Liver circadian clock, a pharmacologic target of cyclin-dependent kinase inhibitor seliciclib.
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.
Iurisci
Ida
I
INSERM, U 776 Rythmes biologiques et cancers, Hôp. P. Brousse, Villejuif, F-94807, France.
Filipski
Elisabeth
E
Sallam
Hatem
H
Harper
Francis
F
Guettier
Catherine
C
Maire
Irène
I
Hassan
Moustapha
M
Iacobelli
Stefano
S
Lévi
Francis
F
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D019540:Area Under Curve; D001683:Biological Clocks / Q000187:drug effects* / Q000502:physiology; D002453:Cell Cycle; D056486:Chemical and Drug Induced Liver Injury; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D005786:Gene Expression Regulation; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D011687:Purines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D000077546:Roscovitine
D000970:Antineoplastic Agents; D011687:Purines; D000077546:Roscovitine; D018844:Cyclin-Dependent Kinases