Liver Circadian Clock, a Pharmacologic Target of Cyclin-Dependent Kinase Inhibitor Seliciclib
Liver Circadian Clock, a Pharmacologic Target of Cyclin-Dependent Kinase Inhibitor Seliciclib
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DOI：
10.1080/07420520903209942
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发表时间：
2009-01-01
影响因子：
2.8
通讯作者：
Levi, Francis
中科院分区：
文献类型：
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作者：
Iurisci, Ida;Filipski, Elisabeth;Levi, Francis
无论是在实验肿瘤模型中还是在癌症患者中，昼夜节律紊乱都会加速恶性生长并缩短生存期。在以前的实验中，肿瘤昼夜节律的破坏是用细胞周期蛋白依赖性激酶(CDKs)的抑制剂赛利康挽救的。这一效应发生在选择性给药时间，并与抗肿瘤活性的提高有关。在目前的研究中，Seliclib改变了小鼠肝脏中时钟基因Rev-erb、PER2和BMal1的强健的昼夜节律mRNA的表达，在ZT时间(ZT)3(即12h光程开始后的3h)给药后，小鼠开始休息，但在ZT19，接近12h暗跨度的中段，小鼠最活跃的时候给药没有改变。然而，根据浓度-时间曲线(AuC)下的肝脏面积估计，肝脏对硒的暴露在ZT19组比ZT3组高80%(p=0.049)。生化测定和光学和电子显微镜显示，昼夜节律紊乱与血清肝酶增加和肝细胞糖原分布改变有关。与ZT19相比，服用ZT3后，肝酶的增加幅度最明显(p<0.04)。Seliclib进一步上调了细胞周期基因c-myc的转录活性(p 0.001)，下调了细胞周期基因wee1的转录活性(p 0.001)，Wee1基因使细胞周期从G2向M转换。这些效应并不依赖于给药时间。总体而言，这些结果表明，在决定其对生物钟的影响方面，塞利西利的昼夜节律时间比药物暴露的量更关键。Seliclib诱导的肝脏分子时钟的破坏可能通过导致时钟控制的解毒途径的中断来解释肝脏毒性。肝脏细胞周期基因表达的改变可能涉及其他机制。昼夜节律代表了CDK抑制剂治疗方案优化的相关靶点。
Circadian disruption accelerates malignant growth and shortens survival, both in experimental tumor models and cancer patients. In previous experiments, tumor circadian disruption was rescued with seliciclib, an inhibitor of cyclin-dependent kinases (CDKs). This effect occurred at a selective dosing time and was associated with improved antitumor activity. In the current study, seliciclib altered robust circadian mRNA expression of the clock genes Rev-erb, Per2, and Bmal1 in mouse liver following dosing at zeitgeber time (ZT) 3 (i.e., 3h after the onset of the 12h light span), when mice start to rest, but not at ZT19, near the middle of the 12h dark span, when mice are most active. However, liver exposure to seliciclib, as estimated by the liver area under the concentrationxtime curve (AUC), was 80% higher at ZT19 than at ZT3 (p = 0.049). Circadian clock disruption was associated with increased serum liver enzymes and modified glycogen distribution in hepatocytes, as revealed by biochemical determinations and optic and electronic microscopy. The extent of increase in liver enzymes was most pronounced following dosing at ZT3, as compared to ZT19 (p 0.04). Seliciclib further up-regulated the transcriptional activity of c-Myc, a cell cycle gene that promotes cell cycle entry and G1-S transition (p 0.001), and down-regulated that of Wee1, which gates cell cycle transition from G2 to M (p 0.001). These effects did not depend upon drug dosing time. Overall, the results suggest the circadian time of seliciclib delivery is more critical than the amount of drug exposure in determining its effects on the circadian clock. Seliciclib-induced disruption of the liver molecular clock could account for liver toxicity through the resulting disruption of clock-controlled detoxification pathways. Modifications of cell cycle gene expression in the liver likely involve other mechanisms. Circadian clocks represent relevant targets to consider for optimization of therapeutic schedules of CDK inhibitors.