Researchers have found that sildenafil — a drug used to treat erectile dysfunction and pulmonary hypertension — is linked to an increased risk of melanoma by promoting cGMP-cGKI signaling cascade. The results, “Sildenafil Potentiates a cGMP-Dependent Pathway to Promote Melanoma Growth,” were published in the journal Cell Reports.
Malignant melanoma is one of the most aggressive cancers and the underlying cause for most deaths due to skin cancer. Melanoma cells were previously shown to hyperactivate the mitogen-activated protein kinase (MAPK) pathway, and its malignant effects were associated with an increased level of cyclic guanosine-3′, 5′-monophosphate (cGMP) as a consequence of PDE5A gene downregulation (the gene encoding for cGMP-degrading phosphodiesterase 5 [PDE5] ).
The results of a prospective cohort study with men in the United States reported that sildenafil, a chemical inhibitor of PDE5, increases the risk of developing melanoma. Researchers investigated the molecular link between cGMP-dependent signaling cascades and melanoma growth, using melanoma cells of both murine and human origin. They discovered that cGMP promotes MAPK signaling and melanoma growth in vitro and in vivo. Most importantly, they discovered that stimulating cGMP signaling in melanoma cells, either by overexpressing cGKIα or pharmacologically via treatment with sildenafil, promoted melanoma growth both in vitro and in vivo.
These findings were translated to humans, where analysis of 418 melanoma patients from The Cancer Genome Atlas (TCGA) showed that those carrying melanoma tumors with high levels of cGKI expression had significantly reduced median survival scores when compared to patients with low cGKI expression. Moreover, as with murine melanoma cells, human melanoma cells also showed a growth-promoting cGMP pathway that responded to pharmacological stimulation with sildenafil.
These results reveal that cGMP-cGKI signaling cascade promotes melanoma cell growth and invasiveness in murine and human melanoma cells. Importantly, sildenafil has pro-melanoma effects by potentiating activation of this pathway.
The study, titled “Application of sequencing, liquid biopsies and patient-derived xenografts for personalized medicine in melanoma,” was led by scientists from the Cancer Research UK Manchester Institute in England. It analyzed circulating tumor DNA – the DNA traces left by tumors in patients’ bloodstream – in blood samples of seven patients with advanced melanoma at The Christie NHS Foundation Trust.