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

1349 Citations (Scopus)

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

Fingerprint

Histone Deacetylases
Valproic Acid
Cell Differentiation
Neoplasms
Cells
Drug Therapy
Hematopoietic Stem Cells
Acute Myeloid Leukemia
Pharmaceutical Preparations
Anticonvulsants
Histones
Tumors
Cultured Cells
Animals
Neoplasm Metastasis
Carcinoma
Growth
Experiments

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Göttlicher, M., Minucci, S., Zhu, P., Krämer, O. H., Schimpf, A., Giavara, S., ... 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

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

In: EMBO Journal, Vol. 20, No. 24, 17.12.2002, p. 6969-6978.

Research output: Contribution to journalArticle

Göttlicher, M, Minucci, S, Zhu, P, Krämer, OH, Schimpf, A, Giavara, S, Sleeman, JP, Lo Coco, F, Nervi, C, Pelicci, PG & Heinzel, T 2002, 'Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells', EMBO Journal, vol. 20, no. 24, pp. 6969-6978. https://doi.org/10.1093/emboj/20.24.6969
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. / Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. In: EMBO Journal. 2002 ; Vol. 20, No. 24. pp. 6969-6978.
@article{009c502d887b46e8a9e8601bcefba468,
title = "Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells",
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.",
keywords = "Cancer therapy, HDAC inhibitor, Histone deacetylase, Leukemia, Valproic acid",
author = "Martin G{\"o}ttlicher and Saverio Minucci and Ping Zhu and Kr{\"a}mer, {Oliver H.} and Annemarie Schimpf and Sabrina Giavara and Sleeman, {Jonathan P.} and {Lo Coco}, Francesco and Clara Nervi and Pelicci, {Pier Giuseppe} and Thorsten Heinzel",
year = "2002",
month = "12",
day = "17",
doi = "10.1093/emboj/20.24.6969",
language = "English",
volume = "20",
pages = "6969--6978",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "Nature Publishing Group",
number = "24",

}

TY - JOUR

T1 - Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells

AU - Göttlicher, Martin

AU - Minucci, Saverio

AU - Zhu, Ping

AU - Krämer, Oliver H.

AU - Schimpf, Annemarie

AU - Giavara, Sabrina

AU - Sleeman, Jonathan P.

AU - Lo Coco, Francesco

AU - Nervi, Clara

AU - Pelicci, Pier Giuseppe

AU - Heinzel, Thorsten

PY - 2002/12/17

Y1 - 2002/12/17

N2 - 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.

AB - 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.

KW - Cancer therapy

KW - HDAC inhibitor

KW - Histone deacetylase

KW - Leukemia

KW - Valproic acid

UR - http://www.scopus.com/inward/record.url?scp=18244383806&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=18244383806&partnerID=8YFLogxK

U2 - 10.1093/emboj/20.24.6969

DO - 10.1093/emboj/20.24.6969

M3 - Article

C2 - 11742974

AN - SCOPUS:18244383806

VL - 20

SP - 6969

EP - 6978

JO - EMBO Journal

JF - EMBO Journal

SN - 0261-4189

IS - 24

ER -