By Jocelyn KaiserJul. 1, 2020 , 1:20 PM

Can the red devil be defanged? Doxorubicin, an old chemotherapy drug that carries this unusual moniker because of its distinctive hue and fearsome toxicity, remains a key treatment for many cancer patients. But a new study reports the drug can be tweaked to reduce its most punishing side effect, cardiac damage, without blunting its ability to curb tumors.

The work, from an academic team in the Netherlands, upends conventional thinking about doxorubicin and related drugs, suggesting they do not need to directly damage DNA to kill cancer cells. “This idea was floating around in the literature for many years, but [until now] it has not been proven experimentally,” says Sherif El-Khamisy, who studies DNA repair at the University of Sheffield. “It’s a great study.”

The team now plans to test two potentially safer versions of doxorubicin’s drug class in people. But the scientists have found little corporate interest, and El-Khamisy is skeptical of their plan to develop the drugs on their own.

Doxorubucin belongs to a class of compounds known as anthracyclines, which were originally extracted from Streptomyces bacteria. They have antibiotic properties but also proved to be some of the most potent chemotherapies ever found; anthracyclines are used to treat 1 million cancer patients each year, particularly those with leukemia and breast cancer.

But because anthracyclines can cause heart damage, physicians often avoid giving them to elderly patients. Many childhood cancers are treated with high doses of the drugs, but cardiac problems sometimes haunt survivors later in life, along with a risk of new tumors, which doctors have attributed to DNA damage from the drugs.

Researchers have tried to reduce the heart risks by, for example, packaging the drugs in fat so they will home in on tumors, with limited success. But chemist Jacques Neefjes and his team at Leiden University and collaborators tried a different approach based on a surprising finding about how the drugs fight cancer, which they and a separate U.S. group reported in 2013. The textbook explanation is that the drugs kill rapidly dividing cells, such as those in a tumor, by blocking an enzyme they need to untangle and repair DNA as they replicate. But the researchers found doxorubicin also kills cancer cells by dislodging histones, the spherical proteins that DNA coils around like a spool to form a structure known as chromatin. This chromatin damage apparently interferes with the transcription of genes into proteins and other cell processes, Neefjes says.

In the new work, the Leiden team tested two anthracycline variants that remove histones without breaking DNA: an approved cancer drug called aclarubicin, and a tweaked version of doxorubicin they call diMe-Doxo. The compounds worked as well as the original drug, if not better, at killing cultured cancer cells and were nearly as effective at slowing tumor growth in mice. Yet mice prone to developing tumors that were dosed with aclarubicin did not show signs of heart damage, suggesting people treated with the drugs might be spared these effects. These mice were also much less likely to develop tumors later, the Leiden team reported online 17 June in the Proceedings of the National Academy of Sciences.

“I’m very excited about their findings,” says Katerina Gurova of the Roswell Park Comprehensive Cancer Center in Buffalo, New York, who is developing a cancer drug that also works by damaging chromatin. “We’re learning more about how to make these widely used drugs less toxic.”

Aclarubicin was once used in Europe for leukemia but was removed from the market in the 1990s because of manufacturing issues. Scientists at the U.S. National Cancer Institute came up with diMe-Doxo in the 1980s, but didn’t develop it further. Neither drug now has patent protection, which means companies aren’t interested, Neefjes says. So his team has raised money from public and private sources to produce diMe-Doxo and aclarubicin at the quality standards required for patients so they can run clinical trials as an academic effort.

Both drugs deserve study, he says—aclarubicin seems to work best on blood cancers whereas diMe-Doxo appears more effective for solid tumors. The group has a large grant from the Dutch Cancer Society to start a clinical trial next year of aclarubicin in relapsed leukemia patients. “We are doing what usually pharma is doing,” Neefjes says.

That will be “challenging,” El-Khamisy says. Drug companies are the experts at the steps, like studying how a compound is metabolized and demonstrating safety, that are needed to win approval for a medicine, he notes. Without a corporate partner, he fears, the study “may be yet another paper that is a good idea, but not really translatable.”