Israeli researchers find sildenafil may restrict cancer metastasis by disrupting cholesterol trafficking

Scientists at the Weizmann Institute of Science in Israel have identified a mechanism by which sildenafil, the active ingredient in the erectile dysfunction drug Viagra, may limit the spread of cancer. The peer-reviewed study, published in Cancer Research, demonstrates that PDE5a inhibitors including sildenafil induce lysosomal cholesterol accumulation in multiple mouse and human cancer models, reducing cholesterol bioavailability and impairing cell migration and metastasis (Cancer Research).

Led by Dr. Yarden Ariav in the laboratory of Prof. Ayelet Erez, the team found that sildenafil blocks the enzyme phosphodiesterase type 5 (PDE5), elevating levels of the signaling molecule cyclic GMP (cGMP). Elevated cGMP binds the lysosomal cholesterol transporter NPC1, impairing cholesterol export in a manner resembling Niemann-Pick type C pathology. Cancer cells proved particularly sensitive due to reduced lysosomal gene expression. The resulting cholesterol depletion disrupts membrane lipid rafts and mitochondrial bioenergetics, limiting metastatic capacity while triggering compensatory cholesterol synthesis via SREBP2 activation (Weizmann Institute).

Combining sildenafil with statins, which block cholesterol biosynthesis, produced additive antimetastatic effects by simultaneously restricting lysosomal cholesterol export and new production. Laboratory work focused on models including triple-negative breast cancer, melanoma, and lung cancer, using high-resolution imaging of mouse models and human patient-derived cancer cell cultures (Times of Israel).

These findings were supported by real-world data. Collaborators from Clalit Health Services analyzed more than 20 years of anonymized medical records from approximately 5 million members, including an observational cohort of about 40,000 males diagnosed with cancer. Statistical analysis showed significantly improved overall survival among patients who had used sildenafil prior to diagnosis, with a stronger dose-dependent benefit when combined with statins. The laboratory results in male mice for lung, colon, and prostate cancers aligned with the human data (Healthline; Weizmann Institute).

The research involved additional contributors from Prof. Eytan Ruppin’s lab at the U.S. National Cancer Institute and physicians and scientists from Clalit’s Beilinson and Hasharon Hospitals (Rabin Medical Center). Prof. Erez noted that the work uncovers a new biological pathway linking a known signaling molecule to intracellular cholesterol regulation that can be harnessed against metastasis. She emphasized the need for clinical trials, including testing sildenafil in women with triple-negative breast cancer, as the observational data primarily involved men due to prescribing patterns (Times of Israel).

Independent experts not involved in the study described the work as well-designed and promising for potential drug repurposing of widely available medications, while stressing that the results remain preclinical and observational. Clinical trials are required before any changes to cancer management, and patients should not start taking sildenafil for this purpose based on current evidence. The study authors similarly cautioned that the analysis examined pre-diagnosis use only and does not establish efficacy for treatment after diagnosis (Healthline; Cancer Research).

Sildenafil was originally developed for cardiovascular conditions before its approval for erectile dysfunction in 1998. The new findings highlight how existing medications and a patient’s broader metabolic context can influence cancer progression beyond tumor-intrinsic mutations.