Nicotinamide increases the sensitivity of chronic myeloid leukemia cells to doxorubicin via the inhibition of SIRT1
Nicotinamide increases the sensitivity of chronic myeloid leukemia cells to doxorubicin via the inhibition of SIRT1
复制标题
烟酰胺通过抑制 SIRT1 增加慢性粒细胞白血病细胞对阿霉素的敏感性
DOI：
10.1002/jcb.29303
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发表时间：
2019-08-12
影响因子：
4
通讯作者：
Zhang, Qiuping
中科院分区：
文献类型：
--
作者：
Pan, Shan;Leng, Jun;Zhang, Qiuping
nad依赖性去乙酰化酶Sirtuin 1 （SIRT1）在白血病发生中起着至关重要的作用。烟酰胺（NAM）是NAD（+）的主要前体和SIRT1的非竞争性抑制剂。在我们的研究中，我们发现NAM通过SIRT1增强了慢性髓性白血病（CML）对阿霉素（DOX）的敏感性。我们发现SIRT1在CML患者中的高表达与疾病进展和耐药性相关。外源性NAM有效抑制SIRT1去乙酰化活性，诱导DOX-resistant K562细胞（K562R）呈剂量依赖性凋亡。值得注意的是，NAM和DOX联合使用可显著抑制肿瘤细胞增殖，诱导细胞凋亡。在K562R细胞中，SIRT1的下调增强了NAM+ dox诱导的细胞凋亡。SIRT1在K562R中的挽救减少了NAM+ dox诱导的细胞凋亡。在机制上，联合处理在体外和体内均显著增加了K562R中caspase-3和PARP的裂解。这些结果表明NAM通过抑制SIRT1增加CML对DOX的敏感性的潜在作用。
The NAD-dependent deacetylase Sirtuin 1 (SIRT1) plays a vital role in leukemogenesis. Nicotinamide (NAM) is the principal NAD(+) precursor and a noncompetitive inhibitor of SIRT1. In our study, we showed that NAM enhanced the sensitivity of chronic myeloid leukemia (CML) to doxorubicin (DOX) via SIRT1. We found that SIRT1 high expression in CML patients was associated with disease progression and drug resistance. Exogenous NAM efficiently repressed the deacetylation activity of SIRT1 and induced the apoptosis of DOX-resistant K562 cells (K562R) in a dose-dependent manner. Notably, the combination of NAM and DOX significantly inhibited tumor cell proliferation and induced cell apoptosis. The knockdown of SIRT1 in K562R cells enhanced NAM+DOX-induced apoptosis. SIRT1 rescue in K562R reduced the NAM+DOX-induced apoptosis. Mechanistically, the combinatory treatment significantly increased the cleavage of caspase-3 and PARP in K562R in vitro and in vivo. These results suggest the potential role of NAM in increasing the sensitivity of CML to DOX via the inhibition of SIRT1.