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Improved Tumor Control through Circadian Clock Induction by Seliciclib, a Cyclin-Dependent Kinase Inhibitor

¹ Institut National de la Santé et de la Recherche Médicale, U776 "Rythmes Biologiques et Cancers," Hôpital Paul Brousse, Villejuif Cedex, France; Université Paris Sud, Orsay, France; ² Department of Oncology and Neurosciences, Università "G. D'Annunzio," Chieti, Italy; ³ Centre National de la Recherche Scientifique, Cell Cycle Group, UPS-2682 & UMR-7151, Roscoff Cedex, France; and ⁴ Cyclacel Ltd., Dundee, United Kingdom

Requests for reprints: Francis Lévi, Institut National de la Santé et de la Recherche Médicale, U776 "Rythmes Biologiques et Cancers" (Université Paris XI), Paul Brousse Hospital, 94800 Villejuif, France. Phone: 33-1-45-59-38-55; Fax: 33-1-45-59-36-02; E-mail: levi-f{at}vjf.inserm.fr.

The circadian timing system and the cell division cycle are frequently deregulated in cancer. The therapeutic relevance of the reciprocal interactions between both biological rhythms was investigated using Seliciclib, a cyclin-dependent kinase (CDK) inhibitor (CDKI). Mice bearing Glasgow osteosarcoma received Seliciclib (300 mg/kg/d orally) or vehicle for 5 days at Zeitgeber time (ZT) 3, 11, or 19. On day 6, tumor mRNA 24-hour expression patterns were determined for clock genes (Per2, Rev-erb, and Bmal1) and clock-controlled cell cycle genes (c-Myc, Wee1, cyclin B1, and CDK1) with quantitative reverse transcription-PCR. Affinity chromatography on immobilized Seliciclib identified CDK1/CDK2 and extracellular signal-regulated kinase (ERK) 1/ERK2, CDK7/CDK9, and casein kinase CK1 as Seliciclib targets, which respectively regulate cell cycle, transcription, and circadian clock in Glasgow osteosarcoma. Seliciclib reduced tumor growth by 55% following dosing at ZT3 or ZT11 and by 35% at ZT19 compared with controls (P < 0.001). Tolerability was also best at ZT3. Mean transcriptional activity of Rev-erb, Per2, and Bmal1 was arrhythmic in the tumors of untreated mice. Seliciclib induced rhythmic clock gene expression patterns with physiologic phase relations only after ZT3 dosing. c-Myc and Wee1 mRNAs displayed synchronous circadian rhythms in the tumors of control mice receiving vehicle only but not in those of mice given the drug. Seliciclib further enhanced Wee1 expression irrespective of dosing time, an effect that reinforced G₂-M gating. Seliciclib also inhibited CK1, which determines circadian period length. The coordination of clock gene expression patterns in tumor cells was associated with best antitumor activity of Seliciclib. The circadian clock and its upstream regulators represent relevant targets for CDKIs. (Cancer Res 2006; 66(22): 10720-8)