A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases.
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.
Richon
V M
VM
Cell Biology Program, Memorial Sloan-Kettering Cancer Center 1275 York Avenue, New York, NY 10021, USA. v-richon@ski.mskcc.org
Emiliani
S
S
Verdin
E
E
Webb
Y
Y
Breslow
R
R
Rifkind
R A
RA
Marks
P A
PA
D000081:Acetamides / Q000494:pharmacology; D000818:Animals; D002277:Carcinoma / Q000378:metabolism; D002454:Cell Differentiation; D002461:Cell Line, Transformed / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D002934:Cinnamates / Q000494:pharmacology*; D004351:Drug Resistance; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D004915:Leukemia, Erythroblastic, Acute / Q000378:metabolism; D008314:Malonates / Q000494:pharmacology; D051379:Mice; D001749:Urinary Bladder Neoplasms / Q000378:metabolism; D000077337:Vorinostat; D000099186:Histone Deacetylase 3
D000081:Acetamides; D002934:Cinnamates; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones; D006877:Hydroxamic Acids; D008314:Malonates; D000077337:Vorinostat; D000099186:Histone Deacetylase 3; C111238:carboxycinnamic acid bishydroxamide; C111239:diethyl-bis(pentamethylene-N,N-dimethylcarboxamide)malonate; C012589:trichostatin A; C110550:HDAC1 protein, human; C014026:hexamethylene bisacetamide