Histone deacetylase inhibition sensitizes osteosarcoma to heavy ion radiotherapy.
Histone deacetylase inhibition sensitizes osteosarcoma to heavy ion radiotherapy.
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DOI：
10.1186/s13014-015-0455-z
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发表时间：
2015-07-16
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影响因子：
--
通讯作者：
Debus J
中科院分区：
文献类型：
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作者：
Blattmann C;Oertel S;Thiemann M;Dittmar A;Roth E;Kulozik AE;Ehemann V;Weichert W;Huber PE;Stenzinger A;Debus J
在过去的三十年里，骨肉瘤患者的治疗或生存率的改善微乎其微。特别是在肿瘤切除不完全的情况下，预后仍然很差。重离子放射治疗（HIT）和现代抗癌药物如组蛋白去乙酰化酶抑制剂（HDACi）在体外对骨肉瘤显示出良好的效果。在这项研究中，我们测试了HIT和HIT与HDACi辛二酰苯胺异羟肟酸（SAHA）的组合在异种移植小鼠模型中的作用。通过皮下注射KHOS-24 OS细胞建立骨肉瘤异种移植物，并用媒介物（DMSO）、SAHA、HIT或HIT和SAHA处理。测定肿瘤生长情况，评价肿瘤坏死率、增殖率、凋亡率以及血管密度。在这里，我们表明，与仅用HIT治疗的肿瘤相比，HIT和SAHA的组合通过增加细胞凋亡率、增加p53和p21 Waf 1/Cip 1的表达、抑制增殖和血管生成来诱导肿瘤生长的显着延迟。HIT，特别是HIT和组蛋白脱乙酰酶抑制的组合是OS中有希望的治疗策略，并且可以在临床试验中进行测试。
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. 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. 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. 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.