Molecular Aspects of Circadian Pharmacology and Relevance for Cancer Chronotherapy

Abstract

The circadian timing system (CTS) controls various biological functions in mammals including xenobiotic metabolism and detoxification, immune functions, cell cycle events, apoptosis and angiogenesis. Although the importance of the CTS is well known in the pharmacology of drugs, it is less appreciated at the clinical level. Genome-wide studies highlighted that the majority of drug target genes are controlled by CTS. This suggests that chronotherapeutic approaches should be taken for many drugs to enhance their effectiveness. Currently chronotherapeutic approaches are successfully applied in the treatment of different types of cancers. The chronotherapy approach has improved the tolerability and antitumor efficacy of anticancer drugs both in experimental animals and in cancer patients. Thus, chronobiological studies have been of importance in determining the most appropriate time of administration of anticancer agents to minimize their side effects or toxicity and enhance treatment efficacy, so as to optimize the therapeutic ratio. This review focuses on the underlying mechanisms of the circadian pharmacology i.e., chronopharmacokinetics and chronopharmacodynamics of anticancer agents with the molecular aspects, and provides an overview of chronotherapy in cancer and some of the recent advances in the development of chronopharmaceutics.

CRY1-CBS binding regulates circadian clock function and metabolism

“…PER and CRY proteins are shuttled to the cytoplasm forming heterodimers that interact with casein kinase Iε (CKIε). Ultimately the heterodimer translocates and returns to the nucleus where it represses BMAL1/CLOCK driven transcription [13][14][15][16][17]. The degradation of CRY and PER proteins relieves the repression of BMAL1/CLOCK, restarting the cycle anew [18].…”

Melatonin Administered before or after a Cytotoxic Drug Increases Mammary Cancer Stabilization Rates in HER2/Neu Mice

“…[2,6,25,35]. In rodents, tolerability to more than 40 anticancer drugs was shown to vary up to 10-fold depending on the dosing times [15]. A meta-analysis of studies of rodent tolerance to antitumor drugs suggests that cyclophosphamide is best tolerated when administered at ZT12, whereas doxorubicin, at ZT08 [36].…”

“…MT was shown to produce oncostatic effect in several cancers [9] and can influence body responses to cytostatic drugs [10]. The available data on the need for combinations of the chemotherapy regimen, chronobiotic agents, and the appropriate time of their administration do not allow to draw unambiguous conclusions about the therapeutic value of such approaches, which are obviously promising [11][12][13][14][15]. In the present study, we used HER2/neu female mice with spontaneous mammary adenocarcinomas to investigate if cytostatic therapy may be influenced by MT provided for a week before or 3 weeks after administering the cytostatic chemotherapy at extreme times of the working day generally adopted at healthcare facilities.…”

HT29 Hücre Hattında Sirkadiyen Ritme Bağlı Gen İfadesinin Kontrolünde Referans Gen Farklılığının Senkronizasyondaki Rolü

“…Türkiye'de ise bu oran her yüz bin kişi de 23,4'dür ("Türkiye Kanser İstatistikleri," 2015). Kolon kanseri üzerine son yıllarda yapılan çalışmalarla terapötik yaklaşımlar önem kazanmıştır (Dallmann, Okyar, & Levi, 2016;Ozturk, Ozturk, Kavakli, & Okyar, 2017).…”