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

• Published in: The EMBO journal Vol. 20; no. 24; pp. 6969 - 6978
• Main Authors: Göttlicher, Martin, Minucci, Saverio, Zhu, Ping, Krämer, Oliver H., Schimpf, Annemarie, Giavara, Sabrina, Sleeman, Jonathan P., Lo Coco, Francesco, Nervi, Clara, Pelicci, Pier Giuseppe, Heinzel, Thorsten
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 17-12-2001; Blackwell Publishing Ltd; Oxford University Press
• Subjects: Animals; cancer therapy; Cell Differentiation - drug effects; Cell Line, Transformed; Cricetinae; Enzyme Inhibitors - pharmacology; HDAC inhibitor; histone deacetylase; Histone Deacetylase Inhibitors; Humans; Leukemia; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Glucocorticoid - genetics; Transcription Factors - genetics; Transcription, Genetic - drug effects; Valproic acid; Valproic Acid - pharmacology
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1093/emboj/20.24.6969

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.