Pädiatrie 5, Olgahospital, Bismarckstr. 8, 70176, Stuttgart, Germany,
Strahlenther Onkol. 2013 Nov;189(11):957-66. doi: 10.1007/s00066-013-0372-8. Epub 2013 Jun 27.
Osteosarcomas (OS) are highly malignant and radioresistant tumors. Histone deacetylase inhibitors (HDACi) constitute a novel class of anticancer agents. We sought to investigate the effect of combined treatment with suberoylanilide hydroxamic acid (SAHA) and radiotherapy in OS in vivo.
Clonogenic survival of human OS cell lines as well as tumor growth delay of OS xenografts were tested after treatment with either vehicle, radiotherapy (XRT), SAHA, or XRT and SAHA. Tumor proliferation, necrosis, microvascular density, apoptosis, and p53/p21 were monitored by immunohistochemistry. The CD95 pathway was performed by flow cytometry, caspase (3/7/8) activity measurements, and functional inhibition of CD95 death signaling.
Combined treatment with SAHA and XRT markedly reduced the surviving fraction of OS cells as compared to XRT alone. Likewise, dual therapy significantly inhibited OS tumor growth in vivo as compared to XRT alone, reflected by reduced tumor proliferation, impaired angiogenesis, and increased apoptosis. Addition of HDACi to XRT led to elevated p53, p21, CD95, and CD95L expression. Inhibition of CD95 signaling reduced HDACi- and XRT-induced apoptosis.
Our data show that HDACi increases the radiosensitivity of osteosarcoma cells at least in part via ligand-induced apoptosis. HDACi thus emerge as potentially useful treatment components of OS.
骨肉瘤（OS）是一种高度恶性和放射抗拒的肿瘤。组蛋白去乙酰化酶抑制剂（HDACi）构成了一类新型的抗癌药物。我们试图研究联合应用 SAHA 和放射治疗对体内骨肉瘤的作用。
采用克隆存活实验检测人骨肉瘤细胞系经药物（载体、放射治疗、SAHA 或放射治疗和 SAHA）处理后的存活分数，采用肿瘤生长延迟实验检测骨肉瘤异种移植瘤的生长延迟。通过免疫组化检测肿瘤增殖、坏死、微血管密度、细胞凋亡和 p53/p21。采用流式细胞术、半胱氨酸天冬氨酸蛋白酶（3/7/8）活性测定和 CD95 死亡信号的功能抑制研究 CD95 途径。
与单独放射治疗相比，SAHA 和放射治疗联合应用可显著降低 OS 细胞的存活分数。同样，与单独放射治疗相比，双重治疗明显抑制了体内骨肉瘤的生长，表现为肿瘤增殖减少、血管生成受损和细胞凋亡增加。在放射治疗中加入 HDACi 可增加 p53、p21、CD95 和 CD95L 的表达。抑制 CD95 信号可减少 HDACi 和放射治疗诱导的细胞凋亡。
我们的数据表明，HDACi 至少部分通过配体诱导的细胞凋亡增加了骨肉瘤细胞的放射敏感性。因此，HDACi 可能成为骨肉瘤的潜在有效治疗成分。
