Each year, scientists across the world dedicate their research to curing cancer. What if the answer was related to the time of day cancer patients take their drugs? A group of scientists from Germany wanted to explore if the body’s 24-hour clock, also known as its circadian rhythm, could impact how well drugs fight cancer.
To test their hypothesis, the scientists monitored how cancer cells behaved on various drugs at different times of day. First, they gathered a diverse group of cells from human breast cancer patients, including some healthy tissue cells and some tumorous cells. They closely monitored the cells’ characteristics such as growth rate, drug response, and circadian rhythm strength. They explained that circadian rhythm strength refers to a cell’s ability to periodically change its behavior, usually dictated by the day-night cycle.
To determine circadian rhythm strength, the scientists used a method called autocorrelation, which measured how similarly the cells behaved at different times. They used a second method to identify the dominant frequency of the cellular signal and its strength over time, called a continuous wavelength transform. They used this method to break down the signals into smaller pieces, each representing a different frequency and time range.
Finally, they looked at both the large-scale and small-scale cellular processes simultaneously using another method to further break down the signal, called multiresolution analysis. They combined these methods to measure how the drugs impacted cell growth over time and identify what changed based on time-dependent or circadian effects.
The researchers grew a group of specialized breast cancer cells known to have a built-in biological clock in a controlled environment. They added the various cancer-fighting drugs at different times of day to assess how their effectiveness varied. They also administered different amounts of the drugs to find the perfect dosage for each time of day. To test how the cells responded over time, they measured the cells’ growth rates by imaging them with a microscope and capturing how quickly they grew in different conditions. The scientists then organized the cells and drugs into groups based on how similarly they responded to the tests.
The researchers also performed tests to measure the efficiency of the drugs they administered. First, they synchronized the cells to a specific circadian phase using a series of light-dark cycles. Then, they administered the drugs at different times of day over 4-hour intervals while monitoring their cell growth and viability using live-cell imaging. The team then compared how the cells responded to the drugs at different circadian phases to identify the best time of day to administer drugs for cancer treatment. The scientists found a strong correlation between the circadian clock and how effective the drugs were.
To more deeply explore the impact of the circadian clock on cell treatments, the scientists also tested the contribution of each genetic component within the cell to its overall drug response. They explained that the genes in our body determine how well the drug suppresses the cancer, and how strongly it can accept the drug. But since we have almost 20,000 genes, the scientists want to match each drug to a target gene that will respond most effectively.
To do this, the team used 2 techniques that collect very large data sets and create a prediction, called linear discriminant analysis and principal component analysis. They used these methods to rank the cells’ genes according to how effectively they helped the cell respond to the drugs, and to identify mutation patterns between genes. They found that different genes express different sensitivities for each drug.
The scientists concluded that circadian cell rhythms affect drug sensitivity and effectiveness. They suggested future workers test other unexplored genes to see if they are sensitive to specific cancer drugs. The team concluded that their results will help scientists to better understand how the body’s 24-hour cycle impacts time-sensitive cancer treatments.
