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  • The EMBO Journal (2001) 20, 6969 - 6978
  • doi:10.1093/emboj/20.24.6969

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

Martin Göttlicher1, Saverio Minucci2, Ping Zhu1, Oliver H. Krämer3, Annemarie Schimpf3, Sabrina Giavara2, Jonathan P. Sleeman1, Francesco Lo Coco4, Clara Nervi5, Pier Giuseppe Pelicci2 and Thorsten Heinzel3

  1. Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, H.-v.-Helmholtz-Platz 1, D-76344 Eggenstein, Germany
  2. Georg-Speyer-Haus, Paul-Ehrlich-Str. 42–44, D-60596 Frankfurt, Germany
  3. European Institute of Oncology, Department of Experimental Oncology, Via Ripamonti 435, 20141 Milan Italy
  4. Department of Cellular Biotechnology and Hematology, University of Rome 'La Sapienza', I-00161 Rome, Italy
  5. Department of Histology and Medical Embryology, University of Rome 'La Sapienza', I-00161 Rome, Italy

Correspondence to:

Martin Göttlicher, E-mail: martin.goettlicher@itg.fzk.de

Thorsten Heinzel, E-mail: heinzel@em.uni-frankfurt.de

Received 27 August 2001; Accepted 26 October 2001; Revised 16 October 2001

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. More over, tumor growth and metastasis formation are significantly reduced in animal experiments. Therefore, valproic acid might serve as an effective drug for cancer therapy.

  • Keywords:

    • cancer therapy,
    • HDAC inhibitor,
    • histone deacetylase,
    • leukemia,
    • valproic acid