How circadian disruptions promote tumor growth and timing of cancer drugs may be vital
A detailed new study has offered incredible insight into how disrupting circadian rhythms can promote tumor growth. The research also suggests that the efficacy of cancer therapies can be improved by more specifically timing the administration of certain drugs to a patient's particular circadian rhythm.
We know that disruptions in the body's overall circadian rhythms can increase a person's risk for a variety of diseases. Long-term night shift workers, for example, do seem to experience slightly higher rates of common cancers and in 2007 the International Agency for Research on Cancer even went so far as to classify shift work that disrupts circadian rhythms as a probable human carcinogen.
New research from the University of Pennsylvania is offering remarkable insights into the underlying mechanisms that seem to connect circadian disruptions to cancer. Initially, the team closely examined human cultured cells using a hormone called dexamethasone to artificially disrupt a cell's circadian clock.
The disruption was revealed to change the expression of multiple genes, most specifically activating CDK4/6 proteins. Excessive activity from these proteins is known to lead to increased cell division rates, and some cancer therapies work to directly inhibit CDK4/6 activity.
The researchers subsequently looked closely at one breast cancer drug called palbociclib. This drug directly targets CDK4/6 activity and it was discovered, in both cell and mouse models, the efficacy of the drug varied when administered at different times of the day, being more effective when administered in the morning.
"Our findings strongly indicate that environmental or physiological disturbances of circadian rhythms such as shift work, abnormal sleep timing, or irregular psycho-sociological stresses can affect variability in both cancer growth and response to cancer drugs," says the study's first author Yool Lee. "Given this, it is reasonable to expect that resetting of the body clock by scheduled light-exposure, meal-times, or exercise, alongside a carefully timed chemotherapy regimen, would improve anti-tumor treatment."
Chronotherapy, the idea that drugs should be delivered at certain times of day to maximize their efficacy, is not particularly new. However, the new insights into our circadian rhythms offer remarkable and unprecedented clarity into these fundamental biological mechanisms. The study also points to new investigational pathways to help mitigate the negative effects of chronic circadian disruptions experienced by night shift workers.
"Better understanding the molecular effects of jet lag, shift work, and other sources of chronic disruption may lead to strategies to minimize the increased cancer risk associated with these behaviors, as well as to better treatment strategies," says Amita Sehgal, senior author on the new study.
The new research was published in the journal PLOS Biology.
Source: Penn Medicine News