Sildenafil, better known as Viagra, has revolutionized the treatment of erectile dysfunction. Its main effect is to dilate blood vessels, and for this reason it is also used to treat other disorders related to vasoconstriction, such as pulmonary hypertension. But almost twenty years after its arrival on the market, this small molecule continues to reserve surprises. New research published in the journal Cancer Research in fact, it reveals that sildenafil, and other molecules of the class of drugs known as Pde5a inhibitors, could be effective in inhibiting the spread of tumor metastases, and could therefore play a fundamental role in the treatment of solid tumors in the future.
The mechanism
In the past, research on the effectiveness of sildenafil in cancer patients had given conflicting results. To understand how a drug designed to act on the cardiovascular system can interfere with the progression of tumors, researchers at the Weizmann Institute of Science thoroughly studied the effect of the drug in the laboratory, working on animal and human tumor cells.
Sildenafil works by inhibiting the enzyme phosphodiesterase type 5, causing increased levels of a substance known as cyclic guanosine monophosphate (cGMP) within the body. This in turn increases the dilation of certain blood vessels, particularly in the penis, thus promoting erection (this is the best-known effect of Viagra, after all). However, the study demonstrated that the accumulation of cGMP has another effect: inside the cells it binds with some proteins responsible for the transport of cholesterol, effectively blocking its activity. Under the effect of sildenafil, cholesterol actually remains trapped inside the cells. And as research shows, tumors are extremely sensitive to this mechanism, particularly in the phases in which tumor cells attempt to break away from the primary mass to give rise to metastases.
Synergy with statins
The researchers hypothesized that by further reducing overall cholesterol availability it was possible to enhance the block of cellular metabolism induced by Pde5a inhibitors. In their tests, in fact, the combination of sildenafil and statins (the drugs commonly prescribed to reduce cholesterol levels in the blood) generated a real metabolic trap for tumor cells.
To verify whether this dynamic found in the test tube was reflected in clinical reality, the researchers analyzed the data of over five million people present in the database of Clalit, one of the main Israeli health insurance companies. Analyzes confirmed that individuals who regularly took sildenafil had superior overall survival rates and a lower risk of metastasis than non-users. The maximum benefit in terms of reduction in mortality was recorded in the group of patients taking both sildenafil and statins at the same time.
From basic research to clinical trials
The use of sildenafil in oncology is extremely attractive: it is a molecule known for decades, safe and potentially very effective. The data emerging from the study, although encouraging, nevertheless require extreme caution. The investigation evaluated the use of the drug by people who were already using it before the onset of the tumor, and does not constitute direct proof of the therapeutic efficacy of sildenafil administered after the diagnosis has already occurred.
Neoplastic cells also possess strong adaptive capabilities and could develop alternative metabolic pathways to circumvent the absence of cholesterol. Controlled and randomized clinical trials will therefore be necessary to establish whether, and in what ways, Pde5a inhibition can become an effective integrative therapy in combating tumor metastases in humans.