Enhancement of in vitro and in vivo tumor cell radiosensitivity by valproic acid
Enhancement of in vitro and in vivo tumor cell radiosensitivity by valproic acid
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DOI：
10.1002/ijc.20774
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发表时间：
2005-04-10
影响因子：
6.4
通讯作者：
Tofilon, PJ
中科院分区：
文献类型：
--
作者：
Camphausen, K;Cerna, D;Tofilon, PJ
丙戊酸(VA)是一种耐受性良好的药物，用于治疗癫痫，最近被证明抑制组蛋白脱乙酰酶(HDAC)。由于HDAC调节染色质结构和基因表达，这些被认为是影响放射反应的参数，我们研究了VA对体外和体内生长的人脑肿瘤细胞放射敏感性的影响。本研究以人脑肿瘤细胞系SF539和U251为研究对象。组蛋白高乙酰化可作为HDAC抑制的指标。用克隆存活实验评价VA对肿瘤细胞体外放射敏感性的影响，并测定辐射诱导的DNA双链断裂的指标--γ-H_2AX的表达。通过对U251移植瘤的肿瘤生长延迟分析，评价VA对脑肿瘤细胞体内放射反应的影响。在VA诱导组蛋白高乙酰化达到最大值时进行照射，可显著提高SF539和U251细胞的放射敏感性。放射增敏伴随着γ-H_2AX的长时间表达。给小鼠注射维生素A后，在U251异种移植瘤中可以明显检测到组蛋白的超乙酰化水平。用VA治疗的小鼠U251肿瘤照射后，辐射诱导的肿瘤生长延迟增加。丙戊酸对体外培养的SF539、U251细胞和体内移植瘤U251均有放射增敏作用，这与诱导组蛋白超乙酰化有关。此外，VA介导的辐射诱导的细胞杀伤增加似乎涉及对DNA DSB修复的抑制。(C)2004年Wiley-Liss公司
Valproic acid (VA) is a well-tolerated drug used to treat seizure disorders and has recently been shown to inhibit histone deacetylase (HDAC). Because HDAC modulates chromatin structure and gene expression, parameters considered to influence radiorespouse, we investigated the effects of VA on the radiosensitivity of human brain tumor cells grown in vitro and in vivo. The human brain tumor cell lines SF539 and U251 were used in our study. Histone hyperacetylation served as an indicator of HDAC inhibition. The effects of VA on tumor cell radiosensitivity in vitro were assessed using a clonogenic survival assay and gammaH2AX expression was determined as a measure of radiation-induced DNA double strand breaks. The effect of VA on the in vivo radioresponse of brain tumor cells was evaluated according to tumor growth delay analysis carried out on U251 xenografts. Irradiation at the time of maximum VA-induced histone hyperacetylation resulted in significant increases in the radiosensitivity of both SF539 and U251 cells. The radiosensitization was accompanied by a prolonged expression of gammaH2AX. VA administration to mice resulted in a clearly detectable level of histone hyperacetylation in U251 xenografts. Irradiation of U251 tumors in mice treated with VA resulted in an increase in radiation-induced tumor growth delay. Valproic acid enhanced the radiosensitivity of both SF539 and U251 cell lines in vitro and U251 xenografts in vivo, which correlated with the induction of histone hyperacetylation. Moreover, the VA-mediated increase in radiation-induced cell killing seemed to involve the inhibition of DNA DSB repair. (C) 2004 Wiley-Liss, Inc.