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Review
. 2021 Jun 21;11(6):585.
doi: 10.3390/jpm11060585.

The Potential Role of Sildenafil in Cancer Management through EPR Augmentation

Mohamed Haider  1   2 , Amr Elsherbeny  3 , Valeria Pittalà  4 , Antonino N Fallica  4 , Maha Ali Alghamdi  5   6 , Khaled Greish  6
Affiliations
Review

The Potential Role of Sildenafil in Cancer Management through EPR Augmentation

Mohamed Haider et al. J Pers Med. .

Abstract

Enhanced permeation retention (EPR) was a significant milestone discovery by Maeda et al. paving the path for the emerging field of nanomedicine to become a powerful tool in the fight against cancer. Sildenafil is a potent inhibitor of phosphodiesterase 5 (PDE-5) used for the treatment of erectile dysfunction (ED) through the relaxation of smooth muscles and the modulation of vascular endothelial permeability. Overexpression of PDE-5 has been reported in lung, colon, metastatic breast cancers, and bladder squamous carcinoma. Moreover, sildenafil has been reported to increase the sensitivity of tumor cells of different origins to the cytotoxic effect of chemotherapeutic agents with augmented apoptosis mediated through inducing the downregulation of Bcl-xL and FAP-1 expression, enhancing reactive oxygen species (ROS) generation, phosphorylating BAD and Bcl-2, upregulating caspase-3,8,9 activities, and blocking cells at G0/G1 cell cycle phase. Sildenafil has also demonstrated inhibitory effects on the efflux activity of ATP-binding cassette (ABC) transporters such as ABCC4, ABCC5, ABCB1, and ABCG2, ultimately reversing multidrug resistance. Accordingly, there has been a growing interest in using sildenafil as monotherapy or chemoadjuvant in EPR augmentation and management of different types of cancer. In this review, we critically examine the basic molecular mechanism of sildenafil related to cancer biology and discuss the overall potential of sildenafil in enhancing EPR-based anticancer drug delivery, pointing to the outcomes of the most important related preclinical and clinical studies.

Keywords: cancer; chemoadjuvant; drug repurposing; phosphodiesterase 5 inhibitors; sildenafil.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
NO/sGC/cGMP pathway and sildenafil mechanism of action in erectile tissues and chemical structure of sildenafil.
Figure 2
Figure 2
Docked position of sildenafil in the PDE-5 active site: ligand is represented in orange; amino acid residues in blue; hydrogen bonds are shown as solid blue lines; face-to-face stacking interaction in solid green lines; hydrogen bonds in dark solid grey lines; water bridges are represented in light solid grey lines. Image from the PLIP web service [20] using the PDB ID 2H42 [18].
Figure 3
Figure 3
Timeline and milestones of sildenafil drug discovery.
Figure 4
Figure 4
Chemical structures and IC50 values of commercial PDE-5 inhibitor.
See this image and copyright information in PMC

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