A promising action of riboflavin as a mediator of leukaemia cell death
A promising action of riboflavin as a mediator of leukaemia cell death
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DOI：
10.1007/s10495-006-9549-2
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发表时间：
2006-10-01
期刊：
影响因子：
7.2
通讯作者：
Ferreira, Carmen Verissima
中科院分区：
文献类型：
--
作者：
De Souza, Ana Carolina Santos;Kodach, Liudmila;Ferreira, Carmen Verissima
除了作为辅酶的组成部分具有关键的生物学功能外，核黄素似乎是一种有前途的抗肿瘤剂，但其潜在的分子机制仍不清楚。在这项工作中，我们证明，当以μM浓度应用辐照核黄素时，会诱导一系列有序的信号事件，最终导致白血病细胞死亡。所涉及的分子机制依赖于 Fas 和 FasL 过度表达引起的 caspase 8 的激活，以及线粒体放大机制，涉及鞘磷脂酶和神经酰胺合酶刺激神经酰胺的产生。该级联的激活导致丝裂原激活蛋白激酶：JNK、MEK 和 ERK 以及生存介质（PKB 和 IAP1）的抑制，促凋亡 Bcl2 成员 Bax 的上调以及细胞周期进程调节因子的下调。重要的是，辐射核黄素诱导细胞凋亡是白血病细胞特异性的，因为正常人淋巴细胞不会对这种化合物做出反应而导致细胞死亡。我们的数据表明，核黄素选择性激活 Fas 级联，并且还构成一种死亡受体结合药物，对正常细胞没有有害副作用，支持使用这种化合物作为对抗癌症疾病的新途径。
Besides having a pivotal biological function as a component of coenzymes, riboflavin appears a promissing antitumoral agent, but the underlying molecular mechanism remains unclear. In this work, we demonstrate that irradiated riboflavin, when applied at mu M concentrations, induces an orderly sequence of signaling events finally leading to leukemia cell death. The molecular mechanism involved is dependent on the activation of caspase 8 caused by overexpression of Fas and FasL and also on mitochondrial amplification mechanisms, involving the stimulation of ceramide production by sphingomyelinase and ceramide synthase. The activation of this cascade led to an inhibition of mitogen activated protein kinases: JNK, MEK and ERK and survival mediators (PKB and IAP1), upregulation of the proapoptotic Bcl2 member Bax and downregulation of cell cycle progression regulators. Importantly, induction of apoptosis by irradiated riboflavin was leukaemia cell specific, as normal human lymphocytes did not respond to the compound with cell death. Our data indicate that riboflavin selectively activates Fas cascade and also constitutes a death receptor-engaged drug without harmful side effects in normal cells, bolstering the case for using this compound as a novel avenue for combating cancerous disease.