Article
The histone deacetylase inhibitors vorinostat and panobinostat initiate apoptotic induction and G1 cell cycle arrest in multidrug resistant sarcoma cell lines
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Authors
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Birgit Lohberger
- Universitätsklinik für Orthopädie und Traumatologie, Medizinische Universität Graz, Graz, Austria
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Nicole Stuendl
- Universitätsklinik für Orthopädie und Traumatologie, Medizinische Universität Graz, Graz, Austria
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Heike Kaltenegger
- Universitätsklinik für Orthopädie und Traumatologie, Medizinische Universität Graz, Graz, Austria
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Andreas Leithner
- Universitätsklinik für Orthopädie und Traumatologie, Medizinische Universität Graz, Graz, Austria
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Eva Bernhart
- Institut für Molekularbiologie und Biochemie, Medizinische Universität Graz, Graz, Austria
| Published: | October 22, 2019 |
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Outline
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Objectives: Synovial sarcoma and high grade chondrosarcoma are characterized by their lack of response to conventional cytotoxic chemotherapy, the tendency to develop lung metastases, and low survival rates. Research within the field prioritizes the development and expansion of new treatment options for dealing with unresectable or metastatic diseases. Numerous clinical trials using histone deacetylases inhibitors (HDACi) have shown specific efficacy as an active antitumor agent for treating a variety of solid tumors. However, as of yet the effect of different HDACi on human synovial- and chondrosarcoma cells has not been investigated.
Methods: The effect of different HDACi on cell viability and proliferation was analyzed using MTS assay and the xCELLigence technology. FACS analysis was performed to determine the cell cycle profiles. The expression of class I HDACs, the phosphorylation of cell cycle regulator proteins, and PARP cleavage was examined using western blotting. The apoptotic induction was proved using Caspase-Glo® 3/7 assay and caspase-3 cleavage FACS analysis. To determine the synergistic effect of HDACi and doxorubicin the MTS assay has been applied.
Results and conclusion: In this study, vorinostat (SAHA), panobinostat (LBH-589), and belinostat (PXD101) decreased cell viability of synovial sarcoma (SW-982) and chondrosarcoma (SW-1353) cells in a time- and dose dependent manner and arrested SW-982 cells in the G1/S phase. Western blot analysis determined the responsible cell cycle regulator proteins. In addition, we found apoptotic induction by caspase 3/7 activity, caspase 3 cleavage, and PARP cleavage. In SW-1353 cells only SAHA showed comparable effects. Noteworthy, all HDACi tested had synergistic effects with the topoisomerase II inhibitor doxorubicin in SW-1353 chondrosarcoma cells making the cells more sensitive to the chemotherapeutic drug.
Our results show for the first time that SAHA and LBH-589 reduced viability of sarcoma cells and arrested them at the G1/S checkpoint, while also inducing apoptosis and enhancing chemotherapeutic sensitivity, especially in chondrosarcoma cells. These data demonstrate the exciting potential of HDACi for use in sarcoma treatment.
