Repurposing Tamoxifen: How a breast cancer drug can treat cardiomyopathy

by Adrienne Mueller, PhD
June 14, 2022

We rely on our hearts to keep beating, but if the muscle fails – the heart will stop. Duchenne muscular dystrophy (DMD) is the most common inherited muscle disorder, affecting 1 in 5000 males. DMD patients typically lose the ability to walk in their teens, and most develop heart disorders as young adults. The disease is caused by genetic mutations that result in loss of the protein dystrophin. In muscle cells, including those in the heart, dystrophin is necessary for anchoring components inside of cells to the matrix outside of cells – and thereby stabilizing the cellular membrane that separates them. Dystrophin is therefore crucial for protecting heart muscle cells from the mechanical stress caused by contractions during heart beats. The walls of muscle cells of DMD patients accrue damage as the muscles continuously contract. Over time, this leads to an overabundance of calcium inside the cells, which triggers a host of reactions that ultimately lead to premature death and scarring of the heart tissue. Scarred heart tissue is much stiffer than healthy heart tissue - meaning the heart cannot beat as well - which in turn puts more strain on the remaining heart muscle cells, and further exacerbates their decline. Ultimately, DMD is lethal. Today, cardiac arrhythmia, or heart rhythm problems, are the leading cause of death in DMD patients – and there is currently no cure for DMD-related heart disorders.

Tamoxifen normalizes heart muscle cell Calcium activity.

Tamoxifen is a drug currently used to treat breast cancer, and, surprisingly, it may be a potent therapy for DMD. Tamoxifen acts on estrogen receptors: proteins which are present in both skeletal muscle and the heart.  Many previous studies have shown that estrogen hormones protect the heart from cardiovascular disease – and help prevent contraction-related stress in muscles. Previous studies have even shown that tamoxifen protects against cell membrane damage and inhibits tissue scarring in the heart.  Even now, clinical trials in Israel and Switzerland are evaluating the efficacy of tamoxifen treatment in DMD patients. However, both of these trials will only assess the efficacy of DMD on skeletal muscles and will not look into the effect of tamoxifen on the heart. Therefore, in an article recently published in npj Regenerative Medicine, a group of investigators in the lab of Helen Blau, PhD, led by Foster Birnbaum, Asuka Eguchi, PhD,  and Gaspard Pardon, PhD, studied the effects of tamoxifen on human stem cell-derived heart muscle cells of patients with DMD.

The investigators used stem cells to study the effects of tamoxifen on stem cell-derived heart muscle cells heart muscle cells in vitro - without needing to perform experiments in human subjects. The investigators examined the effect of tamoxifen on heart muscle cells differentiated from induced pluripotent stem cells from two groups of people: healthy individuals and patients with DMD. They showed that tamoxifen acts in multiple ways to promote the health of DMD stem cell-derived heart muscle cells: it enhances their contractile function, it improves their calcium handling, and it prolongs their survival in a dish. These results show that tamoxifen could delay heart muscle cell loss and tissue scarring in the DMD heart, prolonging the lives of patients with DMD. Birnbaum, Eguchi, and Pardon et al show that the repurposing of a breast cancer drug is an extremely promising candidate for treating DMD patients with heart disorders.

Foster Birnbaum

Dr. Asuka Eguchi

Dr. Gaspard Pardon

Dr. Helen Blau