A Spokane-based study found that the body’s biological clock could play a key role in protecting the heart against the toxicity of radiation treatment for breast cancer.
Researchers at the Washington State University College of Pharmacy and Pharmaceutical Sciences say their findings might help pinpoint the safest times for individuals to receive radiation treatments – and even who shouldn’t have the radiation because their biological clock has been too disrupted.
Simply put, the biological clock is the body’s internal time-keeping mechanism in a 24-hour cycle of rest and activity. That natural mechanism also regulates a variety of processes in bodies.
Breast cancer treatment often includes radiation therapy to fight the disease. However, that option can have long-term consequences for the heart, causing DNA damage in healthy heart cells, researchers say. Over time, this can lead to heart disease and eventually heart failure.
“We’re trying to understand how the biological clock plays a protective role for the heart after radiation therapy,” researcher Shobhan Gaddameedhi said. “There are other studies on people who perform night shift work, and they are more prone to increased heart risk compared to day shift workers.”
Considering that research, the pharmacy group pursued whether the biological clock under normal sleep-rest cycles might help protect the heart in cases of radiation treatment for breast cancer.
“The biological clock regulates up to 50% of the genes in the body,” said Gaddameedhi, also an assistant professor in the Department of Pharmaceutical Sciences and the study’s senior author.
Published in the FASEB Journal, the WSU researchers used a rodent model to find whether the biological clock is involved in what happens if there’s heart toxicity from radiation and whether it could be part of a strategy to reduce that harm.
Their findings showed that after receiving a dose of radiation to the heart, mice with disrupted biological clocks had significantly worse heart function than the control mice.
“It’s been known that breast cancer patients who undergo radiation, they are more prone to cardiovascular risk,” Gaddameedhi added. “The cancer is restricted, but 10 to 12 years down the road, they are dying.
“With this paper, we are sending messages to people that maintaining a healthy biological clock is important especially before they undergo this type of treatment.”
He said the study supports that the biological clock is important to heart function even after radiation therapy.
Additionally, the researchers found the protein BMAL1 – which drives 24-hour rhythms in the expression of many genes – plays a key role in protecting the heart from radiation-related damage.
Panshak Dakup, the study’s first author, said the finding holds promise for personalized medicine.
“For example, in breast cancer patients who have a long history of working night shifts, the expression of biological clock proteins such as BMAL1 may be compromised, and it could be that radiation therapy is not the best option for them,” Dakup said.
Another consideration is that BMAL1 protein has different expressions during a 24-hour cycle, perhaps peaking in the morning or at certain times of days, Dakup said, so it might be better to give the radiation treatment when BMAL1 protein is higher in a patient. That timing might vary depending on a person’s chronotype – whether they are early birds or night owls – as well as on other factors that influence the status of the master biological clock, such as shift work or crossing time zones frequently.
In the future, with BMAL1 protein as a biomarker for susceptibility to radiation-induced DNA damage to the heart, health professions could check the levels of these proteins in blood to monitor risk, Gaddameedhi said.
Dakup conducted the experiments as part of a predoctoral fellowship supported by the American Heart Association. The National Institutes of Health also provided financial support.
In the study’s main experiment, Dakup looked at the heart function of two groups of mice with disrupted clocks compared with a group of control mice.
One group had a genetic mutation that eliminated two genes controlling the body’s master biological clock. A second group had wild mice placed on a simulated rotating shift schedule in which light-dark cycles were reversed weekly, throwing off their clocks.
The third control group consisted of wild mice with healthy biological clocks that were on a simulated day shift schedule. All mice received radiation treatment to the chest that included all of the heart.
Collaborating with Zhaokang Cheng, an assistant professor of pharmaceutical sciences and a cardiovascular biology expert, Dakup used ultrasound echocardiography technology to compare heart function among the three groups before and as long as six weeks after radiation treatment.
In clock-disrupted mice, the heart’s ability to pump blood out and into circulation was compromised due to a loss of elasticity in the heart ventricle. Those mice also had more heart scar tissue than control mice.
The researchers showed that BMAL1 protein levels across 24 hours were significantly lower in clock-disrupted mice versus control mice and peaked at a later time. The study group also found that higher levels of BMAL1 protein were associated with lower DNA damage levels.
In another result, the researchers found that BMAL1 protein interacts with the three DNA-damage response genes important in fighting against radiation-induced DNA damage and cell death.
“When BMAL1 binds to these genes, it is potentially trying to elevate or activate their function against the collateral damage caused by radiation therapy,” Gaddameedhi said.
The researchers’ next step is to test their hypothesis in a cancer model, seeking to pin down the exact mechanism by which the biological clock protects the heart from radiation damage. It could help develop new treatment strategies to be tested later in clinical trials.
Although more research is needed, the researchers are hopeful their work could someday be used to improve outcomes for breast cancer patients.
In addition to Gaddameedhi, Dakup and Cheng, study authors also included Kenneth Porter, Rajendra Gajula and Peeyush Goel.
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