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Pharmacological characterization of histone deacetylase inhibitor and tumor cell-growth inhibition properties of new benzofuranone compounds.
- Source :
-
Current cancer drug targets [Curr Cancer Drug Targets] 2011 Oct; Vol. 11 (8), pp. 919-28. - Publication Year :
- 2011
-
Abstract
- Epigenetic modifications, such as DNA methylation or histone deacetylation, are early events in cell tumorigenesis. The consequences of these modifications are repression of gene transcription and, notably, of tumor suppressor gene transcription. New therapeutic strategies aim to 'normalize' the epigenetic status of cancer cells. Histone deacetylase inhibitors (HDACi) have shown promising effects against proliferation and resistance to apoptosis of a large number of cancer cells. Vorinostat (SAHA), a hydroxamate HDACi, has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of refractory cutaneous T-cell lymphoma (CTCL). However, HDACi are poorly specific, present toxicities and many have very low half-lives in the plasma. Thus, the development of new compounds is necessary in order to increase the potential of HDACi in cancer treatment. We designed an assay, based on bioluminescence resonance energy transfer (BRET) technology, to screen and characterize HDACi activity in living cells. Using our specific and reproducible BRET assay, we characterized the pharmacological properties of benzofuranone HDACi compounds for the induction of histone acetylation and performed a comparison with the properties of suberoylanilide hydroxamic acid (SAHA) and valproic acid (VPA). We defined a benzofuranone HDACi compound that induced histone acetylation at nanomolar concentrations and showed an increased duration of histone acetylation. These properties correlated with the pharmacological properties of this HDACi for the growth inhibition of cancer cells. We, thus, demonstrated the applicability of BRET technology for the screening and characterization of new HDACi compounds in living cells, and identified an interesting benzofuranone HDACi.
- Subjects :
- Acetylation drug effects
Animals
Antineoplastic Agents chemistry
Benzofurans chemistry
Bioluminescence Resonance Energy Transfer Techniques
Cell Line, Tumor
Drug Resistance, Neoplasm
Histone Deacetylase Inhibitors chemistry
Histones genetics
Histones metabolism
Humans
Hydroxamic Acids chemistry
Hydroxamic Acids pharmacology
Inhibitory Concentration 50
Kinetics
Molecular Targeted Therapy
Neoplasms pathology
Rats
Recombinant Fusion Proteins metabolism
Antineoplastic Agents pharmacology
Benzofurans pharmacology
Cell Proliferation drug effects
Drug Design
High-Throughput Screening Assays
Histone Deacetylase Inhibitors pharmacology
Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1873-5576
- Volume :
- 11
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Current cancer drug targets
- Publication Type :
- Academic Journal
- Accession number :
- 21762083
- Full Text :
- https://doi.org/10.2174/156800911797264761