Histone deacetylase inhibition sensitizes osteosarcoma to heavy ion radiotherapy

Background: Minimal improvements in treatment or survival of patients with osteosarcoma have been achieved during the last three decades. Especially in the case of incomplete tumor resection, prognosis remains poor. Heavy ion radiotherapy (HIT) and modern anticancer drugs like histone deacetylase inhibitors (HDACi) have shown promising effects in osteosarcoma in vitro. In this study, we tested the effect of HIT and the combination of HIT and the HDACi suberoylanilide hydroxamic acid (SAHA) in a xenograft mouse model. Methods: Osteosarcoma xenografts were established by subcutaneous injection of KHOS-24OS cells and treated with either vehicle (DMSO), SAHA, HIT or HIT and SAHA. Tumor growth was determined and tumor necrosis, proliferation rate, apoptotic rate as well as vessel density were evaluated. Results: Here, we show that the combination of HIT and SAHA induced a significant delay of tumor growth through increased rate of apoptosis, increased expression of p53 and p21Waf1/Cip1, inhibition of proliferation and angiogenesis compared to tumors treated with HIT only. Conclusion: HIT and in particular the combination of HIT and histone deacetylase inhibition is a promising treatment strategy in OS and may be tested in clinical trials

Combination of suberoylanilide hydroxamic acid with heavy ion therapy shows promising effects in infantile sarcoma cell lines

<p>Abstract</p> <p>Introduction</p> <p>The pan-HDAC inhibitor (HDACI) suberoylanilide hydroxamic acid (SAHA) has previously shown to be a radio-sensitizer to conventional photon radiotherapy (XRT) in pediatric sarcoma cell lines. Here, we investigate its effect on the response of two sarcoma cell lines and a normal tissue cell line to heavy ion irradiation (HIT).</p> <p>Materials and methods</p> <p>Clonogenic assays after different doses of heavy ions were performed. DNA damage and repair were evaluated by measuring γH2AX via flow-cytometry. Apoptosis and cell cycle analysis were also measured via flow cytometry. Protein expression of repair proteins, p53 and p21 were measured using immunoblot analysis. Changes of nuclear architecture after treatment with SAHA and HIT were observed in one of the sarcoma cell lines via light microscopy after staining towards chromatin and γH2AX.</p> <p>Results</p> <p>Corresponding with previously reported photon data, SAHA lead to an increase of sensitivity to heavy ions along with an increase of DSB and apoptosis in the two sarcoma cell lines. In contrast, in the osteoblast cell line (hFOB 1.19), the combination of SAHA and HIT showed a significant radio-protective effect. Laser scanning microscopy revealed no significant morphologic changes after HIT compared to the combined treatment with SAHA. Immunoblot analysis revealed no significant up or down regulation of p53. However, p21 was significantly increased by SAHA and combination treatment as compared to HIT only in the two sarcoma cell lines - again in contrast to the osteoblast cell line. Changes in the repair kinetics of DSB p53-independent apoptosis with p21 involvement may be part of the underlying mechanisms for radio-sensitization by SAHA.</p> <p>Conclusion</p> <p>Our <it>in vitro </it>data suggest an increase of the therapeutic ratio by the combination of SAHA with HIT in infantile sarcoma cell lines.</p