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Belinostat and panobinostat (HDACI): in vitro and in vivo studies in thyroid cancer
Daniel Chan1, Yun Zheng, Jeffrey W Tyner
1National University Hospital, National University Cancer Institute Singapore, 1E Kent Ridge Road, Singapore, 119228, Singapore.
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, p21(Waf), 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.
Insights
New therapies combining histone deacetylase inhibitors (HDACIs) with tyrosine kinase inhibitors (TKIs) show promise for treating advanced thyroid cancer. Belinostat and panobinostat, alone or with TKIs, effectively inhibited cancer cell growth in vitro and in vivo.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Advanced thyroid cancer presents a significant therapeutic challenge due to poor response to conventional treatments.
- There is an unmet need for novel therapeutic strategies and drug combinations to improve outcomes.
Purpose of the Study:
- To evaluate the in vitro and in vivo efficacy of two histone deacetylase inhibitors (HDACIs), belinostat and panobinostat.
- To assess the activity of various tyrosine kinase inhibitors (TKIs) and their combinations with HDACIs against human thyroid cancer cell lines.
Main Methods:
- Cytotoxicity assays, microarray, and immunoblot analyses were employed to determine anti-proliferative effects.
- Synergistic interactions between HDACIs and TKIs were quantified using the Chou-Talalay median effects model.
- In vivo efficacy was evaluated using human thyroid cancer xenografts in immunodeficient mice.
Main Results:
- Belinostat and panobinostat demonstrated activity against diverse thyroid cancer cell lines and belinostat inhibited xenograft growth.
- HDACIs induced apoptosis and modulated key cellular pathways including cell cycle, DNA damage, and apoptosis-related genes.
- Combinations of belinostat or panobinostat with pazopanib or dasatinib exhibited synergistic inhibition of thyroid cancer cell growth in vitro.
Conclusions:
- Histone deacetylase inhibitors (HDACIs) show potential as monotherapy or in combination for aggressive thyroid cancer.
- Selected tyrosine kinase inhibitors (TKIs) combined with HDACIs offer a promising synergistic approach for thyroid cancer treatment.
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