Chronotherapy: Circadian Rhythms and Their Influence in Cancer Therapy

Abstract

Living organisms present rhythmic fluctuations every 24 h in their behavior and metabolism to anticipate changes in the environment. These fluctuations are controlled by a very complex molecular mechanism, the circadian clock, that regulates the expression of multiple genes to ensure the right functioning of the body. An individual’s circadian system is altered during aging, and this is related to numerous age-associated pathologies and other alterations that could contribute to the development of cancer. Nowadays, there is an increasing interest in understanding how circadian rhythms could be used in the treatment of cancer. Chronotherapy aims to understand the impact that biological rhythms have on the response to a therapy to optimize its action, maximize health benefits and minimize possible adverse effects. Clinical trials so far have confirmed that optimal timing of treatment with chemo or immunotherapies could decrease drug toxicity and increase efficacy. Instead, chronoradiotherapy seems to minimize treatment-related symptoms rather than tumor progression or patient survival. In addition, potential therapeutic targets within the molecular clock have also been identified. Therefore, results of the application of chronotherapy in cancer therapy until now are challenging, feasible, and could be applied to clinical practice to improve cancer treatment without additional costs. However, different limitations and variables such as age, sex, or chronotypes, among others, should be overcome before chronotherapy can really be put into clinical practice.

Physiological Rhythms and Biological Variation of Biomolecules: The Road to Personalized Laboratory Medicine

“…Furthermore, the hormonal imbalance between leptin (reduced) and ghrelin (elevated) levels observed in chronotypes with sleep-deprived individuals increases caloric intake, decreases energy expenditure, and leads to weight gain and cardiovascular disease [ 194 , 195 , 196 , 197 ]. Additionally, chronotherapy, i.e., optimal timing of treatment could increase the drug efficacy and decrease the side effects of chemo and other therapeutic interventions [ 198 ].…”

Update on chronotherapy: it's about time

“…In turn, the SCN express circadian genes to synchronise with the light‐dark cycle. Every cell in the body seems to contain a circadian oscillator (so‐called peripheral clocks), which the SCN control by direct innervation, neuropeptides, hormones and body temperature 4 . Light seems to be the strongest Zeitgeber.…”

“…But other Zeitgebers, such as temperature, feeding, exercise and pathogens, fine‐tune the rhythms. Numerous feedback loops synchronise the various clocks 4 …”

“…Insulin glargine is more effective when given in the morning 1 . In cancer patients, chronotherapy improves the efficacy and reduces the toxicity of capecitabine (a prodrug of 5‐fluorouracil), oxaliplatin, doxorubicin plus cisplatin, and, probably, immune checkpoint inhibitors and cancer vaccines 2‐6 . The protective immune response against certain pathogens, such as hepatitis A virus and SARS‐CoV‐2, may depend on the time of day when the vaccine is administered 7 …”

Modeling the Circadian Control of the Cell Cycle and Its Consequences for Cancer Chronotherapy

“…The duration of the cell division cycle is characterized by stochastic variability, but the coupling of the Cdk network to the circadian clock enables cells in some tissues to divide in a synchronized way, on a 24 h time scale. Disruption of this circadian control in cancer cells leads to less synchronized cell division, a feature exploited to optimize the timing of drug administration [ 3 , 4 ]. Here, we illustrate, through computational modeling, how cell–cell variability and (lack of) circadian entrainment impact chronotherapeutic strategies.…”