New Approaches in Oncology for Repositioning Drugs: The Case of PDE5 Inhibitor Sildenafil

Abstract

The use of already-approved drugs to treat new or alternative diseases has proved to be beneficial in medicine, because it reduces both drug development costs and timelines. Most drugs can be used to treat different illnesses, due their mechanisms of action are not restricted to one molecular target, organ or illness. Diverging from its original intent offers an opportunity to repurpose previously approved drugs to treat other ailments. This is the case of sildenafil (Viagra), a phosphodiesterase-5 (PDE5) inhibitor, which was originally designed to treat systemic hypertension and angina but is currently commercialized as erectile dysfunction treatment. Sildenafil, tadalafil, and vardenafil are PDE5 inhibitors and potent vasodilators, that extend the physiological effects of nitric oxide and cyclic guanosine monophosphate (cGMP) signaling. Although most of the biological implications of these signaling regulations remain unknown, they offer a large therapeutic potential for several diseases. In addition, some PDE5 inhibitors’ molecular effects seem to play a key role in different illnesses such as kidney disease, diabetes mellitus, and cancer. In this review, we discuss the molecular effects of PDE5 inhibitors and their therapeutic repurposing in different types of cancer.

Phosphodiesterase-5 Inhibitor Attenuates Anxious Phenotypes and Movement Disorder Induced by Mild Ischemic Stroke in Rats

“…Enhancing NO-cGMP signaling by sildenafil increases blood flow and has neuroprotective effects in the rat model of hypoxic-ischemic brain injury [ 13 ]. Furthermore, upregulation of cGMP signaling by sildenafil activates cGMP-PKG leading to decreased levels of intracellular calcium ions [ 3 , 18 ]. Ca 2+ ions play a vital role as a major initiator and activator in the ischemic cell death pathways [ 15 ].…”

Sildenafil (Viagra®): A Pharmacokinetic (PK) Review

“…Besides that, there have been numerous reports of the use of sildenafil in cardiovascular diseases [24,25], the Raynaud phenomenon [26], cystic fibrosis, cancer [27][28][29][30], diabetes, and neurological disorders such as Alzheimer's. Sildenafil also has 10% activity against PDE6.…”

Pros and Cons of Pharmacological Manipulation of cGMP-PDEs in the Prevention and Treatment of Breast Cancer

“…They are also applied in other diseases, such as male lower urinary tract symptoms (LUTS), psoriasis arthritis, nonalcoholic fatty liver disease (NAFLD), liver cirrhosis, pulmonary arterial hypertension (PAH) [ 55 , 56 , 57 , 58 , 59 , 60 ]. Nevertheless, these compounds, alone or in combination with chemotherapeutics, have been heralded as promising drugs for the treatment of several malignancies, including breast cancer, although their role is yet to be fully clarified [ 61 , 62 , 63 , 64 ].…”