Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells

Martin Göttlicher, Saverio Minucci, Ping Zhu, Oliver H. Krämer, Annemarie Schimpf, Sabrina Giavara, Jonathan P. Sleeman, Francesco Lo Coco, Clara Nervi, Pier Giuseppe Pelicci, Thorsten Heinzel

Research output: Contribution to journalArticle

Abstract

Histone deacetylases (HDACs) play important roles in transcriptional regulation and pathogenesis of cancer. Thus, HDAC inhibitors are candidate drugs for differentiation therapy of cancer. Here, we show that the well-tolerated antiepileptic drug valproic acid is a powerful HDAC inhibitor. Valproic acid relieves HDAC-dependent transcriptional repression and causes hyperacetylation of histones in cultured cells and in vivo. Valproic acid inhibits HDAC activity in vitro, most probably by binding to the catalytic center of HDACs. Most importantly, valproic acid induces differentiation of carcinoma cells, transformed hematopoietic progenitor cells and leukemic blasts from acute myeloid leukemia patients. Moreover, tumor growth and metastasis formation are significantly reduced in animal experiments. Therefore, valproic acid might serve as an effective drug for cancer therapy.

Original languageEnglish
Pages (from-to)6969-6978
Number of pages10
JournalEMBO Journal
Volume20
Issue number24
DOIs
Publication statusPublished - Dec 17 2002

Keywords

  • Cancer therapy
  • HDAC inhibitor
  • Histone deacetylase
  • Leukemia
  • Valproic acid

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

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  • Cite this

    Göttlicher, M., Minucci, S., Zhu, P., Krämer, O. H., Schimpf, A., Giavara, S., Sleeman, J. P., Lo Coco, F., Nervi, C., Pelicci, P. G., & Heinzel, T. (2002). Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO Journal, 20(24), 6969-6978. https://doi.org/10.1093/emboj/20.24.6969