro and in vivo antiproliferative activity against human lymphoid cancers.
  • SAHA demonstrates a favorable therapeutic profile, including cell cycle regulation, apoptosis induction, and tumor growth inhibition.
  • HDACIs represent a promising therapeutic strategy for human lymphoid malignancies.

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