Akyel Yasemin Kubra, Selby Christopher P, Sancar Aziz, Abdo Ashraf N
Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Department of Medical Pharmacology, School of Medicine, Istanbul Medipol University, Istanbul, Türkiye.
J Biol Rhythms. 2025 Jul 24:7487304251349893. doi: 10.1177/07487304251349893.
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.
昼夜节律时钟使身体几乎每个细胞中的基因表达以24小时为周期振荡，并赋予行为和生理许多方面以节律模式。肿瘤中昼夜节律的存在引发了一个问题，即肿瘤在一天中不同时间接受化疗时是否可能有不同反应。我们通过在上午（ZT2）或晚上（ZT14）用顺铂治疗雄性肝癌小鼠模型，并测量对体重、血细胞计数和化学指标、基因表达以及细胞增殖的总体影响，来解决这个问题。我们发现，在接受顺铂治疗的小鼠中，与ZT2治疗的小鼠相比，ZT14治疗的小鼠肿瘤中增殖标记蛋白Ki-67的表达有所降低。通过血清丙氨酸转氨酶（ALT）升高测量的相应肝毒性以及体重减轻在ZT14时也有所降低。ZT14时的总体基因表达比ZT2时更类似于健康肝脏。在ZT14治疗后，肿瘤中的丝裂原活化蛋白激酶（MAPK）和Ras相关蛋白-1（Rap-1）信号通路被特异性下调，这可能与此时治疗后增殖减少有关。这些发现与使用定时化疗来提高药物疗效的可能性相符。
