TY - JOUR
TI - Novel histone deacetylase inhibitors in the treatment of thyroid cancer
AU - Mitsiades, CS
AU - Poulaki, V
AU - McMullan, C
AU - Negri, J and
AU - Fanourakis, G
AU - Goudopoulou, A
AU - Richon, VM
AU - Marks, PA and
AU - Mitsiades, N
JO - Clinical Cancer Research
PY - 2005
VL - 11
TODO - 10
SP - 3958-3965
PB - AMER ASSOC CANCER RESEARCH
SN - 1078-0432
TODO - 10.1158/1078-0432.CCR-03-0776
TODO - null
TODO - Histone deacetylases (HDAC) and histone acetyltransferases exert
opposing enzymatic activities that modulate the degree of acetylation of
histones and other intracellular molecular targets, thereby regulating
gene expression, cellular differentiation, and survival. HDAC inhibition
results in accumulation of acetylated histones and induces
differentiation and/or apoptosis in transformed cells. In this study, we
characterized the effect of two HDAC inhibitors, suberoylanilide
hydroxamic acid (SAHA) and m-carboxycinnamic acid bis-hydroxamide, on
thyroid carcinoma cell lines, including lines originating from
anaplastic and medullary carcinomas. In these models, both SAHA and
m-carboxycinnamic acid bis-hydroxamide induced growth arrest and
caspase-mediated apoptosis and increased p21 protein levels,
retinoblastoma hypophosphorylation, BH3-interacting domain death agonist
cleavage, Bax up-regulation, down-regulation of Bcl-2, A1, and Bcl-X-L
expression, and cleavage of poly (ADP-ribose) polymerase and caspase-8,
-9, -3, -7, and -2. Transfection of Bcl-2 cDNA partially suppressed
SAHA-induced cell death. SAHA down-regulated the expression of the
apoptosis inhibitors FLIP and clAP-2 and sensitized tumor cells to
cytotoxic chemotherapy and death receptor activation. Our studies
provide insight into the tumor type-specific mechanisms of antitumor
effects of HDAC inhibitors and a framework for future clinical
applications of HDAC inhibitors in patients with thyroid cancer,
including histologic subtypes (e.g., anaplastic and medullary thyroid
carcinomas) for which limited, if any, therapeutic options are
available.
ER -