HDAC Inhibitor, Valproic Acid, Induces p53-Dependent Radiosensitization of Colon Cancer Cells
HDAC Inhibitor, Valproic Acid, Induces p53-Dependent Radiosensitization of Colon Cancer Cells
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DOI：
10.1089/cbr.2009.0629
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发表时间：
2009-12-01
影响因子：
3.4
通讯作者：
Wong, Jeffrey Y. C.
中科院分区：
文献类型：
--
作者：
Chen, Xufeng;Wong, Patty;Wong, Jeffrey Y. C.
抑制组蛋白去乙酰化酶（HDAC抑制剂）的药物已被证明可以增强辐射反应。本研究的目的是评估低、最低浓度的HDAC抑制剂丙戊酸（VPA）对结直肠癌细胞辐射反应的影响。仅存在野生型p53的LS174T细胞系和HCT116等基因对分别暴露于电离辐射（IR）、VPA单独或两者联合下。评估克隆成活、γ - h2ax诱导、细胞凋亡、线粒体膜电位的变化以及p53和Bcl-2家族蛋白的线粒体水平。体内研究监测了HCT116/p53（+/+）和HCT116/p53（-/-）异种肿瘤移植小鼠治疗后的肿瘤生长抑制情况。VPA导致放射致敏，这取决于p53状态。在野生型p53细胞（LS174T和HCT116/p53(+/+)）中，与p53无细胞（HCT116/p53(+/+)）相比，VPA+IR后观察到克隆存活率降低，细胞凋亡增加，γ - h2ax水平升高。仅在野生型p53细胞系中，暴露于VPA导致ir诱导的线粒体Bax和Bcl-xL定位、线粒体膜电位和细胞色素c释放增强。仅在野生型p53异种移植物中，VPA也增强了IR后肿瘤生长抑制。这些数据表明VPA可能在提高结直肠癌放疗应答中起重要作用，特别是在野生型p53基因型肿瘤中。
Agents that inhibit histone deacetylases (HDAC inhibitors) have been shown to enhance radiation response. The aim of this study was to evaluate the effects of low, minimally cytotoxic concentrations of the HDAC inhibitor, valproic acid (VPA), on radiation response of colorectal cancer cells. Cell lines LS174T and an isogenic pair of HCT116, which differed only for the presence of wild-type p53, were exposed to ionizing radiation (IR) alone, VPA alone, or the combination. Clonogenic survival, gamma-H2AX induction, apoptosis, changes in mitochondrial membrane potential, and mitochondrial levels of p53 and Bcl-2 family proteins were assessed. In vivo studies monitored tumor growth suppression after therapy in mice bearing HCT116/p53(+/+) and HCT116/p53(-/-) tumor xenografts. VPA led to radiosensitization, which was dependent on p53 status. A decrease in clonogenic survival, an increase in apoptosis, and an increase in levels of gamma-H2AX were observed after VPA+IR, compared to IR alone, in wild-type p53 cells (LS174T and HCT116/p53(+/+)), as opposed to p53 null cells (HCT116/p53(+/+)). Exposure to VPA resulted in enhancement of IR-induced mitochondrial localizations of Bax and Bcl-xL, mitochondrial membrane potential, and cytochrome c release only in wild-type p53 cell lines. VPA also enhanced tumor growth suppression after IR only in wild-type p53 xenografts. These data suggest that VPA may have an important role in enhancing radiotherapy response in colorectal cancer, particularly in tumors with the wildtype p53 genotype.