Iurisci Ida, Filipski Elisabeth, Sallam Hatem, Harper Francis, Guettier Catherine, Maire Irène, Hassan Moustapha, Iacobelli Stefano, Lévi Francis
INSERM, U 776 Rythmes biologiques et cancers, Hôp. P. Brousse, Villejuif, F-94807, France.
Chronobiol Int. 2009 Aug;26(6):1169-88. doi: 10.3109/07420520903209942.
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 alpha, Per2, and Bmal1 in mouse liver following dosing at zeitgeber time (ZT) 3 (i.e., 3 h after the onset of the 12 h light span), when mice start to rest, but not at ZT19, near the middle of the 12 h dark span, when mice are most active. However, liver exposure to seliciclib, as estimated by the liver area under the concentration x time curve (AUC), was approximately 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.
昼夜节律紊乱会加速实验性肿瘤模型和癌症患者的恶性生长并缩短生存期。在先前的实验中，使用细胞周期蛋白依赖性激酶（CDK）抑制剂塞利西利可挽救肿瘤昼夜节律紊乱。这种效应发生在特定的给药时间，并且与抗肿瘤活性的提高有关。在当前研究中，在授时时间（ZT）3（即12小时光照期开始后3小时）给药后，塞利西利改变了小鼠肝脏中生物钟基因Rev-erbα、Per2和Bmal1强大的昼夜节律性mRNA表达，此时小鼠开始休息，但在ZT19（12小时黑暗期中间附近）给药时则未改变，此时小鼠最为活跃。然而，根据浓度-时间曲线下的肝脏面积（AUC）估算，ZT19时肝脏对塞利西利的暴露量比ZT3时高约80%（p = 0.049）。生化测定以及光学和电子显微镜检查显示，昼夜节律时钟紊乱与血清肝酶升高以及肝细胞中糖原分布改变有关。与ZT19相比，ZT3给药后肝酶升高的程度最为明显（p < 0.04）。塞利西利进一步上调了c-Myc的转录活性，c-Myc是一种促进细胞周期进入和G1-S期转换的细胞周期基因（p < 0.001），并下调了Wee1的转录活性，Wee1控制细胞周期从G2期到M期的转换（p < 0.001）。这些效应不依赖于药物给药时间。总体而言，结果表明，在确定塞利西利对昼夜节律时钟的影响时，给药的昼夜时间比药物暴露量更为关键。塞利西利诱导的肝脏分子时钟紊乱可能通过导致时钟控制的解毒途径紊乱而导致肝脏毒性。肝脏中细胞周期基因表达的改变可能涉及其他机制。昼夜节律时钟是优化CDK抑制剂治疗方案时需要考虑的相关靶点。
