Viagra, one of the world’s most recognizable medicines, may have an unexpected role beyond treating erectile dysfunction. Scientists at the Weizmann Institute of Science have found that sildenafil, the drug’s active ingredient, can interfere with a biological process that cancer cells rely on to spread from a primary tumor to distant organs. The study, published in Cancer Research, identifies a previously unrecognized connection between sildenafil, intracellular cholesterol transport and cancer metastasis.
The discovery emerged from research led by Dr. Yarden Ariav in the laboratory of Prof. Ayelet Erez. The team investigated how cancer cells obtain and use cholesterol during metastasis, the process by which malignant cells detach from a primary tumor, travel through the body and establish new tumors. Although cholesterol is often associated with cardiovascular disease, it is also an essential structural and metabolic component of every cell. It helps maintain cellular membranes, supports signaling systems and serves as a building block for several biologically important molecules.
Metastatic cancer cells can be especially dependent on cholesterol because they must constantly remodel their membranes as they migrate, invade tissues and adapt to new environments. These cells also undergo intense metabolic changes that help them survive outside the original tumor. According to the Weizmann researchers, limiting the availability of cholesterol may therefore create a particular vulnerability in cancer cells, reducing their capacity to move and colonize distant organs.
Sildenafil appears to exploit this vulnerability through its established molecular target, phosphodiesterase type 5, or PDE5. The enzyme normally breaks down cyclic guanosine monophosphate, known as cGMP, a signaling molecule involved in blood-vessel relaxation. By inhibiting PDE5, sildenafil increases cGMP levels. This mechanism widens blood vessels and improves blood flow, producing the effect for which Viagra became widely known.
The new study suggests that cGMP has another function relevant to cancer biology. The researchers found that elevated cGMP can bind to a protein involved in transporting cholesterol inside cells. This interaction alters the movement and availability of cholesterol, leaving less of the lipid accessible for cellular processes. While normal cells may tolerate this change, metastatic cancer cells appear to be more sensitive because of their greater demand for cholesterol during migration and invasion.
Experiments in mouse models and in cultures made from human cancer cells indicated that sildenafil reduced the ability of malignant cells to form metastases. The findings point to an anti-metastatic mechanism rather than a direct effect that simply kills tumor cells. By restricting the metabolic resources required for movement and colonization, PDE5 inhibition may make it more difficult for cancer cells to complete the series of steps needed to establish tumors in distant tissues.
The researchers also examined whether sildenafil could work together with statins, drugs commonly prescribed to lower cholesterol levels. Statins inhibit enzymes involved in the body’s cholesterol-production pathway, including the rate-limiting enzyme HMG-CoA reductase. In theory, combining a PDE5 inhibitor with a statin could attack cholesterol availability from two directions: sildenafil would interfere with the transport and use of existing cholesterol, while the statin would reduce the production of new cholesterol. In laboratory and animal experiments, this combination showed stronger anti-metastatic activity than either treatment alone.
To explore whether the experimental observations were reflected in patients, the team analyzed more than two decades of health data from approximately five million members of Clalit Health Services. Statistical analysis found that cancer patients who had taken sildenafil showed significantly improved survival, with the strongest association reported among patients who had also used statins. The population-level findings are consistent with the mouse and cell-culture experiments, but they do not establish that sildenafil or statins caused the improved outcomes. Differences in age, cancer type, disease stage, general health, medical care and other treatments could influence the results.
The researchers emphasize that the findings do not yet justify using Viagra as a cancer treatment. Clinical trials will be needed to determine whether PDE5 inhibitors can safely prevent or slow metastasis in specific cancers, which patients might benefit and what doses or treatment combinations would be appropriate. Still, the work highlights how existing medicines can reveal unexpected connections between seemingly separate diseases. It also supports a broader view of cancer in which tumor genetics interact with metabolism, the patient’s overall physiology and medications prescribed for other conditions. By linking cGMP signaling to cholesterol regulation, the study opens a potential new avenue for limiting cancer spread and illustrates why treating the whole patient may be as important as targeting the tumor itself.
Subject of Research: The potential of sildenafil, a PDE5 inhibitor, to restrict cancer metastasis by disrupting intracellular cholesterol transport and metabolism, including its possible combination with statins.
Web References: https://aacrjournals.org/cancerres/article/doi/10.1158/0008-5472.CAN-26-1818/786876/PDE5a-Inhibition-Restricts-Cancer-Metastasis-by ; https://www.weizmann.ac.il/dept/irb/Erez/
References: Cancer Research; research conducted by scientists at the Weizmann Institute of Science, the U.S. National Cancer Institute, Clalit Health Services and Rabin Medical Center.
Keywords: Cancer, metastasis, sildenafil, Viagra, PDE5, cGMP, cholesterol, statins, cancer metabolism, intracellular transport, drug repurposing
