Why Some Cancer Patients Get Heart Damage During Chemotherapy

Sometimes the unintended consequences of a treatment can seem worse than the disease.

That’s certainly the case for patients who develop chemotherapy-induced cardiotoxicity — a severe side-effect that can lead to heart failure and the discontinuation of anti-cancer treatment.

Now, University of Alberta research published in Nature Communications offers hope for protecting the heart during treatment and also attacking cancer more effectively.

The research team identified a biomarker to predict which patients will be most susceptible to cardiotoxicity and revealed the mechanism behind the heart damage — zeroing in on potential new targets for treatment.

“Some chemotherapy drugs interfere with the DNA replication of cancer cells and cause them to die, which is why they are good therapies. But they can also cause irreversible damage to heart cells,” says principal investigator Gopinath Sutendra, associate professor and co-associate chair of research for the department of medicine in the Faculty of Medicine & Dentistry, and Canada Research Chair in Cardio-Oncology and Molecular Medicine.

“Our goal is for a patient to be able to come in and, before they’re even treated with chemotherapy, we can predict based on what we see in their blood that they may have a higher chance of getting cardiotoxicity or not,” Sutendra says. “That in itself will be beneficial because we will now know what types of therapeutics to give. We really want to prevent any damage to the heart.”

Death due to cardiovascular disease is twice as likely for cancer patients as for the general population, and cardiotoxicity is a leading cause of mortality among cancer survivors.

Unlike the DNA damage caused by chemotherapy to fast-growing cells in the hair or lining of the gut, heart cells are “terminally differentiated,” which means they can’t just start to regrow once the chemo stops, so the damage can be permanent.

The research team examined blood samples from 22 participants in the MANTICORE randomized controlled clinical trial, a U of A-led study to evaluate cardiotoxicity in breast cancer patients taking anthracyclines and taxanes, two classes of chemotherapy drugs known to cause cardiotoxicity in some people.

By comparing blood samples and cardiac function test results from before, during and after chemotherapy, the researchers were able to identify “tumour secreted factors” that send messages from the tumour to other cells. Specifically, they found that higher levels of inosine and hypoxanthine in the blood were associated with a higher risk of cardiotoxicity. Further study of mice with cancer provided more insight into how these signalling pathways work.

“What the tumour is secreting can directly affect the heart at the molecular level, reprogramming it to make it more susceptible to the chemotherapies,” says Sutendra, who is also a member of the U of A’s Cardiovascular Research Institute and Cancer Research Institute of Northern Alberta.

The tumour’s factors bind with a receptor in the heart muscle, which in turn degrades the muscle cells’ defences so that normally tightly-wound and unassailable DNA unwinds a bit and becomes more vulnerable to DNA damaging anti-cancer agents.

Inosine and hypoxanthine are also known to facilitate tumour growth. Sutendra’s team is now developing a drug to shut down the synthesizer that regulates levels of inosine and hypoxanthine, aiming to get a double benefit by protecting heart cells and slowing down cancer growth and metastasis.

“We think it’s a nice target to prevent the adverse effects that can happen on the heart, but it will also be very beneficial against the tumour,” Sutendra says.

The team plans future research to validate the study in other kinds of cancer and to look for other tumour-secreted factors to target. 

In addition, the new knowledge about how to unwind DNA in the heart may prove beneficial someday for patients with heart problems, because it provides insight into a way to regenerate heart cells.

“It’s very interesting how in science you can understand a mechanism in a condition you’re trying to prevent, but you can also harness that information to potentially give therapeutics for other patients,” Sutendra notes. “In this scenario, reverting to a less differentiated state is the first step that needs to occur before a heart cell can replicate. Could we use this understanding to replenish heart cells that are lost after a heart attack?” 

Reference: Tejay S, Lorenzana-Carrillo MA, Huang G, et al. Tumour initiated purinergic signalling promotes cardiomyocyte RBFOX1 degradation and cardiotoxicity from DNA damaging anticancer agents. Nat Commun. 2025;16(1):6861. doi: 10.1038/s41467-025-62172-4

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