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Viagra became a blockbuster drug by changing blood flow. It wasn’t long before doctors figured out it could also be used as a sexual enhancement pill. Now scientists say its active ingredient, sildenafil, may interfere with something far more threatening: cancer’s ability to spread.

A new study reports that sildenafil traps cholesterol inside cancer cells’ recycling compartments, depriving tumors of a material they need to move and invade more tissue. The result is promising, though researchers still need clinical trials to prove that the drug prevents metastasis in patients.

A Familiar Drug Finds an Unfamiliar Target

Sildenafil already has a history of reinvention.

Researchers originally developed the drug for heart-related conditions. It later became Viagra, the erectile-dysfunction medicine approved in 1998, after trials revealed its striking effect on erections. The same chemical is also sold to treat pulmonary arterial hypertension, a dangerous form of high blood pressure in the lungs.

Both uses rely on sildenafil blocking an enzyme called phosphodiesterase type 5, or PDE5. That blockade raises levels of a small signalling molecule called cyclic GMP, or cGMP, which relaxes blood vessels.

The new research suggests that cGMP has another job.

The team, led by researchers at the Weizmann Institute of Science, found that elevated cGMP can bind to proteins that ferry out cholesterol. When these proteins falter, cholesterol piles up inside them instead of reaching the rest of the cell.

For cancer cells, that’s a big problem because although the cells contain cholesterol, it can’t be used to continue the invasion.

Cancer cells use cholesterol to build and organize their outer membranes. Those membranes must bend and reorganize as cells detach from a tumor, crawl through surrounding tissue, enter the bloodstream, and invade another organ. This is where sildenafil seems to work its magic.

In experiments, it depleted cholesterol where the cells needed it. The disruption damaged cholesterol-rich membrane structures and made cancer cells migrate less effectively and form fewer metastases in mouse models. This seemed to affect cancerous cells more than healthy cells.

“We have uncovered a new biological pathway that links a well-known signaling molecule to cholesterol regulation within cells, and shown how this pathway can be harnessed to interfere with the ability of cancer cells to form metastases,” said study leader Ayelet Erez, according to the Weizmann Institute.

A Two-Drug Squeeze on Cholesterol

Cancer cells also reacted to this new cholesterol shortage.

When sildenafil trapped cholesterol, the cells activated a molecular emergency system called SREBP2. It functions like a cholesterol thermostat: when usable supplies fall, it orders the cell to manufacture more.

But researchers say we may also address this with another well-known drug: statins.

Statins, among the world’s most widely prescribed medicines, suppress cholesterol production. The researchers therefore combined sildenafil, which blocked the release of stored cholesterol, with statins, which limited the creation of new cholesterol.

Together, the drugs attacked both ends of the supply chain.

In laboratory and animal experiments, the combination produced a stronger anti-metastatic effect than either approach alone. The strategy resembles shutting a warehouse door while also stopping the factory line from replenishing the product.

But Does It Work in People?

The researchers haven’t carried out clinical trials. But they did look at two decades of records from Clalit Health Services in Israel, which covers about five million members.

They compared outcomes among cancer patients who did and did not use sildenafil. Patients recorded as taking the drug had better survival, according to the study, and the association appeared stronger among those who also used statins.

However, there are caveats, and other things might explain the observed discrepancy.

People who receive sildenafil may differ from non-users in important ways: age, cardiovascular health, income, access to care, cancer stage or other treatments. Researchers can adjust for known differences, but medical-record studies cannot eliminate every hidden bias.

It’s not the first study with this issue. A 2020 study of 12,465 men with non-metastatic colorectal cancer in Sweden associated post-diagnosis use of PDE5 inhibitors with lower cancer-specific mortality and less metastatic disease. Yet users were also younger, healthier and more socioeconomically advantaged, and here too, the possibility of a hidden bias couldn’t be eliminated.

Repurposing Old Meds

No one is saying “take Viagra, it’s good against cancer.” But the study fits a growing effort to repurpose old medicines for cancer.

Drug repurposing can save time because researchers already know much about a medicine’s manufacturing, dosing and side effects. Sildenafil has been used by millions of people, making it far less mysterious than a newly invented compound.

However, without clinical trials, it’s hard to confirm the potential.

Researchers now need trials that assign patients to treatment or placebo and track recurrence, metastasis and survival. Those studies must determine which cancers respond, when treatment should begin and whether sildenafil works best before surgery, after surgery or alongside existing therapies.

Still, the study offers an appealing idea: a drug famous for increasing blood flow may hinder cancer by creating an intracellular traffic jam.

“Beyond their therapeutic promise, our findings highlight that cancer biology is shaped not only by mutations in tumor cells but also by the patient’s metabolic state and by medications they are already taking for other conditions,” Erez said, according to the Weizmann Institute.

The study was published in Cancer Research.