Time of Day-Dependent Responses to Cisplatin Treatment in a Male Mouse Model of Hepatoma.

The circadian clock maintains oscillations in gene expression with a 24-hour periodicity in nearly every cell of the body and confers rhythmic patterns to many aspects of behavior and physiology. The presence of circadian rhythms in tumors leads to the question of whether tumors may respond differently to chemotherapy given at different times of day. We addressed this question using a male mouse model of hepatoma by treating mice in the morning (ZT2) or evening (ZT14) with cisplatin, and measuring gross effects on body weight, blood counts and chemistry, gene expression, and cellular proliferation. We found that among cisplatin-treated mice, there was a reduction in expression of the proliferation marker protein Ki-67 in tumors of mice treated at ZT14 as compared to ZT2. Corresponding hepatotoxicity, as measured by elevated serum alanine aminotransferase (ALT), and body weight loss were also reduced at ZT14. Overall gene expression at ZT14 was more similar to healthy liver than expression at ZT2. Mitogen-activated protein kinase (MAPK) and Ras-related protein-1 (Rap-1) signaling pathways were specifically downregulated in tumors following treatment at ZT14, which may be related to the decreased proliferation, at this treatment time. These findings align with the possible use of timed chemotherapy to enhance drug efficacy.