TY - JOUR
T1 - Belinostat and panobinostat (HDACI)
T2 - In vitro and in vivo studies in thyroid cancer
AU - Chan, Daniel
AU - Zheng, Yun
AU - Tyner, Jeffrey W.
AU - Chng, Wee Joo
AU - Chien, Wen Wen
AU - Gery, Sigal
AU - Leong, Geraldine
AU - Braunstein, Glenn D.
AU - Koeffler, H. Phillip
N1 - Funding Information:
Acknowledgments This work was funded by the Singapore Ministry of Health’s National Medical Research Council under its Singapore Translational Research (STaR) Investigator Award to H. Phillip Koeffler and NIH Grants R01CA026038-32, U54CA137785-01. This study is dedicated to the memory of Professor David Golde, a mentor and friend.
PY - 2013/9
Y1 - 2013/9
N2 - Purpose: Advanced thyroid cancer responds poorly to most therapies. New therapies and combinations are needed. The aim of this study was to examine both in vitro and in vivo activity of two relatively new histone deacetylase inhibitors (HDACIs), belinostat and panobinostat, and a variety of tyrosine kinase inhibitors (TKIs) against a panel of nine human thyroid cancer cell lines. Methods: The anti-proliferative activity and the effects of HDACIs, TKIs and their combinations on thyroid cancer cells were determined by cytotoxicity assays, microarray and immunoblot analyses. Synergism between HDACIs and TKIs was assessed by the median effects model of Chou-Talalay (Calcusyn ®). Results: Belinostat and panobinostat were active against the thyroid cancer cell lines irrespective of their mutational composition, and belinostat was effective in preventing growth of human thyroid cancer xenografts in immunodeficient mice. Further studies showed that both HDACIs induced apoptosis. HDACI also elevated acetylated histone 3, p21Waf, and PARP, and decreased levels of phosphorylated ERK and AKT (Ser473). RNA assay analysis suggested both HDACIs modulated genes associated with the cell cycle, DNA damage and apoptosis. Most of the TKI (pazopanib, motesanib, sorafenib and dasatinib) were either inactive in vitro or were active only at high doses. However, the novel combinations of either pazopanib or dasatinib TKIs with either belinostat or panobinostat synergistically inhibited cell growth of thyroid cancer cells in vitro. Conclusions: In summary, these HDACIs either alone or combined with selected TKIs may have a role in treatment of aggressive thyroid cancer.
AB - Purpose: Advanced thyroid cancer responds poorly to most therapies. New therapies and combinations are needed. The aim of this study was to examine both in vitro and in vivo activity of two relatively new histone deacetylase inhibitors (HDACIs), belinostat and panobinostat, and a variety of tyrosine kinase inhibitors (TKIs) against a panel of nine human thyroid cancer cell lines. Methods: The anti-proliferative activity and the effects of HDACIs, TKIs and their combinations on thyroid cancer cells were determined by cytotoxicity assays, microarray and immunoblot analyses. Synergism between HDACIs and TKIs was assessed by the median effects model of Chou-Talalay (Calcusyn ®). Results: Belinostat and panobinostat were active against the thyroid cancer cell lines irrespective of their mutational composition, and belinostat was effective in preventing growth of human thyroid cancer xenografts in immunodeficient mice. Further studies showed that both HDACIs induced apoptosis. HDACI also elevated acetylated histone 3, p21Waf, and PARP, and decreased levels of phosphorylated ERK and AKT (Ser473). RNA assay analysis suggested both HDACIs modulated genes associated with the cell cycle, DNA damage and apoptosis. Most of the TKI (pazopanib, motesanib, sorafenib and dasatinib) were either inactive in vitro or were active only at high doses. However, the novel combinations of either pazopanib or dasatinib TKIs with either belinostat or panobinostat synergistically inhibited cell growth of thyroid cancer cells in vitro. Conclusions: In summary, these HDACIs either alone or combined with selected TKIs may have a role in treatment of aggressive thyroid cancer.
KW - Histone deacetylases
KW - Novel therapeutic approach
KW - Thyroid cancer
KW - Tyrosine kinase inhibitors
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U2 - 10.1007/s00432-013-1465-6
DO - 10.1007/s00432-013-1465-6
M3 - Article
C2 - 23824064
AN - SCOPUS:84882584727
SN - 0171-5216
VL - 139
SP - 1507
EP - 1514
JO - Journal of Cancer Research and Clinical Oncology
JF - Journal of Cancer Research and Clinical Oncology
IS - 9
ER -