2. Academic Validation
  3. The Potential Role of Sildenafil in Cancer Management through EPR Augmentation

The Potential Role of Sildenafil in Cancer Management through EPR Augmentation

  • J Pers Med. 2021 Jun 21;11(6):585. doi: 10.3390/jpm11060585.
Mohamed Haider 1 2,  Amr Elsherbeny 3,  Valeria Pittalà 4,  Antonino N Fallica 4,  Maha Ali Alghamdi 5 6,  Khaled Greish 6
Affiliations

Affiliations

  • 1 Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates.
  • 2 Research Institute of Medical & Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates.
  • 3 Division of Molecular Therapeutics and Formulation, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK.
  • 4 Department of Drug and Health Science, University of Catania, 95125 Catania, Italy.
  • 5 Department of Biotechnology, College of Science, Taif University, Taif 21974, Saudi Arabia.
  • 6 Department of Molecular Medicine, Princess Al-Jawhara Centre for Molecular Medicine, School of Medicine and Medical Sciences Arabian Gulf University, Manama 329, Bahrain.
PMID: 34205602 DOI: 10.3390/jpm11060585
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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