PT  - JOURNAL ARTICLE
AU  - Yuri Obi-Ioka
AU  - Kentaro Ushijima
AU  - Mikio Kusama
AU  - Eiko Ishikawa-Kobayashi
AU  - Akio Fujimura
TI  - Involvement of Wee1 in the Circadian Rhythm–Dependent Intestinal Damage Induced by Docetaxel
AID  - 10.1124/jpet.113.203299
DP  - 2013 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 242--248
VI  - 347
IP  - 1
4099  - http://jpet.aspetjournals.org/content/347/1/242.short
4100  - http://jpet.aspetjournals.org/content/347/1/242.full
SO  - J Pharmacol Exp Ther2013 Oct 01; 347
AB  - 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.