KD5170, a novel mercaptoketone-based histone deacetylase inhibitor, exerts antimyeloma effects by DNA damage and mitochondrial signaling
KD5170, a novel mercaptoketone-based histone deacetylase inhibitor, exerts antimyeloma effects by DNA damage and mitochondrial signaling
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DOI：
10.1158/1535-7163.mct-08-0183
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发表时间：
2008-06-01
影响因子：
5.7
通讯作者：
Lentzsch, Suzanne
中科院分区：
文献类型：
--
作者：
Feng, Rentian;Ma, Huihui;Lentzsch, Suzanne
组蛋白脱乙酰酶抑制剂已成为有前景的抗癌药物。使用无偏倚的超高通量筛选系统，鉴定出一种新型基于巯基酮的组蛋白脱乙酰酶抑制剂系列，并针对先导化合物 KD5170 进行了优化。 KD5170 通过诱导细胞凋亡来抑制骨髓瘤细胞系的增殖和 CD138(+) 原发性骨髓瘤细胞的活力，并伴有组蛋白乙酰化的增加以及 caspase-3、caspase-8 和 caspase-9 的激活。 KD5170 治疗导致线粒体膜电位丧失，导致细胞色素 c、Smac 和凋亡诱导因子等凋亡因子的释放。此外，KD5170 在骨髓瘤细胞中诱导氧化应激和氧化 DNA 损伤，血红素加氧酶-1 和 H2A.X 磷酸化上调证明了这一点。 KD5170与蛋白酶体抑制剂硼替佐米或肿瘤坏死因子相关凋亡诱导配体的组合可协同增强抗骨髓瘤活性。我们进一步发现，骨髓瘤细胞对 KD5170 的耐药性与 KD5170 治疗下细胞外信号调节激酶/丝裂原激活蛋白激酶途径的激活有关。用丝裂原激活蛋白激酶抑制剂U0126预处理可恢复对KD5170的敏感性，表明KD5170与U0126的组合可以克服耐药性。 KD5170处理的裸鼠骨髓瘤异种移植物的生长受到显着抑制，存活时间延长。用 KD5170 治疗的动物的脾脏和肿瘤组织中组蛋白乙酰化增加。我们的数据表明，KD5170 在体外和体内具有有效的抗骨髓瘤活性，该活性是通过 DNA 损伤和线粒体信号传导以及随后诱导细胞凋亡介导的。
Histone deacetylase inhibitors have emerged as promising anticancer drugs. Using an unbiased ultrahigh throughput screening system, a novel mercaptoketone-based histone deacetylase inhibitor series was identified that was optimized to the lead compound, KD5170. KD5170 inhibited the proliferation of myeloma cell lines and the viability of CD138(+) primary myeloma cells by induction of apoptosis, accompanied by an increase of acetylation of histones and activation of caspase-3, caspase-8, and caspase-9. Treatment with KD5170 caused a loss of mitochondrial membrane potential resulting in release of apoptogenic factors such as cytochrome c, Smac, and apoptosis-inducing factor. Furthermore, KD5170 induced oxidative stress and oxidative DNA damage in myeloma cells as evidenced by the up-regulation of heme oxygenase-1 and H2A.X phosphorylation. Combination of KD5170 with proteasome inhibitor bortezomib or tumor necrosis factor-related apoptosis-inducing ligand synergistically enhanced the antimyeloma activity. We further found that resistance of myeloma cells to KD5170 was associated with activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway under treatment with KD5170. Pretreatment with the mitogen-activated protein kinase inhibitor U0126 restored sensitivity to KD5170, suggesting that the combination of KD5170 with U0126 could overcome drug resistance. Growth of myeloma tumor xenografts in KD5170-treated nude mice was significantly inhibited and survival was prolonged. Histone acetylation was increased in spleen and tumor tissues of animals treated with KD5170. Our data indicate that KD5170 has potent antimyeloma activity in vitro and in vivo, which is mediated by DNA damage and mitochondrial signaling and subsequent induction of apoptosis.