The Potential Role of Sildenafil in Cancer Management through EPR Augmentation

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.

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

“…In breast cancer, MRP5 and 8 can also contribute to resistance to tamoxifen and other chemotherapeutics [ 49 ]. Interestingly, PDE inhibitors were shown to inhibit several MDR transporters (e.g., ABCC4/MRP4, ABCC5/MRP5, ABCB1/P-gp, ABCG2/BCRP), thus enhancing chemotherapeutic drug accumulation in tumor cells and efficacy [ 50 , 51 ].…”

“…Specifically, sildenafil enhanced sensitivity to doxorubicin in p53-mutant MDA-MB231 and p53-null MCF-7/E6 cells and, to a lesser extent, in MCF-7/caspase 3 and 4T1 cell lines, by increasing the apoptotic rate and DNA breaks, i.e., after the phosphorylation of γ-H2AX [ 86 ]. Moreover, the chemoadjuvant activity of sildenafil consisted in increasing the Enhanced Permeation Retention (EPR)-based anticancer drug delivery to the tumor tissue, which locally increased drug concentration [ 51 ].…”

EPR Effect-Based Tumor Targeted Nanomedicine: A Promising Approach for Controlling Cancer

“…A critical issue should be addressed is that the EPR effect is the phenomenon of blood vessels, which is largely dependent on tumor blood flow. While most animal solid tumor models that are rich in blood flow exhibit good EPR effect, many clinical cancers, especially advanced late-stage cancers and refractor cancers, are poor in tumor blood flow due to high coagulation activity and thrombi formation, thus showing unsatisfactory EPR effect [1,2,[10][11][12][13]. Thus, further augmentation of the EPR effect is of great importance and necessity.…”

“…Thus, further augmentation of the EPR effect is of great importance and necessity. In this regard, we should understand that the EPR effect is not a static phenomenon, it is a dynamic event, which could be enhanced by modulating vascular mediators in tumor such as using angiotensin II, NO/nitroglycerin, and angiotensin II, converting enzyme inhibitors and carbon monoxide [1,2,10,11]. A combination of vascular mediators with nanomedicines may become useful strategies for more effective antitumor nanomedicine.…”

“…The discoverer of EPR effect, Professor Hiroshi Maeda, and his former students and colleagues summarized the history; principle; the progress and prospects of EPR effect-based tumor targeting strategies; and the application of nanomedicines [1,2,6,8], in which the concept of EPR effect is not only applied to the development of targeted anticancer drugs [3,4,9] but is also applicable for radiation therapy [5], bacterial therapy of cancer [7], and nucleic acid medicine [14]. Moreover, more papers in the Special Issue emphasized the significance of EPR enhancement, discussing the usefulness of potential EPR enhancers [1,2,[10][11][12][13], which I believe to be an essential issue for successful anticancer therapy using nanomedicine.…”