Romidepsin (FK228), a potent histone deacetylase inhibitor, induces apoptosis through the generation of hydrogen peroxide
Romidepsin (FK228), a potent histone deacetylase inhibitor, induces apoptosis through the generation of hydrogen peroxide
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DOI：
10.1111/j.1349-7006.2010.01645.x
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发表时间：
2010-10-01
期刊：
影响因子：
5.7
通讯作者：
Kawanishi, Shosuke
中科院分区：
文献类型：
--
作者：
Mizutani, Hideki;Hiraku, Yusuke;Kawanishi, Shosuke
Romidepsin (FK228) 是一种有效的组蛋白脱乙酰酶 (HDAC) 抑制剂，具有有效的抗癌活性，但其分子机制尚不清楚。我们研究了 FK228 诱导人白血病细胞系 HL-60 及其过氧化氢 (H(2)O(2)) 抗性亚克隆 HP100 和人结肠癌细胞系 Caco-2 细胞凋亡的机制。孵育 24 小时后，在 HL-60 细胞中可以检测到 FK228 诱导的细胞毒性和 DNA 阶梯形成，而在 HP100 细胞中则无法检测到。曲古抑菌素 A (TSA) 是一种 HDAC 抑制剂，可诱导 HL-60 和 HP100 细胞中 DNA 阶梯的形成。相比之下，FK228 对 HL-60 和 HP100 细胞中 HDAC 活性的抑制程度相似。这些发现表明FK228 诱导的细胞凋亡涉及H(2)O(2) 介导的途径，而TSA 诱导的细胞凋亡则不涉及。流式细胞术揭示了 FK228 处理的细胞中 H(2)O(2) 的形成和线粒体膜电位 (Delta epsilon m) 的变化。 FK228 还诱导 Caco-2 细胞凋亡，但 N-乙酰半胱氨酸可阻止这种凋亡，这表明活性氧参与各种类型肿瘤细胞的凋亡。有趣的是，在无细胞系统中，FK228 在谷胱甘肽存在下产生超氧化物 (O(2)-)，这表明 H(2)O(2) 源自 FK228 氧化还原循环产生的 O(2)- 歧化。因此，除了HDAC抑制之外，FK228产生的H(2)O(2)可能参与其凋亡作用。 （癌症科学 2010 年；）。
Romidepsin (FK228) is a potent histone deacetylase (HDAC) inhibitor, which has a potent anticancer activity, but its molecular mechanism is unknown. We investigated the mechanism of FK228-induced apoptosis in the human leukemia cell line HL-60 and its hydrogen peroxide (H(2)O(2))-resistant sub-clone, HP100, and the human colon cancer cell line Caco-2. Cytotoxicity and DNA ladder formation induced by FK228 could be detected in HL-60 cells after a 24-h incubation, whereas they could not be detected in HP100 cells. Trichostatin A (TSA), an HDAC inhibitor, induced DNA ladder formation in both HL-60 and HP100 cells. In contrast, FK228 inhibited HDAC activity in both HL-60 and HP100 cells to a similar extent. These findings suggest that FK228-induced apoptosis involves H(2)O(2)-mediated pathways and that TSA-induced apoptosis does not. Flow cytometry revealed H(2)O(2) formation and a change in mitochondrial membrane potential (Delta epsilon m) in FK228-treated cells. FK228 also induced apoptosis in Caco-2 cells, which was prevented by N-acetyl-cysteine, suggesting that reactive oxygen species participate in apoptosis in various types of tumor cells. Interestingly, in a cell-free system, FK228 generated superoxide (O(2)-) in the presence of glutathione, suggesting that H(2)O(2) is derived from dismutation of O(2)- produced through redox-cycle of FK228. Therefore, in addition to HDAC inhibition, H(2)O(2) generated from FK228 may participate in its apoptotic effect. (Cancer Sci 2010;).