Targeting mitochondrial enzyme may reduce cardiac effects from chemotherapy drug
Investigators have identified two compounds that appear, in cellular and animal models, to block the cardiac damage caused by the chemotherapy drug doxorubicin. Their report indicates that inhibiting the action of an enzyme key to the generation of cellular energy in mitochondria could prevent doxorubicin-induced damage to cardiac cells without reducing the drug's antitumor effects.
"Doxorubicin-induced cardiomyopathy limits the amount of the drug a patient can receive, which limits the ability to treat cancer, and even low, safer doses can lead to heart failure in up to 8% of patients," explained senior author Randall Peterson, PhD, of the Massachusetts General Hospital Cardiovascular Research Center in Boston.
"Finding an effective cardioprotective drug, which is essentially separating the good and bad effects of this form of chemotherapy, could increase the beneficial effects of doxorubicin against cancer while reducing the rate of heart failure in treated patients."
The study was published in Science Translational Medicine (2014; doi:10.1126/scitranslmed.3010189).
The mechanism behind doxorubicin-induced cardiotoxicity remains unclear, and the only FDA-approved drug for its prevention may also reduce the anticancer effects, possibly leading to the development of secondary tumors.
To conduct a broad search for potential protective compounds, the research team developed a zebrafish model of doxorubicin-induced heart failure against which they screened 3,000 molecules from two chemical libraries for the ability to prevent the kind of cardiac damage caused by the drug.
Eight of the tested chemicals reduced damage to the hearts of zebrafish embryos, and two compounds, visnagin and diphenylurea, were most potent in preventing both structural and functional damage.
Further experiments were done in cells from mice and rats and in living zebrafish and mice that had been treated with doxorubicin. These found that either compound almost completely prevented the death of cardiac cells caused by the chemotherapy drug. In mouse models of both high- and low-dose doxorubicin treatment, visnagin, which is a natural compound synthesized by the toothpick weed, was able to maintain cardiac function.
Investigation of the possible mechanism behind visnagin's protective ability found that the compound binds to and inhibits the action of MDH2, an enzyme essential to the generation of cellular energy by mitochondria. Other agents that block MDH2 activity also protected zebrafish against doxorubicin-induced cardiac damage, and tests in both cellular and animal models of several types of cancer found that neither visnagin nor diphenylurea reduced the antitumor action of doxorubicin.
"We are still trying to determine exactly how inhibition of MDH2 protects the heart, but one intriguing idea is that doxorubicin may kill cardiac and tumor cells in different ways," explained Peterson. "Given the intense energy requirements of the beating heart, we speculate that cardiac cells may be especially susceptible to metabolic disturbance caused by doxorubicin and that inhibiting MDH2 may correct the metabolic imbalance and prevent the cells from dying.
"It remains to be seen if visnagin's protective effects are restricted to doxorubicin or if it can protect the heart from other kinds of damage," he added.