Abstract

Docetaxel, a semi-synthetic 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-hr light/dark cycle. Intestinal damage after repeated dosing of docetaxel (20 mg/kg) for 3 weeks was more severe at 14HALO than at 2HALO (hours after light on). The intestinal protein expressions of Wee1, phosphorylated CDK1, and cleaved Caspase-3 were higher in the 14HALO group than in the 2HALO group, while that of survivin was lower in the 14HALO group. Thus, it is speculated that elevated Wee1 expression more inhibited CDK1 activity by phosphorylation, which in turn caused the lower expression of survivin and consequently more activated Caspase-3 in the 14HALO group. There were no significant differences in plasma docetaxel concentrations between the 2 and 14HALO 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 14HALO. 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.