Protein Identified in Cancer Treatment-Related Heart Damage

A protein, known as FOXO1, plays a critical role in heart damage resulting from treatment with the chemotherapy drug anthracycline.

Researchers have shown that a protein, known as FOXO1, plays a critical role in heart damage resulting from treatment with the chemotherapy drug anthracycline.

Using a cell model, researchers also demonstrated that suppressing FOXO2 through the use of FOXO1 inhibitor drugs could prevent the chemotherapy-induced heart damage. Their discovery opens up possibilities for new treatment strategies to reduce heart damage from cancer treatment, which could help increase the life expectancy of cancer survivors, according to the study authors.

Published in the Journal of Biological Chemistry, the new study builds on earlier work done by study co-author Brian Jensen, a cardiologist at the University of North Carolina Chapel Hill. Jensen measured the size of patients’ hearts starting 1 month after they received doxorubicin until 6 months afterwards and found that their hearts had become smaller.

"We believe the reason that the heart eventually undergoes failure is because chemotherapy initially makes the heart smaller," said senior study author Zhaokang Cheng, an assistant professor in the WSU College of Pharmacy and Pharmaceutical Sciences, in a press release.

Since a smaller heart has to labor more to pump the same amount of blood through the body, Cheng explained that this may over time lead the heart to grow larger to meet the body's demand. This forced growth weakens the heart and may ultimately cause it to fail.

In the new study, the research team set out to understand why the heart initially becomes smaller in response to doxorubicin chemotherapy treatment, which carries 2 possible explanations: that doxorubicin causes cell death, reducing the overall number of heart cells or that it causes a reduction in the size of each heart cell, known as atrophy.

First, the researchers delved into how chemotherapy might cause heart cell death. In a previous study, the WSU research team showed that doxorubicin can activate a protein known as CDK2. They also demonstrated that this activation of CDK2 led to increased expression of a gene known as Bim, which causes cell death. However, it was not clear how CDK2 activation and Bim expression were connected. Their new study revealed FOXO1 as being the missing link.

FOXO1 is a transcription factor, a protein that binds to the DNA of other genes to turn them on or off. The rodent model showed that CDK2 can activate FOXO1 and when FOXO1 becomes active it increases Bim expression, which eventually leads to cell death.

They then looked at whether manipulating FOXO1 could protect the heart during chemotherapy. In another rodent study, they administered doxorubicin along with a drug that inhibitors FOXO1. The research team found that both the overall heart size and the heart cell size were maintained.

Finally, they examined how exactly the FOXO1 inhibitor protects the heart from both cell death and atrophy. For cell death, inhibiting FOXO1 decreases the expression of the Bim gene, which plays a critical role in cell death. For atrophy, the research team found that inhibiting FOXO1 reduces the expression of a gene called MuRF1. A previous study by Jensen had suggested that MuRF1 is involved in doxorubicin-induced atrophy, but the mechanism by which this happened had been unclear until now.

If their findings withstand further research and clinical trials, the team's discovery may eventually lead to promising new treatment strategies or drugs that combine the FOXO1 inhibitor with doxorubicin or other anthracyclines. This would allow health care providers to maximize the efficacy of cancer treatment while minimizing damaging adverse effects to the heart.

Reference

  • Researchers have shown that a protein known as FOXO1 plays a critical role in heart damage resulting from treatment with anthracycline chemotherapy drug [news release]. Washington State University website. Published April 9, 2020. https://news.wsu.edu/2020/04/09/research-identifies-critical-protein-cancer-treatment-related-heart-damage/. Accessed April 13, 2020.