The Potential Role of Sildenafil in CancerManagement Through EPR Augmentation
Open accessAbstract
Enhanced permeation retention (EPR) was a significant milestone discovery by Maeda et al. paving the road for the emerging nanomedicine as a powerful tool in the fight against cancer. Sildenafil is a potent inhibitor of phosphodiesterase 5 (PDE-5) used for treatment of erectile dysfunction (ED) through the relaxation of smooth muscles and the modulation of vascular endothelial permeability. Overexpression of PDE-5 was reported in lung, colon, metastatic breast cancers and bladder squamous carcinoma. Accordingly, there has been a growing interest in using sildenafil as monotherapy or chemoadjuvant in EPR augmentation and management of different types of cancer. Sildenafil had 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 expression of Bad and Bax proapoptotic proteins. It was also reported that the use of sildenafil prior to the administration of Doxorubicin (DOX) increased its EPR-related concentration in breast cancer tissues by 2 folds. Further, a substantial reason of anticancer chemotherapeutic failure is due to multidrug resistance (MDR), exacerbated by the overexpression of ATP-binding cassette (ABC) transporters such as ABCB1 and ABCCs. Sildenafil has demonstrated inhibitory effects on the efflux activity of ABCC4, ABCC5, ABCB1, and ABCG2, ultimately reversing MDR caused by these transporters. In this review, we critically examine the overall potential of sildenafil in enhancing EPR-based anticancer drug delivery pointing up the outcome of the most important related preclinical and clinical studies.
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The EPR effect can be enhanced by modifying vascular intermediaries such as angiotensin II, nitroglycerin or NO, CO, and enzyme inhibitors.
“The EPR effect can be enhanced by modifying vascular intermediaries such as angiotensin II, nitroglycerin or NO, CO, and enzyme inhibitors [7,8,9,10].”
From Approaches to Improve EPR-Based Drug Delivery for Cancer Therapy and Diagnosis (2023) · cites this paper as [10]
Section 5 (page not provided) says that the PDE5 inhibitor sildenafil can augment the EPR effect and describes a nitric oxide donor used to improve it. The passages do not support the sentence’s other listed examples: angiotensin II, nitroglycerin, or CO. (LLM, conf=0.85)
Experimental — accuracy not yet measuredMany clinical cancers such as late-stage and refractory tumors are associated with poor blood flow due to coagulation and thrombi formation, exhibiting poor EPR effect.
“However, many clinical cancers such as late-stage tumors and refractory tumors are associated with poor blood flow due to the coagulation and thrombi formation exhibiting poor EPR effect [7,8,9,10,11,12].”
From Approaches to Improve EPR-Based Drug Delivery for Cancer Therapy and Diagnosis (2023) · cites this paper as [10]
Section 5 (page unavailable) links improved tumor blood supply with EPR augmentation. It does not say that late-stage or refractory tumors commonly have poor blood flow or poor EPR, or attribute either to coagulation and thrombi formation. (LLM, conf=0.72)
Experimental — accuracy not yet measured
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- Authors
- Haider, M., Elsherbeny, A., Pittalà, V., Fallica, A. N., Alghamdi, M. A., & Greish, K.
- Affiliations
- Cairo University (EG)
- University of Nottingham (GB)
- University of Catania (IT)
- Taif University (SA)
- Arabian Gulf University (BH)
- Corresponding author
- Haider, Mohamed
- Greish, Khaled
- ORCID
- Venue
- Journal of Personalized Medicine
- Publisher
- MDPI AG
- Published
- 2021-04-26
- Volume
- 11
- Issue
- 6
- Pages
- 585-585
- ISSN
- 2075-4426 (ISSN-L)
- PMC
- PMC8234771
- OpenAlex
- W3158979140
- Cited by
- 42
- References
- 80
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 9 · 2023: 7 · 2022: 9 · 2021: 4
- FWCI
- 0.54
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Personalized Medicine (publishedVersion, cc-by)
- Preprints.org (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Arabian Gulf University (E002-PI-04/18)
- University of Sharjah (2101110345)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
- Keywords
- sildenafil, enhanced permeability and retention effect, cancer nanomedicine, phosphodiesterase-5 inhibition, apoptosis, multidrug resistance, ABC transporters, tumor vascular permeability, reactive oxygen species, Bcl-2 family proteins, caspase activation, cell cycle arrest, anticancer drug delivery
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