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.
Highlights
Soft tissue sarcomas (STS) are a rare class of malignant tumors with varying histology and mostly aggressive characteristics, both locally and in the formation of distant metastases [1]
Histone acetylation induced by histone acetyl transferases (HATs) is associated with gene transcription, while histone hypoacetylation induced by histone deacetylase (HDAC) activity is associated with gene silencing [9]
To investigate the influence of HDAC inhibitors on sarcoma cell growth, SW-982 and SW-1353 cells were exposed to SAHA (0.5, 1.0, 2.5, 5.0, 10.0, 15.0 μM), LBH-589 (0.01, 0.05, 0.1, 0.25, 0.5, 1.0, 5.0 μM), or PXD101 (0.5, 1.0, 2.5, 5.0 μM) for 48 h
Summary
Soft tissue sarcomas (STS) are a rare class of malignant tumors with varying histology and mostly aggressive characteristics, both locally and in the formation of distant metastases [1]. HDACs play an important role in epigenetic gene regulation by deacetylating both, histone and nonhistone (e.g. transcription factors) proteins, thereby regulating important cellular processes such as cell-cycle progression and apoptosis [10, 11]. A key element that allows cancer development is the deregulation of histone acetylation as well as the mutation and/or aberrant expression of HDACs. class I subfamily members HDAC 1, 2, 3, and 8 are deregulated in many cancer types contributing to enhanced cell cycle progression and proliferation. Transitions between G1, S, and G2/M phases are regulated by coordinated actions of cyclins, cyclindependent kinases (CDKs), and CDK inhibitors All of these can be modulated by diverse intracellular signals transduced from extracellular growth cues [16]
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