Histone deacetylase inhibitors enhance the chemosensitivity of tumor cells with cross-resistance to a wide range of DNA-damaging drugs
Histone deacetylase inhibitors enhance the chemosensitivity of tumor cells with cross-resistance to a wide range of DNA-damaging drugs
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DOI：
10.1111/j.1349-7006.2007.00669.x
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发表时间：
2008-02-01
期刊：
影响因子：
5.7
通讯作者：
Kohno, Michiaki
中科院分区：
文献类型：
--
作者：
Ozaki, Kei-ichi;Kishikawa, Futaba;Kohno, Michiaki
尽管DNA损伤剂是临床使用中最有效的抗癌药物之一，但它们的总体有效性受到对这些药物的交叉耐药性的发展的限制。鉴于组蛋白去乙酰化酶（HDAC）抑制剂增加了核心组蛋白的乙酰化，导致开放的染色质构型更容易被DNA靶向药物所接近，我们研究了HDAC抑制剂是否可能增强DNA损伤药物在6种表现出不同顺铂敏感性的人卵巢肿瘤细胞系中的细胞毒性。低浓度的HDAC抑制剂，单独表现出很小的细胞毒性，显着增强诱导凋亡细胞死亡不仅由顺铂，而且由各种各样的DNA靶向抗癌药物在这些肿瘤细胞系，无论其敏感性的相应药物。相反，HDAC抑制剂不增加代谢拮抗剂或微管靶向剂的细胞毒性。HDAC抑制剂增强丝氨酸-139（DNA双链断裂的标志物）上的组蛋白H2 AX的磷酸化以及肿瘤细胞中DNA损伤剂诱导的活性氧物质的积累。活性氧的产生增强似乎是负责这些药物的组合诱导的增强的凋亡细胞死亡。这些结果表明，HDAC抑制剂与多种DNA损伤剂的组合是用于根除肿瘤细胞的有希望的化学治疗策略，无论细胞对DNA损伤抗癌药物是否敏感或耐药。
Although DNA-damaging agents are among the most effective anticancer drugs in clinical use, their overall effectiveness is limited by the development of cross-resistance to these drugs. Given that histone deacetylase (HDAC) inhibitors increase the acetylation of core histones, resulting in an open chromatin configuration that is more accessible to DNA-targeting agents, we examined whether HDAC inhibitors might enhance the cytotoxicity of DNA-damaging drugs in six human ovarian tumor cell lines that exhibit different cisplatin sensitivities. Low concentrations of HDAC inhibitors, which alone exhibited little cytotoxicity, markedly enhanced the induction of apoptotic cell death not only by cisplatin but also by a wide variety of DNA-targeting anticancer drugs in these tumor cell lines, irrespective of their sensitivities to the respective drugs. In contrast, HDAC inhibitors did not increase the cytotoxicity of metabolic antagonists or microtubule-targeting agents. HDAC inhibitors potentiated both the phosphorylation of histone H2AX on serine-139 (a marker of DNA double-strand breaks) as well as the accumulation of reactive oxygen species induced by DNA-damaging agents in tumor cells. The enhanced generation of reactive oxygen species appeared to be responsible for the enhanced apoptotic cell death induced by the combination of these drugs. These results indicate that the combination of an HDAC inhibitor with a wide variety of DNA-damaging agents is a promising chemotherapeutic strategy for the eradication of tumor cells, regardless of whether the cells are sensitive or resistant to the DNA-damaging anticancer drugs.