Chemistry and Biology of Deoxynyboquinone, a Potent Inducer of Cancer Cell Death
Chemistry and Biology of Deoxynyboquinone, a Potent Inducer of Cancer Cell Death
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DOI：
10.1021/ja100610m
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发表时间：
2010-04-21
影响因子：
15
通讯作者：
Hergenrother, Paul J.
中科院分区：
文献类型：
--
作者：
Bair, Joseph S.;Palchaudhuri, Rahul;Hergenrother, Paul J.
脱氧尼波醌（DNQ）是一种有效的麻醉剂，其作用机制尚不清楚。在这里，我们描述了一种简单的合成路线，这种蒽醌，我们使用这种材料来确定DNQ诱导癌细胞死亡的机制。DNQ通过采用三个钯介导的偶联反应的路线在七个线性步骤中合成。在缺氧和常氧条件下生长的癌细胞上进行的实验强烈表明，DNQ经历生物还原成其半醌，然后被分子氧再氧化，形成诱导细胞死亡的超氧化物。此外，用DNQ处理的细胞的总体转录物谱显示与氧化应激相关的转录物升高，这一结果在蛋白质水平上通过蛋白质印迹法证实。与大多数其他产生活性氧（ROS）的抗癌药物相反，DNQ在培养中有效诱导癌细胞死亡，IC 50值在16至210 nM之间。此外，与实验性治疗药物elesclomol不同，DNQ在缺氧条件下仍然能够诱导癌细胞死亡。DNQ的这种机制理解将允许更全面地评估直接ROS生成作为抗癌策略的潜力，并且DNQ本身具有作为新型抗癌剂的潜力。
Deoxynyboquinone (DNQ) is a potent antineoplastic agent with an unknown mechanism of action. Here we describe a facile synthetic route to this anthraquinone, and we use this material to determine the mechanism by which DNQ induces death in cancer cells. DNQ was synthesized in seven linear steps through a route employing three palladium-mediated coupling reactions. Experiments performed on cancer cells grown in hypoxia and normoxia strongly suggest that DNQ undergoes bioreduction to its semiquinone, which then is re-oxidized by molecular oxygen, forming superoxide that induces cell death. Furthermore, global transcript profiling of cells treated with DNQ shows elevation of transcripts related to oxidative stress, a result confirmed at the protein level by Western blotting. In contrast to most other antineoplastic agents that generate reactive oxygen species (ROS), DNQ potently induces death of cancer cells in culture, with IC50 values between 16 and 210 nM. In addition, unlike the experimental therapeutic elesclomol, DNQ is still able to induce cancer cell death under hypoxic conditions. This mechanistic understanding of DNQ will allow for a more comprehensive evaluation of the potential of direct ROS generation as an anticancer strategy, and DNQ itself has potential as a novel anticancer agent.