The histone deacetylase inhibitor valproic acid sensitizes human and canine osteosarcoma to doxorubicin.
The histone deacetylase inhibitor valproic acid sensitizes human and canine osteosarcoma to doxorubicin.
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DOI：
10.1007/s00280-010-1287-z
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发表时间：
2011-01
影响因子：
3
通讯作者：
Thamm, Douglas H.
中科院分区：
文献类型：
--
作者：
Wittenburg, Luke A.;Bisson, Liam;Rose, Barbara J.;Korch, Christopher;Thamm, Douglas H.
骨肉瘤(OS)在许多患者中仍然是一种无法治愈并最终致命的疾病，需要新的治疗形式。改进的OS模型更接近于模拟人类疾病，将提供关于新疗法效用的更可靠信息。狗的自发性OS可能提供了这样的模型。组蛋白脱乙酰酶(HDAC)酶的药理抑制有多种抗肿瘤作用，但与标准的细胞毒疗法联合使用时可能显示出最大的效用。我们试图确定HDAC抑制剂丙戊酸(VPA)对犬和人OS对阿霉素(DOX)敏感性的体外和体内影响。我们在异种移植模型中评估了VPA/DOX联合治疗的体外抗增殖和凋亡作用，VPA治疗引起的组蛋白乙酰化和核DOX聚集的变化，以及联合治疗的体内疗效。用临床上可达到的VPA浓度处理犬和人OS细胞系，可导致组蛋白乙酰化增加，但抗增殖作用不明显。VPA与阿霉素(DOX)预先孵育后，可显著抑制细胞生长，促进细胞凋亡，并呈剂量依赖性增加核内DOX积聚。在犬OS异种移植模型中，VPA和DOX联合应用优于任何一种单一治疗。这些结果证明了在目前的OS治疗方案中添加HDAC抑制剂的基本原理，并说明了人类和犬OS对HDAC抑制剂的反应相似之处，进一步增强了犬OS模型的可信度。
Osteosarcoma (OS) remains an incurable and ultimately fatal disease in many patients, and novel forms of therapy are needed. Improved models of OS that more closely mimic human disease would provide more robust information regarding the utility of novel therapies. Spontaneous OS in dogs may provide such a model. Pharmacologic inhibition of histone deacetylase (HDAC) enzymes has a variety of anti-tumor effects but may demonstrate the most utility when utilized in combination with standard cytotoxic therapies. We sought to determine the in vitro and in vivo effects of the HDAC inhibitor valproic acid (VPA) on doxorubicin (DOX) sensitivity in canine and human OS. We evaluated the in vitro anti-proliferative and apoptotic effects of VPA/DOX combination treatment, alterations in histone acetylation and nuclear DOX accumulation resulting from VPA treatment, and the in vivo efficacy of combination therapy in a xenograft model. Treatment of canine and human OS cell lines with clinically achievable VPA concentrations resulted in increased histone acetylation but modest anti-proliferative effects. Pre-incubation with VPA followed by doxorubicin (DOX) resulted in significant growth inhibition and potentiation of apoptosis, associated with a dose-dependent increase in nuclear DOX accumulation. The combination of VPA and DOX was superior to either monotherapy in a canine OS xenograft model. These results demonstrate a rationale for the addition of HDAC inhibitors to current protocols for the treatment of OS and illustrate the similarities in response to HDAC inhibitors between human and canine OS, lending further credibility to the canine OS model.
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