Circadian Rhythms, Disease and Chronotherapy

Abstract

Circadian clocks are biological timing mechanisms that generate 24-h rhythms of physiology and behavior, exemplified by cycles of sleep/wake, hormone release, and metabolism. The adaptive value of clocks is evident when internal body clocks and daily environmental cycles are mismatched, such as in the case of shift work and jet lag or even mistimed eating, all of which are associated with physiological disruption and disease. Studies with animal and human models have also unraveled an important role of functional circadian clocks in modulating cellular and organismal responses to physiological cues (ex., food intake, exercise), pathological insults (e.g. virus and parasite infections), and medical interventions (e.g. medication). With growing knowledge of the molecular and cellular mechanisms underlying circadian physiology and pathophysiology, it is becoming possible to target circadian rhythms for disease prevention and treatment. In this review, we discuss recent advances in circadian research and the potential for therapeutic applications that take patient circadian rhythms into account in treating disease.

Keywords: chronobiology; chronopathology; chronotherapy; circadian clock; circadian disruption.

Figure 1.

Circadian-disruptive factors and chronotherapeutic interventions in physiology and disease. Abbreviations: CRY = cryptochrome; ROR = Receptor-related orphan receptor. Reciprocal interactions of circadian clocks with other physiological pathways constitute systemic circadian physiology. Multiple factors that disrupt circadian rhythms can increase the risk of disease onset and severity, which in turn feeds forward to cause more chrono-disruption. Conversely, several types of chrono-therapeutic interventions can be implemented to enhance or restore circadian rhythms and thereby reduce disease progression and improve the response to treatment; CKI = casein kinase 1

Figure 2.

Timing of disease symptoms and therapeutic interventions. Abbreviations: NSAIDS = nonsteroidal anti-inflammatory drugs; ACE = angiotensin-converting enzyme; BCG = Bacillus calmette–Guérin; TRF = Time-restricted feeding. The timing of therapeutic interventions is mostly associated with the daily susceptibility of diseases. a higher evening antiepileptic drug dose can reduce nocturnal and early-morning seizures. Night time administration of most anti-hypertensive and anti-inflammatory drugs effectively reduces the early morning severity of the cardio-metabolic and auto-immune disease symptoms, via preemptive suppression of the disease-relevant enzymes or proinflammatory cytokine activities that rise during sleep. On the other hand, morning vaccinations appear to induce better innate and adaptive immune responses. Morning bright light therapy improves circadian rhythms, sleep and, mood disorders. daytime TRf or exercise in the late afternoon can improve circadian rhythms and metabolic symptoms, particularly in patients with diabetes and obesity. Tnf-α = Tumor necrosis factor alpha IL-6 = Interleukin 6

Figure 3.

Chronotherapy for the treatment of cancer. Chronotherapy with anti-cancer medicine or regimen has been proposed to improve host tolerance and safety (a) and tumor cytotoxicity (b). (a) Tissue tolerance to timed anti-cancer therapy. The anti-phasic peak and trough level of DPD, an elimination enzyme of 5-FU, and TS, have been associated with the reduced toxicity of circadian-timed 5-FU treatment. Also, daily variations of GSH, a potent anti-oxidant, have been used as a host tolerance biomarker for the use of platinum-based anti-cancer drugs (e.g. oxaliplatin, cisplatin). Doxorubicin and radiation are generally more effective, with fewer side effects, in the morning. (b) Tumor toxicity in response to timed anti-tumor agents. Several anti-cancer drugs target phases of the tumor cell cycle including G1 phase (Seliciclib), G-S phase-transition (Palbocicilib), S phase (5-FU), and M phase (docetaxel). Notably, some tumor tissues display anti-phasic cell cycle rhythms to host ones, highlighting the potential efficacy of timed chemotherapy to coincide with high tumor cell vulnerability and low toxicity to normal tissue. Abbreviations: M = mitosis; G = Cell growth; DPD = dihydropyrimidine dehydrogenase; GSH = glutathione; TS = thymidine synthase; 5-FU = 5-fluorouracil; S = DNA synthesis.