{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T16:43:09Z","timestamp":1790095389339,"version":"4.0.1"},"reference-count":77,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,6,21]],"date-time":"2021-06-21T00:00:00Z","timestamp":1624233600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009606","name":"Arabian Gulf University","doi-asserted-by":"publisher","award":["E002-PI-04\/18"],"award-info":[{"award-number":["E002-PI-04\/18"]}],"id":[{"id":"10.13039\/100009606","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016714","name":"University of Sharjah","doi-asserted-by":"publisher","award":["2101110345"],"award-info":[{"award-number":["2101110345"]}],"id":[{"id":"10.13039\/100016714","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/jpm11060585","type":"journal-article","created":{"date-parts":[[2021,6,21]],"date-time":"2021-06-21T13:29:58Z","timestamp":1624282198000},"page":"585","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["The Potential Role of Sildenafil in Cancer Management through EPR Augmentation"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3150-9275","authenticated-orcid":false,"given":"Mohamed","family":"Haider","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates"},{"name":"Research Institute of Medical & Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0437-4299","authenticated-orcid":false,"given":"Amr","family":"Elsherbeny","sequence":"additional","affiliation":[{"name":"Division of Molecular Therapeutics and Formulation, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1856-0308","authenticated-orcid":false,"given":"Valeria","family":"Pittal\u00e0","sequence":"additional","affiliation":[{"name":"Department of Drug and Health Science, University of Catania, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1899-8414","authenticated-orcid":false,"given":"Antonino N.","family":"Fallica","sequence":"additional","affiliation":[{"name":"Department of Drug and Health Science, University of Catania, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5424-388X","authenticated-orcid":false,"given":"Maha Ali","family":"Alghamdi","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, College of Science, Taif University, Taif 21974, Saudi Arabia"},{"name":"Department of Molecular Medicine, Princess Al-Jawhara Centre for Molecular Medicine, School of Medicine and Medical Sciences Arabian Gulf University, Manama 329, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0787-7070","authenticated-orcid":false,"given":"Khaled","family":"Greish","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Princess Al-Jawhara Centre for Molecular Medicine, School of Medicine and Medical Sciences Arabian Gulf University, Manama 329, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1056\/NEJM199805143382009","article-title":"A Pill for Impotence","volume":"338","author":"Utiger","year":"1998","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1016\/0960-894X(96)00323-X","article-title":"Sildenafil (Viagra(TM)), a potent and selective inhibitor of type 5 CGMP phosphodiesterase with utility for the treatment of male erectile dysfunction","volume":"6","author":"Terrett","year":"1996","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1152\/physrev.00030.2010","article-title":"Mammalian cyclic nucleotide phosphodiesterases: Molecular mechanisms and physiological functions","volume":"91","author":"Francis","year":"2011","journal-title":"Physiol. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1038\/nrd893","article-title":"Phosphodiesterase 5 inhibitors: Current status and potential applications","volume":"1","author":"Rotella","year":"2002","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1152\/physrev.1995.75.4.725","article-title":"Cyclic nucleotide phosphodiesterases: Functional implications of multiple isoforms","volume":"75","author":"Beavo","year":"1995","journal-title":"Physiol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2554","DOI":"10.1111\/bph.14205","article-title":"PDE5 inhibitors\u2014Pharmacology and clinical applications 20 years after sildenafil discovery","volume":"175","author":"Andersson","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1124\/mol.66.1.144","article-title":"Binding of tritiated sildenafil, tadalafil, or vardenafil to the phosphodiesterase-5 catalytic site displays potency, specificity, heterogeneity, and cGMP stimulation","volume":"66","author":"Blount","year":"2004","journal-title":"Mol. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"13729","DOI":"10.1074\/jbc.274.20.13729","article-title":"Cyclic GMP phosphodiesterase-5: Target of sildenafil","volume":"274","author":"Corbin","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2760","DOI":"10.1046\/j.1432-1327.2000.01297.x","article-title":"Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cGMP-binding activities","volume":"267","author":"Corbin","year":"2000","journal-title":"Eur. J. Biochem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1067\/mai.2001.119555","article-title":"Cyclic nucleotide phosphodiesterases","volume":"108","author":"Essayan","year":"2001","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.sxmr.2018.06.005","article-title":"The Serendipitous Story of Sildenafil: An Unexpected Oral Therapy for Erectile Dysfunction","volume":"7","author":"Goldstein","year":"2019","journal-title":"Sex. Med. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1038\/nrd2030","article-title":"Sildenafil: From angina to erectile dysfunction to pulmonary hypertension and beyond","volume":"5","author":"Ghofrani","year":"2006","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1111\/j.1464-410X.2005.05614.x","article-title":"Phosphodiesterase type 5 inhibitors for erectile dysfunction","volume":"96","author":"Carson","year":"2005","journal-title":"BJU Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.2174\/1381612053764869","article-title":"Highly Active Antiretroviral Therapy: Current State of the Art, New Agents and Their Pharmacological Interactions Useful for Improving Therapeutic Outcome","volume":"11","author":"Barbaro","year":"2005","journal-title":"Curr. Pharm. Des."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.sxmr.2017.08.001","article-title":"Update on the Safety of Phosphodiesterase Type 5 Inhibitors for the Treatment of Erectile Dysfunction","volume":"6","author":"Yafi","year":"2018","journal-title":"Sex. Med. Rev."},{"key":"ref_16","first-page":"115","article-title":"Ocular safety of Viagra, (sildenafil citrate)","volume":"97","author":"Laties","year":"1999","journal-title":"Trans. Am. Ophthalmol. Soc."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"21469","DOI":"10.1074\/jbc.M512527200","article-title":"Multiple conformations of phosphodiesterase-5: Implications for enzyme function and drug development","volume":"281","author":"Wang","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/nature01914","article-title":"Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules","volume":"425","author":"Sung","year":"2003","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3459","DOI":"10.2174\/138161206778343118","article-title":"Phosphodiesterase 5 Inhibitors\u2014Drug Design and Differentiation Based on Selectivity, Pharmacokinetic and Efficacy Profiles","volume":"12","author":"Supuran","year":"2006","journal-title":"Curr. Pharm. Des."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"W443","DOI":"10.1093\/nar\/gkv315","article-title":"PLIP: Fully automated protein-ligand interaction profiler","volume":"43","author":"Salentin","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"335","DOI":"10.31887\/DCNS.2006.8.3\/tban","article-title":"The role of serendipity in drug discovery","volume":"8","author":"Ban","year":"2006","journal-title":"Dialogues Clin. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2387","DOI":"10.1016\/j.ijcard.2013.01.008","article-title":"Classification of myocardial infarction and unstable angina: A re-assessment","volume":"167","author":"Deckers","year":"2013","journal-title":"Int. J. Cardiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S0002-9149(99)00043-0","article-title":"Effects of sildenafil citrate on human hemodynamics","volume":"83","author":"Jackson","year":"1999","journal-title":"Am. J. Cardiol."},{"key":"ref_24","first-page":"47","article-title":"Sildenafil: An orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction","volume":"8","author":"Boolell","year":"1996","journal-title":"Int. J. Impot. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0002-9149(99)00042-9","article-title":"Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro","volume":"83","author":"Wallis","year":"1999","journal-title":"Am. J. Cardiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1016\/0006-291X(90)92168-Y","article-title":"Nitric oxide and cyclic GMP formation upon electrical field stimulation cause relaxation of corpus cavernosum smooth muscle","volume":"170","author":"Ignarro","year":"1990","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/S1367-5931(98)80123-3","article-title":"Chemotherapeutic potential of phosphodiesterase inhibitors","volume":"2","author":"Perry","year":"1998","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/j.jsxm.2016.01.016","article-title":"Pharmacotherapy for Erectile Dysfunction: Recommendations From the Fourth International Consultation for Sexual Medicine (ICSM 2015)","volume":"13","author":"Hatzimouratidis","year":"2016","journal-title":"J. Sex. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1093\/eurheartj\/ehx700","article-title":"Sildenafil for improving outcomes in patients with corrected valvular heart disease and persistent pulmonary hypertension: A multicenter, double-blind, randomized clinical trial","volume":"39","author":"Bermejo","year":"2018","journal-title":"Eur. Heart J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2148","DOI":"10.1056\/NEJMc051946","article-title":"Sildenafil Citrate Therapy for Pulmonary Arterial Hypertension","volume":"353","author":"Ghofrani","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.1056\/NEJMoa1811737","article-title":"Nintedanib plus Sildenafil in Patients with Idiopathic Pulmonary Fibrosis","volume":"379","author":"Kolb","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1016\/j.jacc.2003.10.056","article-title":"Clinical efficacy of sildenafil in primary pulmonary hypertension: A randomized, placebo-controlled, double-blind, crossover study","volume":"43","author":"Sastry","year":"2004","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nrd.2018.168","article-title":"Drug repurposing: Progress, challenges and recommendations","volume":"18","author":"Pushpakom","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1001\/jama.1987.03390100015002","article-title":"AZT (zidovudine) just a step away from FDA approval for AIDS therapy","volume":"257","author":"Marwick","year":"1987","journal-title":"JAMA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1126\/science.1249543","article-title":"How thalidomide works against cancer","volume":"343","author":"Stewart","year":"2014","journal-title":"Science"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/j.sxmr.2019.06.001","article-title":"A Review of Economic Evaluations of Erectile Dysfunction Therapies","volume":"8","author":"Rezaee","year":"2020","journal-title":"Sex. Med. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1203\/00006450-199802000-00002","article-title":"Cyclic-GMP-binding, cyclic-GMP-specific phosphodiesterase (PDE5) gene expression is regulated during rat pulmonary development","volume":"43","author":"Sanchez","year":"1998","journal-title":"Pediatr. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e520","DOI":"10.1097\/MJT.0000000000000766","article-title":"Sildenafil for Pulmonary Arterial Hypertension","volume":"26","author":"Bhogal","year":"2019","journal-title":"Am. J. Ther."},{"key":"ref_39","first-page":"3311","article-title":"Sildenafil inhibits the growth of human colorectal cancer in vitro and in vivo","volume":"5","author":"Mei","year":"2015","journal-title":"Am. J. Cancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"367","DOI":"10.2174\/1871520617666171103100959","article-title":"The Rationale for Repurposing Sildenafil for Lung Cancer Treatment","volume":"18","author":"Keats","year":"2018","journal-title":"Anticancer Agents Med. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"18202","DOI":"10.1073\/pnas.1006965107","article-title":"Sildenafil increases chemotherapeutic efficacy of doxorubicin in prostate cancer and ameliorates cardiac dysfunction","volume":"107","author":"Das","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4399","DOI":"10.18632\/oncotarget.6749","article-title":"Sildenafil (Viagra) sensitizes prostate cancer cells to doxorubicin-mediated apoptosis through CD95","volume":"7","author":"Das","year":"2016","journal-title":"Oncotarget"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1080\/1061186X.2017.1405427","article-title":"Sildenafil citrate improves the delivery and anticancer activity of doxorubicin formulations in a mouse model of breast cancer","volume":"26","author":"Greish","year":"2018","journal-title":"J. Drug Target."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3661","DOI":"10.2147\/DDDT.S107490","article-title":"Sildenafil potentiates the antitumor activity of cisplatin by induction of apoptosis and inhibition of proliferation and angiogenesis","volume":"10","author":"Othman","year":"2016","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.4103\/jcrt.JCRT_675_19","article-title":"Sildenafil enhances cisplatin-induced apoptosis in human breast adenocarcinoma cells","volume":"16","author":"Hassanvand","year":"2020","journal-title":"J. Cancer Res. Ther."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.3389\/fonc.2020.01274","article-title":"Phosphodiesterase Type 5 Inhibitors Synergize Vincristine in Killing Castration-Resistant Prostate Cancer Through Amplifying Mitotic Arrest Signaling","volume":"10","author":"Hsu","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"99451","DOI":"10.18632\/oncotarget.19807","article-title":"Curcumin interacts with sildenafil to kill GI tumor cells via endoplasmic reticulum stress and reactive oxygen\/nitrogen species","volume":"8","author":"Roberts","year":"2017","journal-title":"Oncotarget"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"6862","DOI":"10.1002\/jcp.29580","article-title":"(Curcumin + sildenafil) enhances the efficacy of 5FU and anti-PD1 therapies in vivo","volume":"235","author":"Dent","year":"2020","journal-title":"J. Cell. Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1615\/CritRevEukaryotGeneExpr.2013006875","article-title":"Review of poly (ADP-ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases","volume":"24","author":"Morales","year":"2014","journal-title":"Crit. Rev. Eukaryot. Gene Expr."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Muniyan, S., Rachagani, S., Parte, S., Halder, S., Seshacharyulu, P., Kshirsagar, P., Siddiqui, J.A., Vengoji, R., Rauth, S., and Islam, R. (2020). Sildenafil potentiates the therapeutic efficacy of docetaxel in advanced prostate cancer by stimulating NO-cGMP signaling. Clin. Cancer Res., 26.","DOI":"10.1158\/1078-0432.CCR-20-1569"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1111\/j.1349-7006.2012.02328.x","article-title":"PDE5 inhibitors, sildenafil and vardenafil, reverse multidrug resistance by inhibiting the efflux function of multidrug resistance protein 7 (ATP-binding Cassette C10) transporter","volume":"103","author":"Chen","year":"2012","journal-title":"Cancer Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2516","DOI":"10.1007\/s11095-014-1347-x","article-title":"Co-delivery of Sildenafil (Viagra(\u00ae)) and Crizotinib for synergistic and improved anti-tumoral therapy","volume":"31","author":"Marques","year":"2014","journal-title":"Pharm. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.procbio.2019.06.013","article-title":"Arginyl-glycyl-aspartic acid (RGD) containing nanostructured lipid carrier co-loaded with doxorubicin and sildenafil citrate enhanced anti-cancer effects and overcomes drug resistance","volume":"84","author":"Hajipour","year":"2019","journal-title":"Process. Biochem."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Ji, L., Li, H., Gao, P., Shang, G., Zhang, D.D., Zhang, N., and Jiang, T. (2013). Nrf2 Pathway Regulates Multidrug-Resistance-Associated Protein 1 in Small Cell Lung Cancer. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0063404"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"339","DOI":"10.15171\/apb.2017.041","article-title":"The Different Mechanisms of Cancer Drug Resistance: A Brief Review","volume":"7","author":"Mansoori","year":"2017","journal-title":"Adv. Pharm. Bull."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Di Nicolantonio, F., Mercer, S.J., Knight, L.A., Gabriel, F.G., Whitehouse, P.A., Sharma, S., Fernando, A., Glaysher, S., Di Palma, S., and Johnson, P. (2005). Cancer cell adaptation to chemotherapy. BMC Cancer, 5.","DOI":"10.1186\/1471-2407-5-78"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1186\/1479-7364-3-3-281","article-title":"Human ATP-binding cassette (ABC) transporter family","volume":"3","author":"Vasiliou","year":"2009","journal-title":"Hum. Genom."},{"key":"ref_58","first-page":"641","article-title":"Chemosensitization of solid tumor cells by alteration of their susceptibility to apoptosis","volume":"3","author":"Cree","year":"2002","journal-title":"Curr. Opin. Investig. Drugs"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3829","DOI":"10.1158\/1078-0432.CCR-15-0088","article-title":"Development of Olaparib for BRCA-Deficient Recurrent Epithelial Ovarian Cancer","volume":"21","author":"Tewari","year":"2015","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1023\/A:1012866803188","article-title":"V Overview: ABC transporters and human disease","volume":"33","author":"Gottesman","year":"2001","journal-title":"J. Bioenerg. Biomembr."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3029","DOI":"10.1158\/0008-5472.CAN-10-3820","article-title":"Sildenafil reverses ABCB1- and ABCG2-mediated chemotherapeutic drug resistance","volume":"71","author":"Shi","year":"2011","journal-title":"Cancer Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3735","DOI":"10.1158\/0008-5472.CAN-11-0375","article-title":"Roles of sildenafil in enhancing drug sensitivity in cancer","volume":"71","author":"Shi","year":"2011","journal-title":"Cancer Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1016\/j.rmed.2005.03.026","article-title":"Acute and chronic effects of sildenafil in patients with pulmonary arterial hypertension","volume":"99","author":"Preston","year":"2005","journal-title":"Respir. Med."},{"key":"ref_64","first-page":"4564","article-title":"Vascular permeability and microcirculation of gliomas and mammary carcinomas transplanted in rat and mouse cranial windows","volume":"54","author":"Yuan","year":"1994","journal-title":"Cancer Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/nm0195-27","article-title":"Angiogenesis in cancer, vascular, rheumatoid and other disease","volume":"1","author":"Folkman","year":"1995","journal-title":"Nat. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1016\/S0002-9440(10)65006-7","article-title":"Openings between defective endothelial cells explain tumor vessel leakiness","volume":"156","author":"Hashizume","year":"2000","journal-title":"Am. J. Pathol."},{"key":"ref_67","first-page":"6387","article-title":"A new concept for macromolecular therapeutics in cancer chemotherapy: Mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs","volume":"46","author":"Matsumura","year":"1986","journal-title":"Cancer Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1016\/0959-8049(94)00514-6","article-title":"Influence of molecular weight on passive tumour accumulation of a soluble macromolecular drug carrier","volume":"31A","author":"Seymour","year":"1995","journal-title":"Eur. J. Cancer"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.jconrel.2004.03.027","article-title":"SMA-doxorubicin, a new polymeric micellar drug for effective targeting to solid tumours","volume":"97","author":"Greish","year":"2004","journal-title":"J. Control. Release"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"510","DOI":"10.2745\/dds.22.510","article-title":"SMANCS dynamic therapy for various advanced solid tumors and promising clinical effects","volume":"22","author":"Nagamitsu","year":"2007","journal-title":"Drug Deliv. Syst."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.brainres.2008.06.122","article-title":"PDE5 inhibitors enhance tumor permeability and efficacy of chemotherapy in a rat brain tumor model","volume":"1230","author":"Black","year":"2008","journal-title":"Brain Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"3052","DOI":"10.1039\/D0BM00466A","article-title":"Enhanced nanoparticle accumulation by tumor-acidity-activatable release of sildenafil to induce vasodilation","volume":"8","author":"Zhang","year":"2020","journal-title":"Biomater. Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1111\/cts.12121","article-title":"Sildenafil increases muscle protein synthesis and reduces muscle fatigue","volume":"6","author":"Wiktorowicz","year":"2013","journal-title":"Clin. Transl. Sci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"205","DOI":"10.3816\/CLM.2004.n.029","article-title":"Clinical Responses to Sildenafil in Waldenstrom\u2019s Macroglobulinemia","volume":"5","author":"Treon","year":"2004","journal-title":"Clin. Lymphoma"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1016\/j.jaad.2014.02.005","article-title":"An open-label study to evaluate sildenafil for the treatment of lymphatic malformations","volume":"70","author":"Danial","year":"2014","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Poklepovic, A., Qu, Y., Dickinson, M., Kontos, M.C., Kmieciak, M., Schultz, E., Bandopadhyay, D., Deng, X., and Kukreja, R.C. (2018). Randomized study of doxorubicin-based chemotherapy regimens, with and without sildenafil, with analysis of intermediate cardiac markers. CardioOncology, 4.","DOI":"10.1186\/s40959-018-0033-2"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"4874","DOI":"10.1002\/jcp.27276","article-title":"Neratinib augments the lethality of [regorafenib\u2009+\u2009sildenafil]","volume":"234","author":"Booth","year":"2019","journal-title":"J. Cell. Physiol."}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/11\/6\/585\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:20:01Z","timestamp":1760163601000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/11\/6\/585"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,21]]},"references-count":77,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["jpm11060585"],"URL":"https:\/\/doi.org\/10.3390\/jpm11060585","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints202104.0679.v1","asserted-by":"object"}]},"ISSN":["2075-4426"],"issn-type":[{"value":"2075-4426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,21]]}}}