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PMID: 9501205 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 95 ·No. 6 ·1998-03-17 ·Pages 3003-7

Richon VM, Emiliani S, Verdin E, Webb Y, Breslow R, Rifkind RA, Marks PA

Abstract

Hybrid polar compounds (HPCs) have been synthesized that induce terminal differentiation and/or apoptosis in various transformed cells. We have previously reported on the development of the second-generation HPCs suberoylanilide hydroxamic acid (SAHA) and m-carboxycinnamic acid bishydroxamide (CBHA) that are 2,000-fold more potent inducers on a molar basis than the prototype HPC hexamethylene bisacetamide (HMBA). Herein we report that CBHA and SAHA inhibit histone deacetylase 1 (HDAC1) and histone deacetylase 3 (HDAC3) activity in vitro. Treatment of cells in culture with SAHA results in a marked hyperacetylation of histone H4, but culture with HMBA does not. Murine erythroleukemia cells developed for resistance to SAHA are cross-resistant to trichostatin A, a known deacetylase inhibitor and differentiation inducer, but are not cross-resistant to HMBA. These studies show that the second-generation HPCs, unlike HMBA, are potent inhibitors of HDAC activity. In this sense, HMBA and the second-generation HPCs appear to induce differentiation by different pathways.

MeSH Terms
Acetamides/pharmacology Animals Carcinoma/metabolism Cell Differentiation Cell Line, Transformed/drug effects Cell Transformation, Neoplastic Cinnamates/pharmacology Drug Resistance Histone Deacetylase 1 Histone Deacetylase Inhibitors Histone Deacetylases Histones/metabolism Humans Hydroxamic Acids/pharmacology Leukemia, Erythroblastic, Acute/metabolism Malonates/pharmacology Mice Urinary Bladder Neoplasms/metabolism Vorinostat
Chemicals
Acetamides Cinnamates Histone Deacetylase Inhibitors Histones Hydroxamic Acids Malonates carboxycinnamic acid bishydroxamide diethyl-bis(pentamethylene-N,N-dimethylcarboxamide)malonate trichostatin A Vorinostat HDAC1 protein, human Histone Deacetylase 1 Histone Deacetylases histone deacetylase 3 hexamethylene bisacetamide
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Richon V M
Cell Biology Program, Memorial Sloan-Kettering Cancer Center 1275 York Avenue, New York, NY 10021, USA. [email protected]
Emiliani S
Verdin E
Webb Y
Breslow R
Rifkind R A
Marks P A
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.95.6.3003
Email
[email protected]
Published
1998-03-17
Pages
3003-7
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC19684
Subset
IM
Grants
NCI NIH HHS · CA-0874823 · United States
External Links
PubMed source DOI: 10.1073/pnas.95.6.3003 PMC Full Text View journal details
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