Treatments That Target and Kill Only Diseased Cells in PAH Possible, Researchers Say
Medications that specifically trigger cell death in remodeled blood vessels, without damaging the heart or healthy blood vessels, may be used to treat pulmonary arterial hypertension (PAH), researchers suggest.
Their study, “Apoptosis-based therapy to treat pulmonary arterial hypertension,” published in the Journal of Rare Diseases Research & Treatment, calls for clinical studies to explore the concept, particularly since many cell-death boosting drugs are already on the market.
One of the challenges in developing PAH treatments is that the condition frequently is diagnosed only after extensive changes in lung blood vessels are present. This means that a treatment, optimally, needs to not only slow the progression of further changes, but also reverse the damage already present.
Researchers at Georgetown University Medical Center have spent the past decade examining whether drugs that trigger apoptosis, the technical term for programmed cells death, may offer such a treatment.
But the road to developing such a PAH drug is not straightforward. Drugs triggering cell death are often used in cancer therapies, and this use clearly shows that these drugs also have the potential to kill heart cells — which would be entirely unacceptable since PAH patients suffer from right-sided heart disease.
It is crucial that a treatment intended to kill cells contributing to disease will not hurt those making up healthy lung blood vessels.
The research team believes it is on the right track in navigating this delicate balance. Starting out by testing different classes of cancer drugs in a rat model of PAH, researchers found that three types of drugs could reduce the thickness of lung blood vessels.
They decided to focus experiments on a drug called daunorubicin. A chemotherapy, it has been in use for more than 50 years, but what attracted the attention of the Georgetown team was a recent study showing that the drug could trigger programmed cell death in cultured human pulmonary artery smooth muscle cells.
Experiments showed that daunorubicin only killed cells in diseased blood vessels, leaving healthy blood vessels unaffected. This seemingly strange selectivity, making remodeled tissue more sensitive to drugs that trigger cell death, could be explained by changes in molecular pathways triggered by PAH.
The team then went on to the question of heart toxicity. They identified two compounds, dexrazoxane and pifithrin-α, both of which protect the heart against drug-induced toxicity, that worked to block cell death in the heart without preventing other drugs from killing cells multiplying in diseased lung blood vessels.
“Collectively, these data generated using animal models of PAH suggest that combining cell-killing drugs and cardioprotectants with the currently available vasodilator therapies may present optimal therapeutic strategies to treat this lethal disease,” the researchers concluded.