title: Involvement of Wee1 in the circadian rhythm-dependent intestinal damage induced by docetaxel.
abstract: Docetaxel, a semisynthetic taxane, is effective for the treatment of some solid cancers; however, docetaxel-induced intestinal damage leads to poor prognosis in some patients. Although such adverse effects have been reported to depend on the dosing-time of docetaxel, the mechanisms involved remain unclear. Wee1 expression is controlled by the clock gene complex, clock/bmal1, and contributes to cell-cycle progression. The present study was undertaken to evaluate the potential role of Wee1 in the circadian rhythm-dependent profile of docetaxel. Male mice were maintained under a 12-hour light/dark cycle. Intestinal damage after repeated dosing of docetaxel (20 mg/kg) for 3 weeks was more severe at 14 hours after light on (HALO) than at 2 HALO. The intestinal protein expressions of Wee1, phosphorylated CDK1, and cleaved Caspase-3 were higher in the 14-HALO group than in the 2-HALO group, whereas that of survivin was lower in the 14-HALO group. Thus, it is speculated that elevated Wee1 expression inhibited CDK1 activity more by phosphorylation, which in turn caused the lower expression of survivin and consequently more activated Caspase-3 in the 14-HALO group. There were no significant differences in plasma docetaxel concentrations between the 2- and 14-HALO groups. Bindings of CLOCK and BMAL1 to the E-box regions at the wee1 gene promoter were not altered by docetaxel treatment at 2 and 14 HALO. These findings suggest that Wee1 is directly or indirectly involved in the mechanism of the circadian rhythm-dependent changes in docetaxel-induced intestinal damage. However, the mechanism for a circadian rhythm-dependent change in intestinal Wee1 expression by docetaxel remains to be determined.
authors.affiliation: Division of Clinical Pharmacology, Department of Pharmacology (Y.O.-I., K.U., E.I.-K., A.F.), and Department of Dentistry, Oral and Maxillofacial Surgery (Y.O.-I., M.K.), Jichi Medical University, Tochigi, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Obi-Ioka
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ushijima
authors.forename: Mikio
authors.initials: M
authors.lastname: Kusama
authors.forename: Eiko
authors.initials: E
authors.lastname: Ishikawa-Kobayashi
authors.forename: Akio
authors.initials: A
authors.lastname: Fujimura
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D018797:Cell Cycle Proteins / Q000502:physiology*; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology*; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009687:Nuclear Proteins / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D043823:Taxoids / Q000633:toxicity*
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D043823:Taxoids; D000077143:Docetaxel; D011505:Protein-Tyrosine Kinases; C499348:Wee1 protein, mouse