Some medications developed to treat one disease may show unexpected effects in other areas of medicine. This phenomenon, known as drug repurposing, makes it possible to study substances whose safety and general functioning are already known, but which could act on biological mechanisms different from those for which they were originally created.

A recent study explored one of these cases: the possible effect of sildenafil, the active ingredient mainly known for its use in erectile dysfunction and pulmonary hypertension, on cancer progression and, in particular, on the process of metastasis.

But the question is, how does this happen?…

Metastasis requires an enormous amount of energy

Metastasis is the process by which cancer cells leave the original tumor, invade nearby tissues, enter the circulation, and establish new lesions in distant organs. But it is not a simple process, and to achieve it, a tumor cell must constantly modify its shape, reorganize its membrane, move, resist adverse conditions, and adapt to new environments.

These activities require energy and cellular materials. One of the most important is cholesterol. Although it is usually associated mainly with cardiovascular health, cholesterol is also an essential component of all cells. It forms part of their membranes, contributes to the organization of different internal structures, and participates in multiple signaling processes.

That is why metastatic cells have a particularly high demand for cholesterol and ATP, the cell’s main immediate source of energy. For this reason, limiting the availability of these resources could especially affect metastatic capacity, even when the effect on the growth of the primary tumor is less pronounced.

What roles do PDE5A and cGMP play?

PDE5A is a phosphodiesterase, meaning an enzyme responsible for breaking down a signaling molecule called cyclic guanosine monophosphate, or cGMP. This messenger normally participates in muscle relaxation and the regulation of blood flow.

Sildenafil blocks PDE5A. As a consequence, cGMP is no longer broken down as quickly and accumulates inside the cells. In blood vessels, this increase promotes vasodilation and, consequently, a reduction in blood pressure. However, the new study proposes that, inside tumor cells, cGMP may also perform a much less well-known metabolic function.

Through molecular simulations and laboratory experiments, the team found that cGMP could bind directly to NPC1, a protein that is essential for making use of cholesterol stored in some less commonly discussed cellular reserves, the lysosomes.

NPC1: The exit door for cholesterol

Lysosomes can be imagined as cellular processing and recycling centers. Different materials arrive there to be degraded, reused, or redistributed. When a cell takes in cholesterol from outside, part of it reaches the lysosome and must later be transported to other regions of the cell.

NPC1 functions as a kind of exit door for that cholesterol. When its activity decreases, cholesterol becomes trapped inside the lysosome and cannot be used properly in the plasma membrane, mitochondria, or other compartments.

This creates a paradox: the cell may contain a large total amount of cholesterol, but at the same time suffer from a lack of available cholesterol because it is trapped in the lysosomes. It is similar to having food stored in a warehouse whose door cannot be opened. The resources exist, but they do not reach the place where they are needed.

The researchers observed that sildenafil produced lysosomal cholesterol accumulation, alterations in lysosomal pH, and decreases in proliferation, colony formation, and tumor cell migration.

Less available cholesterol, less ability to move

When cholesterol became trapped in the lysosomes, other cellular structures began to be affected. One of them was the lipid rafts, small organized regions of the membrane that bring together receptors and signaling proteins.

These platforms are important for the processes that allow a tumor cell to attach, move, invade tissues, and colonize distant organs. After sildenafil treatment, the researchers detected a reduction in lipid rafts. When external cholesterol was added, part of the organization of these structures and the migratory capacity could be restored, supporting the idea that the lack of available cholesterol was an important cause of the observed effect.

The mitochondria, the centers of cellular energy production, were also affected. The treated cells showed lower ATP production and an increase in mitochondrial reactive oxygen species, molecules that disrupt their proper functioning. In other words, the cells not only lost materials needed to reorganize their membranes, but also part of the energy required to move and survive during metastasis.

The tumor tries to compensate for the shortage

Cells have mechanisms to detect when they lack usable cholesterol. In response, they activate an “emergency pathway” that increases the production of enzymes responsible for making new cholesterol.

Sildenafil activated this compensatory response. Although cholesterol remained trapped in the lysosomes, the tumor cells began to produce more cholesterol through this pathway. The researchers used this reaction as a second therapeutic opportunity. If sildenafil made it difficult for cholesterol to leave the lysosome, a statin could simultaneously reduce its production. Statins inhibit HMG-CoA reductase, a central enzyme in cholesterol synthesis. In this way, the combination attacked two different sources.

The combination with lovastatin reduced proliferation and migration more strongly and increased apoptosis. In animal models of breast, prostate, and colon cancer, reductions in tumor growth or metastatic burden were also observed, although the magnitude of the additional benefit varied between models.

Figure 1.  PDE5A inhibition increases cGMP, disrupts NPC1-mediated cholesterol export from lysosomes, and reduces cholesterol availability for membrane signaling, mitochondrial function, and autophagy. Statins further limit cholesterol synthesis, enhancing the anti-metastatic effect.

What was found in patients?

The researchers constructed a matched cohort of 40,567 men with cancer, between 35 and 65 years of age, diagnosed between 2008 and 2017. The objective was to examine whether recorded use of sildenafil and statins was associated with survival during the five years following diagnosis.

Among statin users, one or two sildenafil dispensations were associated with a 17% reduction in the risk of death, while three or more dispensations were associated with a 31% reduction, compared with non-users. In patients with type 2 diabetes and cancer, the combination of statins with at least three dispensations was associated with a 41% reduction.

These results are interesting, but they must be interpreted with caution. A statistical association does not prove that the medication caused greater survival. The study was retrospective and may not have recorded medications obtained privately. In addition, it did not include complete information about tumor stage and the cancer treatments received, factors that can profoundly influence prognosis.

A promising possibility, but still experimental

Rather than presenting a new cure, the study reveals a metabolic vulnerability: metastatic cells need cholesterol not only to be present, but also to circulate properly within them. Interrupting that distribution system could, in the future, become a complementary strategy to limit the spread of cancer.

Main reference:

Ariav, Y., Hayek, S., Cantore, T., Sanghvi, N., Adler, L. N., Darzi, N., Pal, L. R., Crawford, D. R., Malleron, T., Silverbeck, J., Yardeni, E., Hajaj, E., Ben-Zeev, E., Sinha, S., Ziman, S., Shlomai, A., Malitsky, S., Itkin, M., Levin-Zaidman, S., … Erez, A. (2026). PDE5a inhibition restricts cancer metastasis by disrupting NPC1-mediated cholesterol trafficking through a non-canonical cGMP-dependent pathway. Cancer Research. https://doi.org/10.1158/0008-5472.CAN-26-1818