The findings, published in the peer-reviewed journal Cancer Research, suggest that sildenafil interferes with a newly discovered mechanism cancer cells use to obtain cholesterol needed for metastasis, the process by which tumours spread from their original site to distant organs.
The study was led by Dr Yarden Ariav in the laboratory of Prof. Ayelet Erez at the Weizmann Institute in Rehovot. Researchers found that sildenafil limits cancer cells’ ability to access cholesterol, an essential component of cell membranes that cancer cells require as they detach from the original tumour, travel through the body and establish new tumours elsewhere.
“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,” Erez said.
While scientists have long known that cancer cells depend on cholesterol, the newly identified pathway explains how sildenafil can deprive them of that resource. According to the researchers, reducing cholesterol availability makes it more difficult for cancer cells to form metastases, which account for the vast majority of cancer-related deaths.
Sildenafil works by blocking an enzyme known as phosphodiesterase type 5, or PDE5, increasing levels of the signaling molecule cyclic guanosine monophosphate, commonly known as cGMP. The increase in cGMP relaxes blood vessels, the mechanism that made Viagra a widely prescribed treatment for erectile dysfunction after its approval in 1998.
The researchers discovered that cGMP has another, previously unknown function. It binds to a protein that transports cholesterol within cells, reducing the amount of cholesterol available for cellular functions. Cancer cells appear to be especially vulnerable to this reduction because of their high demand for cholesterol during metastasis.
Targeting Cancer’s Fuel Supply
The team also found evidence that combining sildenafil with statins, widely used cholesterol-lowering medications taken by more than 200 million people worldwide, could produce an even stronger anti-metastatic effect. While sildenafil limits cancer cells’ access to existing cholesterol inside cells, statins reduce the body’s production of new cholesterol, potentially making the combination more effective than either treatment alone.
To test their findings, the scientists used mouse models, human cancer cell cultures and medical data collected over two decades from approximately 5 million members of Clalit Health Services, one of Israel’s largest healthcare providers.
Analysis of the Clalit database found significantly improved survival among cancer patients who had taken sildenafil, with the greatest benefit observed in patients who also used statins. While the findings show an association rather than proving cause and effect, they were consistent with the laboratory results from mice and human cancer cells.
“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.
Erez, who also serves as dean of Weizmann’s Miriam and Aaron Gutwirth Medical School while practising as a physician, said the research supports a broader approach to cancer treatment.
“Our study underscores the importance of treating the whole patient — not just the cancer — when tailoring the most effective therapy,” she said.
An estimated 90 million men worldwide have used Viagra since it entered the market. Because sildenafil is already approved for medical use, the researchers said the findings could accelerate efforts to evaluate the drug combination in clinical trials. However, the researchers cautioned that more studies are needed before the findings can be used to treat cancer patients.