The secret lies in a resource that tumor cells need to conquer new organs: cholesterol. In human cells and mice, sildenafil appears to disrupt its use by cancer cells. An analysis of nearly five million people also provides an encouraging signal. But it is still much too early to talk about a treatment for cancer.
Viagra, from the bloodstream to cancer cells
Its name immediately brings to mind erectile dysfunction. However, sildenafil was not originally designed for this. During its development, the drug was notably studied against high blood pressure and chest pain linked to a reduction in blood flow to the heart. Since its approval in 1998, it has become one of the best-known treatments for erectile dysfunction.
Today, a team from the Weizmann Institute of Science in Israel is discovering a completely different interest. In a study published in the journal Cancer Researchresearchers led by Professor Ayelet Erez and Dr Yarden Ariav were interested in a central question in oncology:
how to prevent a tumor from leaving its original organ to colonize other parts of the body?
Because it is metastases that make many cancers particularly difficult to treat. To move, survive in the blood circulation and then settle in a new organ, tumor cells must profoundly modify their functioning. And for this, they particularly need cholesterol.
Cancer cells need cholesterol to spread
Cholesterol isn’t just associated with blood tests or cardiovascular disease. In the body, this molecule plays an essential role, particularly in the constitution and renewal of the membranes which surround the cells. However, researchers have discovered that this resource seems particularly important for cancer cells when they seek to leave the initial tumor.
The identified mechanism begins with an enzyme called PDE5. Sildenafil blocks it, leading to an increase in a messenger molecule called cGMP. It is already this mechanism which explains the well-known effect of Viagra: the increase in cGMP promotes the dilation of blood vessels and therefore the influx of blood necessary for an erection.
But Ayelet Erez’s team discovered that cGMP doesn’t stop there. It also binds to a protein called
NPC1involved in the transport of cholesterol inside cells. Result: part of the cholesterol remains trapped in lysosomes, small cellular structures responsible in particular for recycling and transporting molecules.
The tumor cell then has less usable cholesterol. This lack seems particularly penalizing when it attempts to move and form a metastasis.
In mice, metastases decrease… but the tumor remains there
The researchers first studied the phenomenon on cells from breast, lung and colon cancers. In the laboratory, sildenafil reduced their multiplication and their ability to migrate.
Then the team moved on to animal models. In mice, the treatment led to a reduction in the number of secondary tumors in the lungs, sometimes by more than half. A spectacular result in appearance, but which must be interpreted with caution: sildenafil does not make the initial tumor disappear.
Its potential interest would be different. It could make cancer cells less able to leave their home territory and colonize other organs. This nuance is essential. It is therefore not, at this stage, a drug that “treats cancer”, but an avenue targeting more specifically one of the mechanisms responsible for its dissemination.
And the researchers then asked another question: what happens if we further deprive the tumor cell of cholesterol?
With statins, researchers imagine a double lock
Faced with the reduction in available cholesterol, cancer cells do not remain passive. The work shows that they activate in particular a factor called SREBP2which stimulates their own cholesterol production. In other words, when one door is closed, the cell attempts to open another. This is where statins could come into play. These drugs, prescribed to millions of people to reduce cholesterol levels, slow down its production by the body.
The researchers’ reasoning then becomes particularly interesting: sildenafil would limit access to cholesterol already present in the cell, while statins would prevent it from producing more.
In their experimental models, this association reinforces the effect observed on the ability of cancer cells to form metastases.
The lead, however, is not based solely on laboratory experiments. The researchers also delved into the medical data of Clalit Health Servicesone of Israel’s leading health organizations.
Nearly five million files provide a signal, but not yet proof
The team analyzed twenty years of data concerning approximately
five million people. In this population, researchers observed better survival in cancer patients who took sildenafil, particularly when the drug was combined with a statin.
According to the reported analysis, patients who received at least three prescriptions for sildenafil in the six months before their diagnosis had an approximately lower five-year risk of death. 26% to that of non-users. With the sildenafil-statin combination, the reduction was approximately 32%.
These figures are obviously intriguing. But they do not allow us to conclude that Viagra reduces deaths from cancer.
For what ? Because an analysis of medical data, even involving several million people, does not replace a randomized clinical trial. Patients who take sildenafil may differ from others in many aspects: age, health status, treatments, cardiovascular diseases, access to care or even characteristics of their cancer.
These results must therefore be considered as a signal to exploreand not as the demonstration of an anti-cancer effect. Ayelet Erez herself calls for caution.
“Our study highlights the importance of treating the whole patient – and not just the cancer – when it comes to tailoring the most effective treatment.”.
This idea is perhaps the most interesting scope of this work. Cancer is not just about the mutations present in a tumor. Its evolution also depends on the biological environment in which the tumor cells live, the patient’s metabolism and, potentially, the medications he is already taking for other diseases. The researchers believe they have uncovered “a new biological pathway” linking a well-known signaling molecule to the regulation of cholesterol in cells.
However, the road to possible treatment is still long. Before considering prescribing sildenafil with the aim of preventing metastases, it will be necessary to confirm these results in clinical trials and determine which cancers, which patients and which therapeutic combinations could really benefit from it.