Viagra was originally developed to treat high blood pressure and chest pain caused by reduced blood flow to the heart, but over the past three decades it has become the world’s best-known therapy for erectile dysfunction. In the future, this blockbuster drug may find yet another use. In a study published recently in Cancer Research, scientists in the lab of Prof. Ayelet Erez at the Weizmann Institute of Science found that sildenafil, Viagra’s active ingredient, may restrict cancer metastasis through a newly discovered biological mechanism.
The researchers, led by Dr. Yarden Ariav in Erez’s lab, showed that sildenafil limits cancer cells’ ability to make use of cholesterol, an essential component of cellular membranes. Cholesterol is particularly important for cancer cells seeking to break away from the primary tumor, migrate throughout the body and invade distant organs. When their access to cholesterol is disrupted, these cells have a harder time forming metastases.
Sildenafil creates this disruption by blocking an enzyme called phosphodiesterase type 5, or PDE5, thereby increasing the levels of a signaling molecule known as cGMP. Elevated cGMP levels dilate blood vessels, increasing blood flow to the penis – the effect that has made Viagra a successful treatment for erectile dysfunction. But Erez’s team discovered that cGMP also binds to a protein responsible for transporting cholesterol within cells. As a result, less cholesterol is available for the cell’s needs, and cancer cells, it turns out, are particularly vulnerable to this reduction in cholesterol supply.
Statistical analysis of the Clalit database revealed significantly improved survival among cancer patients who took sildenafil, particularly when it was combined with statins
The researchers also found that combining drugs from the Viagra family with statins – another widely used class of drugs, which reduce cholesterol production in the body – may be even more effective at restricting metastasis. The combination could not only limit cancer cells’ access to existing cholesterol but also prevent them from producing new cholesterol, potentially enhancing the anti-metastatic effect.
The research team – which included scientists from the lab of Prof. Eytan Ruppin at the U.S. National Cancer Institute, researchers from Clalit Health Services’ Innovation Division led by Prof. Shay Ben-Shachar and physicians and scientists from Rabin Medical Center (Beilinson and Hasharon hospitals) – based its findings on mouse models of cancer, cultures of cancer cells from human patients and data collected over 20 years from some 5 million Clalit members. Consistent with the findings in mice and human cell cultures, statistical analysis of the Clalit database revealed significantly improved survival among cancer patients who took sildenafil, particularly when it was combined with statins.
Science Numbers
An estimated 90 million men worldwide have taken Viagra since it was approved for medical use in 1998. More than 200 million people around the world currently take statins.
“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,” says Erez, who is also a practicing physician in addition to serving as a senior researcher and dean of Weizmann’s Miriam and Aaron Gutwirth Medical School. “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 adds: “Our study underscores the importance of treating the whole patient – not just the cancer – when tailoring the most effective therapy.”
Prof. Ayelet Erez’s research is supported by the David and Fela Shapell Family Center for Genetic Disorders Research; the Moross Integrated Cancer Center; the EKARD Institute for Cancer Diagnosis Research; the Abisch-Frenkel RNA Therapeutics Center; the Sagol Institute for Longevity Research; and the Koret Foundation.
Prof. Erez serves as dean of the Miriam and Aaron Gutwirth Medical School. She is the incumbent of the Sir Ernst B. Chain Professorial Chair. The Blumberg Family Research Fellow Chair in Honor of Talia Lynn Steckman supports a staff scientist in Prof. Erez’s lab.