Histone deacetylase inhibitors vorinostat and panobinostat induce G1 cell cycle arrest and apoptosis in multidrug resistant sarcoma cell lines

Eva Bernhart; Nicole Stuendl; Heike Kaltenegger; Christian Windpassinger; Nicholas Donohue; Andreas Leithner; Birgit Lohberger

doi:10.18632/oncotarget.20460

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Research Papers:

Histone deacetylase inhibitors vorinostat and panobinostat induce G1 cell cycle arrest and apoptosis in multidrug resistant sarcoma cell lines

Eva Bernhart, Nicole Stuendl, Heike Kaltenegger, Christian Windpassinger, Nicholas Donohue, Andreas Leithner and Birgit Lohberger _

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Oncotarget. 2017; 8:77254-77267. https://doi.org/10.18632/oncotarget.20460

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Abstract

Eva Bernhart1, Nicole Stuendl2, Heike Kaltenegger2, Christian Windpassinger3, Nicholas Donohue2, Andreas Leithner2 and Birgit Lohberger2

1Institute of Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria

2Department of Orthopedics and Trauma, Medical University of Graz, 8036 Graz, Austria

3Institute of Human Genetics, Medical University of Graz, 8010 Graz, Austria

Correspondence to:

Birgit Lohberger, email: [email protected]

Keywords: G1 cell cycle arrest, vorinostat, belinostat, sarcoma, panobinostat

Received: January 31, 2017 Accepted: July 26, 2017 Published: August 24, 2017

ABSTRACT

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 synovial- and chondrosarcoma cells has not been investigated. 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.

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Research Papers:

Histone deacetylase inhibitors vorinostat and panobinostat induce G1 cell cycle arrest and apoptosis in multidrug resistant sarcoma cell lines

Abstract