Circadian dysregulation and elevated cancer risk in the night shift… : Oncology Times

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circadian dysregulation; Circadian rhythm:

circadian dysregulation; Circadian rhythm

Circadian clocks are universal timing mechanisms that produce approximately 24-hour rhythms in cellular and bodily functions. Chronic dysregulation of circadian rhythms has been identified as a risk factor for multiple health conditions, and a growing number of studies have found evidence linking chronic circadian disruption and cancer (Discovery of cancer 2020; doi:10.1158/2159-8290.CD-20-0413; Res. Cancer 2019; doi: 10.1158/0008-5472.CAN-19-0566). Epidemiological studies suggest that cancer is more prevalent among night shift workers due to circadian dysregulation (Chronobiol Med 2019; https://doi.org/10.33069/cim.2019.0022). However, the underlying mechanisms remain unclear.

A recent study aimed to provide new insights into the possible mechanistic role that circadian disruption of cancer hallmark pathway genes may play in the increased risk of cancer in shift workers compared to those who work regular daytime hours. The results of the study were published in the Pineal Research Journal (2021; https://doi.org/10.1111/jpi.12726).

In a collaboration between the Washington State University (WSU) Center for Sleep and Performance Research and the U.S. Department of Energy’s Pacific Northwest National Laboratory (PNNL), scientists from WSU worked with bioinformatics experts from PNNL to conduct a controlled laboratory study. To study the circadian transcriptome of cancer hallmark pathway genes and associated biological pathways that may be disrupted by night shift work, the researchers focused on looking for changes in circulating leukocytes extracted from healthy young adults in the course of a constant 24-hour routine protocol after 3 days of simulated day or night shift.

To recreate and control a simulated work schedule, 14 participants spent 7 days inside the sleep lab at WSU Health Sciences Spokane. Half worked a simulated 3-day night shift, while the other half worked a simulated 3-day day shift schedule. After completing their simulated shifts, the workers maintained the same routine used to study the internally generated biological rhythms of humans independent of any external influence, including a 24-hour period where they were kept awake in a semi-reclined posture at constant room temperature and light exposure and received identical snacks every hour. Blood samples were taken every 3 hours during this 24 hour cycle.

The results revealed that the simulated night work schedule significantly altered the normal circadian rhythmicity of genes involved in hallmark cancer pathways. Notably, a DNA repair pathway showed significant enrichment of rhythmic genes after the simulated daytime work schedule, but not after the simulated nighttime work schedule. To compound the risk of cancer, leukocytes isolated from the blood of night shift workers showed more signs of DNA damage than from day shift workers. In functional tests, scientists showed that there was an increased sensitivity to endogenous and exogenous sources of DNA damage after exposure to a simulated night shift.

After researchers exposed isolated leukocytes to ionizing radiation at two different times of the day, cells that were irradiated in the evening showed increased DNA damage in the night state compared to the night state. day state. This suggests that overnight participants’ leukocytes were more vulnerable to external radiation damage, a known risk factor for DNA damage and cancer.

Oncology time Connected with lead author, Bala Subrahmanya Chakravarthy Koritala, PhD, for more information on their research and the role of chronotherapy and the patient’s circadian clock in cancer care. Koritala was previously a postdoctoral fellow at Washington State University and is now a research scientist at Cincinnati Children’s Hospital Medical Center.

Oncology time: What are the major challenges of cancer chronotherapy?

Koritala: “The expression of half of human genes and physiology follows a 24-hour cycle (circadian rhythm); this has medical implications. Several factors can influence the effect of a drug, including its absorption, distribution, abundance of target cells, metabolism, and clearance. It is possible that one or all of them may oscillate, not oscillate, or oscillate out of phase in different tissues.

“It can be counterproductive to deliver a drug when its target is at peak levels if its metabolizing enzymes are also at peak levels. The majority of anticancer drugs have not been characterized for their 24-hour pharmacokinetic and pharmacodynamic effects for the chronotherapy of cancer. Moreover, the robustness of the circadian system and the phase variations in cancer patients represent a challenge for the optimization of circadian medicine or cancer chronotherapy.

Oncology time: What is the potential clinical significance of this study?

Koritala: “Night work is prevalent in modern 24/7 society, and epidemiological evidence has shown an increased risk of cancer among night workers. Therefore, understanding the biomolecular mechanisms of cancer risk in night shift workers is important for the development of clinical diagnostic and preventive strategies.

“In the present study, we uncovered a novel mechanism by which circadian dysregulation of DNA repair and increased DNA damage is a potential cause of increased cancer risk with night shift Our genetic targets identified from this study can help develop biomarkers for the early detection of cancer risk with night work.

Oncology time: Can the restoration of circadian rhythms by pharmacological and behavioral intervention decrease the risk of developing cancer, alter tumor progression and produce new therapeutic avenues?

Koritala: “The administration of melatonin and phototherapy are considered treatment strategies for circadian rhythm disorders. Although few studies suggest that melatonin can control tumor growth in cancer patients, the role of circadian rhythm restoration in melatonin cancer treatment requires further study.

Oncology time: What are the next steps to follow up on this study?

Koritala: “In the present study, we clearly demonstrated circadian disruption of DNA repair in humans after exposure to a nighttime condition. We conducted a follow-up study to assess the efficacy of cisplatin chronotherapy for breast cancer after exposure to a broken clock condition using a mouse model. Cisplatin is one of the most widely used drugs for the treatment of cancer. It kills cancer cells by interfering with DNA repair processes and inducing DNA damage. Since DNA repair activity is rhythmic and peaks at a specific time of day, we hypothesized that cisplatin chronotherapy with interrupted clock was ineffective. As expected, we observed that the efficacy of cisplatin treatment for breast cancer is time-dependent only in the presence of the circadian clock. This study has just been published in the journal Toxicology and Applied Pharmacology (2022; doi: 10.1016/j.taap.2022.115863). »

Dibash Kumar Das is a contributing writer.

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