Common chemo drug may cause heart toxicity

Doxorubicin is a chemotherapy drug commonly used to treat certain types of cancer, such as breast, bladder, stomach, lung, and ovarian cancer. Sometimes, it is also used to treat cancer of the uterus.

The drug stops cancer cells from spreading by blocking an enzyme that cancer cells need in order to divide and multiply.

Despite the drug’s widespread use, its effects on the body’s immunometabolism — that is, how the body’s metabolism regulates the behavior of immune cells — are largely unknown.

So, researchers at the University of Alabama at Birmingham (UAB) set out to fill this research gap by investigating the effects of the drug doxorubicin on the immunometabolism of mice.

Ganesh Halade, Ph.D. — an assistant professor in UAB’s Division of Cardiovascular Disease — led the researchers, who have now published their findings in the American Journal of Physiology: Heart and Circulatory Physiology.

How doxorubicin affects the heart, spleen

Halade and colleagues treated 2-month-old, cancer-free male mice with either a high or low dose of the drug. The researchers also treated a group of control mice with saline solution.

After sacrificing the rodents, the team studied the effects of the drug on their organs and tissues.

Doxorubicin caused fibrosis of the heart, in which the heart’s walls stiffen and cannot contract as much. This, in turn, causes the heart to malfunction. As a result, the mice’s hearts couldn’t pump as much blood as they should.

The drug also induced programmed cell death and caused the heart and spleen to shrink.

The main roles of the spleen are to filter the blood and protect the body against pathogens.

This organ — which is the largest in the lymphatic system — stores immune cells and, in the case of a heart attack, releases and sends them to the site of the heart injury to clear the damage. In this study, however, the researchers showed that doxorubicin harms the spleen.

The drug also reduced levels of two enzymes key for the body’s immune response: lipoxygenases and cyclooxygenases.

Doxorubicin decreased the levels of these enzymes in the left ventricle of the heart. In turn, this lowered the levels of other lipid mediators that would normally stop the inflammation.

Also, the drug killed a group of immune cells called CD169+ macrophages, which induced a wasting syndrome in the spleen.

The name macrophages literally means “big eaters,” as the main job of these large white blood cells is to locate and “eat up” pathogens.

Finally, the drug upset the balance of two cell signaling molecules: chemokines and cytokines. As the authors explain, this suggests that the leukocytes in the spleen were less able to defend the body against pathogens.

These findings, explains Halade, suggest that doxorubicin has a “splenocardiac impact” that needs to be studied further in order to minimize the harms of the drug on the heart and spleen.

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