By age 38, the patient’s breast cancer had spread to her bones, a
typically fatal turn of events. She became an alcoholic, and her doctors
stopped all cancer treatment, instead giving her a drug to discourage
her drinking. She died 10 years later, after an inebriated fall from a
window. But an autopsy revealed something unexpected: Her bone tumors
had melted away, leaving only a few cancer cells in her marrow.
That 1971 case report, along with numerous lab studies, have
suggested that the 6-decade-old drug disulfiram (commercially known as
Antabuse), which makes people feel sick from drinking small amounts of
alcohol, might also be a cancer fighter. Now, researchers have finally
figured out how—by blocking a molecule that is part of a process that
gets rid of cellular waste.
“This paper solves a puzzle that has persisted in cancer research for
decades,” says cancer biologist Michele Pagano of New York University
School of Medicine in New York City, who was not involved in the study.
Starting in the 1970s, scientists found that disulfiram killed cancer
cells and slowed tumor growth in animals. It increased survival in
women who had breast tumors removed in a small clinical trial published in 1993.
But since then, disulfiram hasn’t gotten much attention for treating
cancer, partly because scientists disagreed about how it worked.
In the new study, a Danish-Czech-U.S. team first firmed up the drug’s
anticancer effects by combing through Denmark’s unique cancer
registry—more than 240,000 cases diagnosed between 2000 and 2013, along
with data on the medications each patient took. Of the more than 3000
patients taking Antabuse, the cancer death rate was 34% lower for the 1177 who stayed on the drug compared with those who stopped taking it, the researchers report today in Nature.
The drug was an equal opportunity anticancer weapon; its benefits held
for prostate, breast, and colon cancer, as well as cancer overall.
The researchers also confirmed that disulfiram slows the growth of
breast cancer tumors in mice, particularly if combined with a copper
supplement, which was already known to enhance its effects. They then
showed that when the mice broke down disulfiram, its main metabolite,
ditiocarb, forms a complex with copper that blocks the machinery that
cells use to dispose of misfolded and unneeded proteins. “Everything is
frozen,” says cancer biologist Jiri Bartek of the Danish Cancer Society
Research Center in Copenhagen, a co-leader of the study. Partly because
of the resulting protein buildup, the cancer cells become stressed and
die.
Although some approved cancer drugs and others in development
interfere with the same protein cleanup process, known as the
ubiquitin-proteasome system, disulfiram targets only a specific
molecular complex within this machinery. That could explain why it is so
effective, Pagano says. Bartek’s team also solved another puzzle—why
normal cells aren’t harmed by disulfiram, even when patients take it for
years. For unclear reasons, the copper metabolite is 10 times more
abundant in tumor tissue compared with other tissues, the group found.
Despite the compelling 1971 anecdote, disulfiram probably “is not a
cure” for most cancer patients, cautions cancer biologist Thomas
Helleday of the Karolinska Institute in Stockholm. However, the drug
could help extend the lives of patients with metastatic cancer—it’s
already shown evidence of doing so when combined with chemotherapy in a small lung cancer trial.
Bartek and collaborators are now launching trials to test a
disulfiram-copper combo as a treatment for metastatic breast and colon
cancers and for glioblastoma, a type of brain cancer.
Finding a new use for an approved drug is appealing because the
compound has already passed safety testing. However, “big pharma
probably won’t be interested” in developing disulfiram for cancer
because there’s no patent protection on the drug, Bartek says. Still, if
the pending clinical trials provide convincing evidence, Halleday
points out, oncologists could go ahead and prescribe it anyway as an
inexpensive treatment.
Source Link: http://www.sciencemag.org/news/2017/12/old-drug-alcoholism-finds-new-life-cancer-treatment
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