Previous studies have demonstrated that the alcohol abuse drug disulfiram has anticancer properties. But until now, researchers had not found the mechanism by which the drug can target cancer. New research sheds light, paving the way for the repurposing of the drug, according to MNT.
This study was conducted by an international team of researchers led by Jiri Bartek, of the Danish Cancer Society Research Center in Copenhagen.
Disulfiram — also known by the brand name Antabuse — has been used for decades to treat chronic alcohol abuse. While the drug is not a cure for chronic alcoholism, it does discourage those with alcohol abuse issues from drinking.
Previous studies have shown that the drug has anti-tumor activity both in vitro and in vivo. But as Bartek and colleagues explain in their paper, the drug hasn’t yet been repurposed for cancer treatment because the mechanism and molecular pathways through which the drug may act against cancer were unknown.
As the study’s authors explain, given the rising global incidence of cancer and the failure of many medications in the face of tumor resistance, identifying new possibilities for using already existing drugs is key.
In fact, the World Health Organization (WHO) estimate that in the next two decades, the number of new cancer cases will rise by 70 percent. Cancer is already the second leading cause of death worldwide.
In this context, drug repurposing is a safe, cost- and time-effective alternative. Testing new drugs can be expensive and time-consuming, but drug repurposing uses medications for which most of the relevant testing has already been done.
An old, safe drug may save lives worldwide
So, Bartek and colleagues set out to unravel the mystery of disulfiram’s anticancer properties.
First, they carried out a nationwide epidemiological study of more than 3,000 Danish people, which showed that cancer patients who continued to take disulfiram were much less likely to die from cancer compared with those who stopped taking the treatment.
Then, the researchers carried out in vitro studies of cancer cells and in vivo studies of mice and identified the metabolite of disulfiram that enables the drug to fight off cancer: the so-called ditiocarb-copper complex.
The researchers also identified ways to further detect and analyze how this metabolite complex accumulates in tumors. Finally, and importantly, the researchers found the molecular pathway through which this ditiocarb-copper complex acts to suppress cancer cells.
They write, “[O]ur functional and biophysical analyses reveal the molecular target of disulfiram’s tumor-suppressing effects as NPL4, an adaptor of p97 […] segregase, which is essential for the turnover of proteins involved in multiple regulatory and stress-response pathways in cells.”
“Our results help to explain the anticancer activity of the alcohol-abuse drug disulfiram,” say Bartek and his colleagues.
“From a broader perspective, our study illustrates the potential of multifaceted approaches to drug repurposing,” they add, “providing novel mechanistic insights, identification of new cancer-relevant targets, and encouragement for further clinical trials.”
The researchers conclude: “[Disulfiram is] an old, safe, and public domain drug that might help to save lives of patients with cancer worldwide.”