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

Marian Cruz-Burgos,Carlos D Cruz-Hernández,Mauricio Rodríguez-Dorantes,Miguel Morales-Pacheco,Vanessa Gonzalez-Covarrubias,Ignacio Camacho-Arroyo,Alberto Losada-Garcia,Samantha I Trujillo-Bornios,Sergio A Cortés-Ramírez

doi:10.3389/fonc.2021.627229

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.

Highlights

The development of new drugs is a long, arduous and expensive process; drug repurposing represents an alternative and effective strategy, which reduces both development costs and timeliness by using already approved compounds to offer alternative clinical options.Drug repurposing, or repositioning, is defined as the process of finding new medical indications and uses for existing drugs [1, 2]
A significant improvement in the total of International Prostate Symptom Score (IPSS) but insignificant changes in the maximum flow rate (Qmax) and in the post void residual were observed. This indicates that the use of tamsulosin and low-dose sildenafil to treat low urinary tract symptoms (LUTS) following brachytherapy leads to LUTS improvement [59].The mechanism of cell death induced by the treatment with sildenafil and DOX in prostate cancer (PCa) cells involves increased surface localization of CD95 (Fas receptor or APO-is a dead receptor) in the membrane, with concomitant inactivation of NF-kB and suppression of FLIP and FAP-1 (Fas-associated phosphatase-1, negative regulator of Fas) expression
This study found a little association between sildenafil exposure and melanoma

Summary

INTRODUCTION

The development of new drugs is a long, arduous and expensive process; drug repurposing represents an alternative and effective strategy, which reduces both development costs and timeliness by using already approved compounds to offer alternative clinical options. This indicates that the use of tamsulosin and low-dose sildenafil to treat LUTS following brachytherapy leads to LUTS improvement [59].The mechanism of cell death induced by the treatment with sildenafil and DOX in PCa cells involves increased surface localization of CD95 (Fas receptor or APO-is a dead receptor) in the membrane, with concomitant inactivation of NF-kB and suppression of FLIP (inhibitory protein that blocks TRAILmediated cell dead) and FAP-1 (Fas-associated phosphatase-1, negative regulator of Fas) expression These mechanistic studies may contribute to expanding the use of PDE5 inhibitors in enhancing chemotherapeutic efficacy in PCa tumors expressing CD95, a surface receptor that induces apoptosis in cancer cells [60]. In synthesis more research is still needed to probe if sildenafil is associated with melanoma risk

DISCUSSION

Findings

CONCLUDING REMARKS