TY - JOUR
T1 - Histone deacetylase inhibitors
T2 - Insights into mechanisms of lethality
AU - Rosato, Roberto R.
AU - Grant, Steven
N1 - Funding Information:
This work was supported by awards CA63753, CA61774 and CA93738 from the NIH, DAMD-17-03-1-0209 from the Department of Defense, The V Foundation and award 6045-03 from the Leukaemia and Lymphoma Society of America.
PY - 2005/8
Y1 - 2005/8
N2 - Histone deacetylases (HDACs) have recently emerged as an important target for therapeutic intervention in cancer and potentially other human diseases. By modulating the acetylation status of histones, histone deacetylase inhibitors (HDACIs) alter the transcription of genes involved in cell growth, maturation, survival and apoptosis, among other processes. Early clinical results suggest a potentially useful role for HDACIs in the treatment of certain forms of lymphoma (e.g., cutaneous T cell lymphoma) and acute leukaemia. An unresolved question is how HDACIs induce cell death in tumour cells. Recent studies suggest that acetylation of nonhistone proteins may play an important role in the biological effects of this class of compounds, and may explain lack of correlation between histone acetylation and induction of cell death by HDACIs in some circumstances. Recently, attention has focussed on the effects of HDACIs on disruption of co-repressor complexes, induction of oxidative injury, upregulation of the expression of death receptors, generation of lipid second messengers such as ceramide, interference with the function of chaperone proteins and modulation of the activity of NF-κB as critical determinants of lethality. Aside from providing critical insights into the mechanism of action of HDACIs in neoplastic disease, these findings may provide a foundation for the rational development of combination studies, involving HDACIs in combination with either conventional cytotoxic drugs as well as more novel targeted agents.
AB - Histone deacetylases (HDACs) have recently emerged as an important target for therapeutic intervention in cancer and potentially other human diseases. By modulating the acetylation status of histones, histone deacetylase inhibitors (HDACIs) alter the transcription of genes involved in cell growth, maturation, survival and apoptosis, among other processes. Early clinical results suggest a potentially useful role for HDACIs in the treatment of certain forms of lymphoma (e.g., cutaneous T cell lymphoma) and acute leukaemia. An unresolved question is how HDACIs induce cell death in tumour cells. Recent studies suggest that acetylation of nonhistone proteins may play an important role in the biological effects of this class of compounds, and may explain lack of correlation between histone acetylation and induction of cell death by HDACIs in some circumstances. Recently, attention has focussed on the effects of HDACIs on disruption of co-repressor complexes, induction of oxidative injury, upregulation of the expression of death receptors, generation of lipid second messengers such as ceramide, interference with the function of chaperone proteins and modulation of the activity of NF-κB as critical determinants of lethality. Aside from providing critical insights into the mechanism of action of HDACIs in neoplastic disease, these findings may provide a foundation for the rational development of combination studies, involving HDACIs in combination with either conventional cytotoxic drugs as well as more novel targeted agents.
KW - Apoptosis
KW - Ceramide
KW - Epigenetics
KW - Extrinsic pathway
KW - Heat-shock protein
KW - Histone deacetylase inhibitor (HDACI)
KW - NF-κB
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U2 - 10.1517/14728222.9.4.809
DO - 10.1517/14728222.9.4.809
M3 - Review article
C2 - 16083344
AN - SCOPUS:23644434852
SN - 1472-8222
VL - 9
SP - 809
EP - 824
JO - Expert Opinion on Therapeutic Targets
JF - Expert Opinion on Therapeutic Targets
IS - 4
ER -