Tamoxifen Increases Survival of DMD Heart Muscle in Cell Study

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

An overhead view of a petri dish is shown alongside an image of a dropper poised above another petri dish.

Treatment with the breast cancer medicine tamoxifen improved the functionality and survival of heart muscle cells in a cellular model of Duchenne muscular dystrophy (DMD), a study reports.

The study, “Tamoxifen treatment ameliorates contractile dysfunction of Duchenne muscular dystrophy stem cell-derived cardiomyocytes on bioengineered substrates,” was published in the journal npj Regenerative Medicine.

In DMD, the body is unable to make the dystrophin protein, which normally helps to cushion muscle cells during movement. As a result, muscles become increasingly damaged. This affects skeletal muscle (the muscles that control movement) and also heart muscles. A form of heart disease called dilated cardiomyopathy is one of the leading causes of death in DMD.

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Recent evidence has suggested that tamoxifen (sometimes known by the brand name Soltamox) may help to protect muscle cells from damage in DMD. Tamoxifen is widely approved to treat some kinds of breast cancer; it works by modulating the activity of the protein receptor for the hormone estrogen. These protein receptors are expressed by many cells throughout the body, including muscle cells.

Recent results from the Phase 3 TAM-DMD clinical trial (NCT03354039) showed that treatment with tamoxifen did not significantly slow the progression of motor function worsening, compared with placebo, in boys with DMD. The researchers noted that TAM-DMD and other trials of tamoxifen generally have focused on the treatment’s effect on skeletal muscle, not heart muscle. Indeed, they said these trials, generally months long, are likely too short to detect any effect on heart disease that can take years to develop.

“Therefore, an analysis of the effects of tamoxifen in human DMD cardiomyocytes [cells that drive heart contraction] is timely and would inform our understanding of the potential of this drug to delay the onset of dilated cardiomyopathy,” the researchers wrote.

To find out more, the team, led by scientists at Stanford University in California, conducted a series of experiments using human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs).

Simplistically, this cellular model involves taking easily accessible cells (e.g., skin or blood cells) from human volunteers. Then, through a series of biochemical manipulations, the cells are “reverse engineered” to produce stem cells, which then are grown to create heart muscle cells. Since the cells are still genetically identical to the people they came from, cells from someone with DMD will retain the disease-causing mutation.

The researchers grew these cardiomyocytes in a specific setup that let them assess how the cells were contracting, comparable to how they would move in the human heart. Results showed that, in iPSC-CM models derived from DMD patients, treatment with 4-hydroxytamoxifen — the active metabolite of tamoxifen — slowed the rate at which the cells beat.

In the context of DMD, a slower rate of contraction typically means that there is less mechanical stress on heart cells and, consequently, less damage accumulates over time. The researchers noted that this effect did not appear to decline with time up to 12 days of treatment.

Consistently, tamoxifen treatment improved the survival of DMD cardiomyocytes — from less than 20% of cells surviving after 12 days, to about 30% of cells surviving with tamoxifen. Survival of DMD cardiomyocytes remained significantly shorter than for non-DMD cells, even with tamoxifen treatment.

The results “demonstrate that 4-hydroxytamoxifen treatment prolongs cell survival, underscoring the potential for tamoxifen in preventing the premature loss of cardiomyocytes in the DMD heart,” the researchers wrote.

Further experiments showed that 4-hydroxytamoxifen treatment increased the contractile function of cardiomyocytes and helped to normalize calcium signaling in the cells, which is dysfunctional in DMD.

“Our findings highlight that repurposing of the breast cancer drug, tamoxifen, may be beneficial to DMD patients with cardiomyopathy, as the active metabolite improves contractile function and delays premature cell death in DMD cardiomyocytes,” the scientists concluded.