{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T23:28:08Z","timestamp":1790638088362,"version":"4.1.0"},"reference-count":105,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,2,26]],"date-time":"2021-02-26T00:00:00Z","timestamp":1614297600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013394","name":"Instituto Nacional de Medicina Gen\u00f3mica","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013394","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>The use of already-approved drugs to treat new or alternative diseases has proved to be beneficial in medicine, because it reduces both drug development costs and timelines. Most drugs can be used to treat different illnesses, due their mechanisms of action are not restricted to one molecular target, organ or illness. Diverging from its original intent offers an opportunity to repurpose previously approved drugs to treat other ailments. This is the case of sildenafil (Viagra), a phosphodiesterase-5 (PDE5) inhibitor, which was originally designed to treat systemic hypertension and angina but is currently commercialized as erectile dysfunction treatment. Sildenafil, tadalafil, and vardenafil are PDE5 inhibitors and potent vasodilators, that extend the physiological effects of nitric oxide and cyclic guanosine monophosphate (cGMP) signaling. Although most of the biological implications of these signaling regulations remain unknown, they offer a large therapeutic potential for several diseases. In addition, some PDE5 inhibitors\u2019 molecular effects seem to play a key role in different illnesses such as kidney disease, diabetes mellitus, and cancer. In this review, we discuss the molecular effects of PDE5 inhibitors and their therapeutic repurposing in different types of cancer.<\/jats:p>","DOI":"10.3389\/fonc.2021.627229","type":"journal-article","created":{"date-parts":[[2021,2,26]],"date-time":"2021-02-26T06:54:04Z","timestamp":1614322444000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":61,"title":["New Approaches in Oncology for Repositioning Drugs: The Case of PDE5 Inhibitor Sildenafil"],"prefix":"10.3389","volume":"11","author":[{"given":"Marian","family":"Cruz-Burgos","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Losada-Garcia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos D.","family":"Cruz-Hern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio A.","family":"Cort\u00e9s-Ram\u00edrez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignacio","family":"Camacho-Arroyo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Gonzalez-Covarrubias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Morales-Pacheco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha I.","family":"Trujillo-Bornios","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauricio","family":"Rodr\u00edguez-Dorantes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,2,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1468","article-title":"Drug repositioning: Identifying and developing new uses for existing drugs","volume":"3","author":"Ashburn","year":"2004","journal-title":"Nat Rev Drug Discov"},{"key":"B2","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.phrs.2017.07.013","article-title":"Drug repurposing in cancer","volume":"124","author":"Sleire","year":"2017","journal-title":"Pharmacol Res"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2017.00273","article-title":"Giving drugs a second chance: Overcoming regulatory and financial hurdles in repurposing approved drugs as cancer therapeutics","volume":"7","author":"Hernandez","year":"2017","journal-title":"Front Oncol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"442","DOI":"10.3332\/ecancer.2014.442","article-title":"The Repurposing Drugs in Oncology (ReDO) Project","author":"Pantziarka","year":"2014","journal-title":"Ecancermedicalscience"},{"key":"B5","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1177\/2040620711413165","article-title":"The rise, fall and subsequent triumph of thalidomide: lessons learned in drug development","volume":"2","author":"Rehman","year":"2011","journal-title":"Ther Adv Hematol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1586\/14737140.5.5.759","article-title":"Thalidomide and dexamethasone: therapy for multiple myeloma","volume":"5","author":"Kumar","year":"2005","journal-title":"Expert Rev Anticancer Ther"},{"key":"B7","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1186\/s12885-017-3594-9","article-title":"New use of low-dose aspirin and risk of colorectal cancer by stage at diagnosis: a nested case-control study in UK general practice","volume":"17","author":"Garc\u00eda Rodr\u00edguez","year":"2017","journal-title":"BMC Cancer"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcz050","article-title":"11\u03b2-Hydroxysteroid dehydrogenase type 1 inhibition in idiopathic intracranial hypertension: a double-blind randomized controlled trial","volume":"2","author":"Markey","year":"2020","journal-title":"Brain Commun"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-2641","article-title":"Pre-operative \u03b2 -blockade with propranolol reduces biomarkers of metastasis in breast cancerx202F;: a Phase II randomized trial","volume":"26","author":"Hiller","year":"2019","journal-title":"Clin Cancer Res"},{"key":"B10","doi-asserted-by":"publisher","first-page":"680","DOI":"10.3332\/ecancer.2016.680","article-title":"Repurposing Drugs in Oncology (ReDO)-Propranolol as an anti-cancer agent","volume":"10","author":"Pantziarka","year":"2016","journal-title":"Ecancermedicalscience"},{"key":"B11","doi-asserted-by":"publisher","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":"B12","doi-asserted-by":"publisher","first-page":"91","DOI":"10.3233\/ADR-200166","article-title":"Sildenafil for the Treatment of Alzheimer\u2019s Disease: A Systematic Review","volume":"4","author":"Sanders","year":"2020","journal-title":"J Alzheimers Dis Rep"},{"key":"B13","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1111\/j.1476-5381.1986.tb10191.x","article-title":"Pilot experiments on the actions of drugs injected into the human corpus cavernosum penis","volume":"87","author":"Brindley","year":"1986","journal-title":"Br J Pharmacol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5347(17)44172-3","article-title":"Intracavernous self-injection with phentolamine and papaverine for the treatment of impotence","volume":"137","author":"Gasser","year":"1987","journal-title":"J Urol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1111\/j.1368-5031.2005.00578.x","article-title":"Past, present, and future: A 7-year update of Viagra\u00ae (sildenafil citrate)","volume":"59","author":"Jackson","year":"2005","journal-title":"Int J Clin Pract"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/S0377-1237(01)80090-3","article-title":"VIAGRAx202F;: IS IT A WONDER DRUGx202F;","volume":"57","author":"Saini","year":"2001","journal-title":"Med J Armed Forces India"},{"key":"B17","first-page":"S26","article-title":"Four-year review of sildenafil citrate","author":"McCullough","year":"2002","journal-title":"Rev Urol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1111\/j.1743-6109.2006.00270.x","article-title":"Nitric oxide in the penis - Science and therapeutic implications from erectile dysfunction to priapism","volume":"3","author":"Burnett","year":"2006","journal-title":"J Sex Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1126\/science.1378650","article-title":"Nitric oxide: A physiologic mediator of penile erection","volume":"257","author":"Burnett","year":"1992","journal-title":"Science (80- )"},{"key":"B20","doi-asserted-by":"publisher","first-page":"3C","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":"B21","volume-title":"VIAGRA (sildenafil citrate) label","year":"2010"},{"key":"B22","doi-asserted-by":"publisher","first-page":"824","DOI":"10.3332\/ecancer.2018.824","article-title":"Repurposing drugs in oncology (ReDO)-selective PDE5 inhibitors as anti-cancer agents","volume":"12","author":"Pantziarka","year":"2018","journal-title":"Ecancermedicalscience"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-410X.2006.06501.x","article-title":"Pre-clinical evidence for the use of phosphodiesterase-5 inhibitors for treating benign prostatic hyperplasia and lower urinary tract symptoms","volume":"98","author":"Tinel","year":"2006","journal-title":"BJU Int"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-410X.2006.05955.x","article-title":"Effects of long-term vardenafil treatment on the development of fibrotic plaques in a rat model of Peyronie\u2019s disease","volume":"97","author":"Ferrini","year":"2006","journal-title":"BJU Int"},{"key":"B25","article-title":"Modulatory effect of sildenafil in diabetes and electroconvulsive shock-induced cognitive dysfunction in rats","volume":"58","author":"Patil","year":"2006","journal-title":"Pharmacol Rep"},{"key":"B26","doi-asserted-by":"publisher","first-page":"5S","DOI":"10.1046\/j.0306-5251.2001.00027.x","article-title":"Pharmacokinetics of sildenafil citrate after single oral doses in healthy male subjects: Absolute bioavailability, food effects and dose proportionality","volume":"53","author":"Nichols","year":"2002","journal-title":"Br J Clin Pharmacol Suppl"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ijir.3901522","article-title":"The role of pharmacokinetics and pharmacodynamics in phosphodiesterase-5 inhibitor therapy","volume":"19","author":"Mehrotra","year":"2007","journal-title":"Int J Impot Res"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.107.162511","article-title":"Phosphodiesterase type 5: Expanding roles in cardiovascular regulation","volume":"101","author":"Kass","year":"2007","journal-title":"Circ Res"},{"key":"B29","unstructured":"Clinical Annotation for rs5443 (GNB3); sildenafil; Erectile Dysfunction (level 2B Efficacy)2018"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1097\/01.ju.0000058369.72348.ba","article-title":"Sildenafil response is influenced by the G protein \u03b23 subunit GNB3 C825T polymorphism: A pilot study","volume":"169","author":"Sperling","year":"2003","journal-title":"J Urol"},{"key":"B31","unstructured":"(IARC) IA for R on C Cancer Today\n            FerlayJ\n            ErvikM\n            LamF"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.21837","article-title":"Phosphodiesterase type 5 and cancers: Progress and challenges","volume":"8","author":"Barone","year":"2017","journal-title":"Oncotarget"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1740","DOI":"10.3390\/cancers11111740","article-title":"Phosphodiesterase 5 (PDE5) is highly expressed in cancer-associated fibroblasts and enhances breast tumor progression","volume":"11","author":"Catalano","year":"2019","journal-title":"Cancers (Basel)"},{"key":"B34","doi-asserted-by":"publisher","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J Clin"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-13-0048","article-title":"Sulindac selectively inhibits colon tumor cell growth by activating the cGMP\/PKG pathway to suppress wnt\/\u03b2-catenin signaling","volume":"12","author":"Li","year":"2013","journal-title":"Mol Cancer Ther"},{"key":"B36","doi-asserted-by":"publisher","first-page":"e0125518","DOI":"10.1371\/journal.pone.0125518","article-title":"Elevation of soluble guanylate cyclase suppresses proliferation and survival of human breast cancer cells","volume":"10","author":"Wen","year":"2015","journal-title":"PloS One"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2019.01.027","article-title":"Propranolol selectively inhibits cervical cancer cell growth by suppressing the cGMP\/PKG pathway","volume":"111","author":"Gong","year":"2019","journal-title":"BioMed Pharmacother"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2011.08260.x","article-title":"Cyclic GMP induced apoptosis via protein kinase G in oestrogen receptor-positive and -negative breast cancer cell lines","volume":"278","author":"Fallahian","year":"2011","journal-title":"FEBS J"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.7555\/JBR.31.20160133","article-title":"The interaction between the Wnt\/\u03b2-catenin signaling cascade and PKG activation in cancer","volume":"31","author":"Lee","year":"2017","journal-title":"J Biomed Res"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-09-0758","article-title":"Sulindac sulfide selectively inhibits growth and induces apoptosis of human breast tumor cells by phosphodiesterase 5 inhibition, elevation of cyclic GMP, and activation of protein kinase G","volume":"8","author":"Tinsley","year":"2009","journal-title":"Mol Cancer Ther"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1158\/1940-6207.CAPR-11-0095","article-title":"Inhibition of PDE5 by sulindac sulfide selectively induces apoptosis and attenuates oncogenic Wnt\/\u03b2-catenin-mediated transcription in human breast tumor cells","volume":"4","author":"Tinsley","year":"2011","journal-title":"Cancer Prev Res"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgaa001","article-title":"Sildenafil triggers tumor lethality through altered expression of HSP90 and degradation of PKD2","volume":"41","author":"Chen","year":"2020","journal-title":"Carcinogenesis"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.arcmed.2012.08.006","article-title":"Evaluation of PDE5 and PDE9 Expression in Benign and Malignant Breast Tumors","volume":"43","author":"Karami-Tehrani","year":"2012","journal-title":"Arch Med Res"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-1900","article-title":"Expression and function of phosphodiesterase type 5 in human breast cancer cell lines and tissues: Implications for targeted therapy","volume":"22","author":"Catalano","year":"2016","journal-title":"Clin Cancer Res"},{"key":"B45","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1038\/s41419-017-0202-5","article-title":"PDE5 inhibition eliminates cancer stem cells via induction of PKA signaling","volume":"9","author":"Klutzny","year":"2018","journal-title":"Cell Death Dis"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2016.09.003","article-title":"Effect of sildenafil on human aromatase activity: From in vitro structural analysis to catalysis and inhibition in cells","volume":"165","author":"Baravalle","year":"2017","journal-title":"J Steroid Biochem Mol Biol"},{"key":"B47","doi-asserted-by":"publisher","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":"B48","doi-asserted-by":"publisher","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":"El-Naa","year":"2016","journal-title":"Drug Des Devel Ther"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-010-0765-7","article-title":"Influence of the phosphodiesterase-5 inhibitor, sildenafil, on sensitivity to chemotherapy in breast tumor cells","volume":"124","author":"Di","year":"2010","journal-title":"Breast Cancer Res Treat"},{"key":"B50","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s40959-018-0033-2","article-title":"Randomized study of doxorubicin-based chemotherapy regimens, with and without sildenafil, with analysis of intermediate cardiac markers","volume":"4","author":"Poklepovic","year":"2018","journal-title":"Cardiooncology"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.2174\/156802607779941198","article-title":"The novel functions of cGMP-specific phosphodiesterase 5 and its inhibitors in carcinoma cells and pulmonary\/cardiovascular vessels","volume":"7","author":"Zhu","year":"2007","journal-title":"Curr Top Med Chem"},{"key":"B52","doi-asserted-by":"publisher","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":"B53","doi-asserted-by":"publisher","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":"B54","doi-asserted-by":"publisher","DOI":"10.1007\/s00345-012-0848-7","article-title":"Potential therapeutic applications of phosphodiesterase inhibition in prostate cancer","volume":"31","author":"Hamilton","year":"2013","journal-title":"World J Urol"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2018.00681","article-title":"Phosphodiesterase type 5 (PDE5) inhibitors sensitize topoisomerase II inhibitors in killing prostate cancer through PDE5-independent impairment of HR and NHEJ DNA repair systems","author":"Chang","year":"2019","journal-title":"Front Oncol"},{"key":"B56","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/S0149-2918(01)80027-8","article-title":"Sildenafil citrate: A therapeutic update","volume":"23","author":"Boyce","year":"2001","journal-title":"Clin Ther"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1097\/01.ju.0000164286.47518.1e","article-title":"The efficacy of sildenafil citrate following radiation therapy for prostate cancer: Temporal considerations","volume":"174","author":"Ohebshalom","year":"2005","journal-title":"J Urol"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1111\/j.1743-6109.2008.01170.x","article-title":"Predictors of response to sildenafil citrate following radiation therapy for prostate cancer","volume":"6","author":"Teloken","year":"2009","journal-title":"J Sex Med"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1007\/s00345-016-1777-7","article-title":"Clinical efficacy of combination therapy with an alpha blocker and low-dose sildenafil on post-therapy lower urinary tract symptoms after low-dose-rate brachytherapy for prostate cancer","volume":"34","author":"Yu","year":"2016","journal-title":"World J Urol"},{"key":"B60","doi-asserted-by":"publisher","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":"B61","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2013.07.041","article-title":"Phosphodiesterase 5 inhibitor acts as a potent agent sensitizing acute myeloid leukemia cells to 67-kDa laminin receptor-dependent apoptosis","volume":"587","author":"Kumazoe","year":"2013","journal-title":"FEBS Lett"},{"key":"B62","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.canlet.2016.05.010","article-title":"Phosphodiesterase 5\/protein kinase G signal governs stemness of prostate cancer stem cells through Hippo pathway","volume":"378","author":"Liu","year":"2016","journal-title":"Cancer Lett"},{"key":"B63","doi-asserted-by":"publisher","first-page":"100797","DOI":"10.1016\/j.tranon.2020.100797","article-title":"Prostate Cancer Cell Phenotypes Remain Stable Following PDE5 Inhibition in the Clinically Relevant Range","volume":"13","author":"Hankey","year":"2020","journal-title":"Transl Oncol"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-019-0730-9","article-title":"TMPRSS2-ERG activates NO-cGMP signaling in prostate cancer cells","volume":"38","author":"Zhou","year":"2019","journal-title":"Oncogene"},{"key":"B65","doi-asserted-by":"publisher","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":"B66","doi-asserted-by":"publisher","DOI":"10.1891\/9780826121646.0002","article-title":"Cancer statistics, 2018","volume":"7","author":"Siegel","year":"2018","journal-title":"CA Cancer J Clin"},{"key":"B67","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21590","article-title":"Cancer Facts & Figures 2020","volume":"70","year":"2020","journal-title":"CA Cancer J Clin"},{"key":"B68","article-title":"Longitudinal Adherence to Colorectal Cancer Screening Guidelines","volume":"22","author":"Cyhaniuk","year":"2016","journal-title":"Am J Manag Care"},{"key":"B69","article-title":"Colon Cancer Treatment (PDQ\u00ae): Health Professional Version","author":"Bethesda","year":"2020","journal-title":"PDQ Cancer Information Summaries"},{"key":"B70","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1038\/s41392-020-0116-z","article-title":"Comprehensive review of targeted therapy for colorectal cancer","volume":"5","author":"Xie","year":"2020","journal-title":"Signal Transduct Target Ther"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2017-2222","article-title":"Sildenafil suppresses inflammation-driven colorectal cancer in mice","volume":"10","author":"Islam","year":"2017","journal-title":"Cancer Prev Res"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.14309\/ctg.0000000000000173","article-title":"The Association Between Phosphodiesterase-5 Inhibitors and Colorectal Cancer in a National Cohort of Patients","volume":"11","author":"Sutton","year":"2020","journal-title":"Clin Transl Gastroenterol"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.27276","article-title":"Neratinib augments the lethality of [regorafenib + sildenafil]","volume":"234","author":"Booth","year":"2019","journal-title":"J Cell Physiol"},{"key":"B74","doi-asserted-by":"publisher","first-page":"3593","DOI":"10.1200\/JCO.2020.38.15_suppl.3593","article-title":"Phase I study of regorafenib and sildenafil in advanced solid tumors","volume":"38","author":"Poklepovic","year":"2020","journal-title":"J Clin Oncol"},{"key":"B75","article-title":"Exisulind induction of apoptosis involves guanosine 3\u2019,5\u2019-cyclic monophosphate phosphodiesterase inhibition, protein kinase G activation, and attenuated \u03b2-catenin","volume":"60","author":"Thompson","year":"2000","journal-title":"Cancer Res"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.18632\/aging.101545","article-title":"Phosphodiesterase-5 inhibitors for colon cancer chemoprevention","volume":"10","author":"Islam","year":"2018","journal-title":"Aging (Albany NY)"},{"key":"B77","doi-asserted-by":"publisher","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":"B78","doi-asserted-by":"publisher","first-page":"3648","DOI":"10.7150\/jca.21783","article-title":"Potential synergistic effect of phosphodiesterase inhibitors with chemotherapy in lung cancer","volume":"8","author":"Domvri","year":"2017","journal-title":"J Cancer"},{"key":"B79","doi-asserted-by":"publisher","first-page":"87","DOI":"10.3322\/caac.21262","article-title":"Global cancer statistics, 2012","volume":"65","author":"Torre","year":"2015","journal-title":"CA Cancer J Clin"},{"key":"B80","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.pharmthera.2014.10.003","article-title":"PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer","volume":"147","author":"Das","year":"2015","journal-title":"Pharmacol Ther"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2018.03.046","article-title":"Inhibitors of phosphodiesterase as cancer therapeutics","volume":"150","author":"Peng","year":"2018","journal-title":"Eur J Med Chem"},{"key":"B82","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1007\/s11095-013-1134-0","article-title":"Pharmacological modulation of cytotoxicity and cellular uptake of anti-cancer drugs by PDE5 inhibitors in lung cancer cells","volume":"31","author":"Li","year":"2014","journal-title":"Pharm Res"},{"key":"B83","doi-asserted-by":"publisher","first-page":"S0360-3016(20)3456-0","DOI":"10.1016\/j.ijrobp.2020.11.038","article-title":"Polymorphonuclear-MDSCs facilitate tumor regrowth after radiation by suppressing CD8+ T cells","author":"Zhang","year":"2021","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"B84","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1007\/s11060-014-1690-0","article-title":"Phosphodiesterase type 5 inhibitor Tadalafil increases Rituximab treatment efficacy in a mouse brain lymphoma model","volume":"122","author":"Wang","year":"2015","journal-title":"J Neurooncol"},{"key":"B85","doi-asserted-by":"publisher","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":"B86","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0010108","article-title":"Phosphodiesterase type 5 inhibitors increase herceptin transport and treatment efficacy in mouse metastatic brain tumor models","volume":"5","author":"Hu","year":"2010","journal-title":"PloS One"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.14656","article-title":"Type 5 phosphodiesterase regulates glioblastoma multiforme aggressiveness and clinical outcome","volume":"8","author":"Cesarini","year":"2017","journal-title":"Oncotarget"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2015.10.024","article-title":"The cyclic GMP\/protein kinase G pathway as a therapeutic target in head and neck squamous cell carcinoma","volume":"370","author":"Tuttle","year":"2016","journal-title":"Cancer Lett"},{"key":"B89","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1158\/1078-0432.CCR-14-1711","article-title":"Tadalafil reduces myeloid-derived suppressor cells and regulatory t cells and promotes tumor immunity in patients with head and neck squamous cell carcinoma","author":"Weed","year":"2015","journal-title":"Clin Cancer Res"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-14-1716","article-title":"Tadalafil augments tumor specific immunity in patients with head and neck squamous cell carcinoma","volume":"21","author":"Califano","year":"2015","journal-title":"Clin Cancer Res"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01206","article-title":"The Reversal of Immune Exclusion Mediated by Tadalafil and an Anti-tumor Vaccine Also Induces PDL1 Upregulation in Recurrent Head and Neck Squamous Cell Carcinoma: Interim Analysis of a Phase I Clinical Trial","volume":"10","author":"Weed","year":"2019","journal-title":"Front Immunol"},{"key":"B92","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1159\/000447076","article-title":"Leukemia","volume":"43","author":"Juliusson","year":"2016","journal-title":"Prog Tumor Res"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0701688","article-title":"Phosphodiesterase profile of human B lymphocytes from normal and atopic donors and the effects of PDE inhibition on B cell proliferation","volume":"123","author":"Gantner","year":"1998","journal-title":"Br J Pharmacol"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-01-0075","article-title":"Sildenafil and vardenafil, types 5 and 6 phosphodiesterase inhibitors, induce caspase-dependent apoptosis of B-chronic lymphocytic leukemia cells","volume":"101","author":"Sarfati","year":"2003","journal-title":"Blood"},{"key":"B95","doi-asserted-by":"publisher","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":"B96","doi-asserted-by":"publisher","first-page":"2858","DOI":"10.1038\/s41467-020-15546-9","article-title":"Pre-clinical modeling of cutaneous melanoma","volume":"11","author":"Rebecca","year":"2020","journal-title":"Nat Commun"},{"key":"B97","doi-asserted-by":"publisher","first-page":"6892","DOI":"10.1038\/nature00766","article-title":"Mutations of the BRAF gene in human cancer","volume":"417","author":"Davies","year":"2002","journal-title":"Nature"},{"key":"B98","article-title":"Detection of Mutations in the Mitogen-Activated Protein Kinase Pathway in Human Melanoma","volume":"9","author":"Alsina","year":"2003","journal-title":"Clin Cancer Res"},{"key":"B99","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.ccr.2010.10.029","article-title":"Oncogenic BRAF induces melanoma cell invasion by downregulating the cGMP-specific phosphodiesterase PDE5A","volume":"19","author":"Arozarena","year":"2011","journal-title":"Cancer Cell"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1001\/jamainternmed.2014.594","article-title":"Sildenafil use and increased risk of incident melanoma in US men: A prospective cohort study","volume":"174","author":"Li","year":"2014","journal-title":"JAMA Intern Med"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djx086","article-title":"Meta-Analysis of the Association between Phosphodiesterase Inhibitors (PDE5Is) and Risk of Melanoma","volume":"109","author":"Loeb","year":"2017","journal-title":"J Natl Cancer Inst"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2018.10.040","article-title":"Targeting the crosstalk between cytokine-induced killer cells and myeloid-derived suppressor cells in hepatocellular carcinoma","volume":"70","author":"Yu","year":"2019","journal-title":"J Hepatol"},{"key":"B103","article-title":"Exisulind, a novel proapoptotic drug, inhibits rat urinary bladder tumorigenesis","volume":"61","author":"Piazza","year":"2001","journal-title":"Cancer Res"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejso.2017.08.010","article-title":"Perioperative therapies \u2013 Enhancing the impact of cancer surgery with repurposed drugs","author":"Pantziarka","year":"2017","journal-title":"Eur J Surg Oncol"},{"key":"B105","doi-asserted-by":"publisher","first-page":"e1431082","DOI":"10.1080\/2162402X.2018.1431082","article-title":"Phosphodiesterase-5 inhibition reduces postoperative metastatic disease by targeting surgery-induced myeloid derived suppressor cell-dependent inhibition of Natural Killer cell cytotoxicity","volume":"7","author":"Tai","year":"2018","journal-title":"Oncoimmunology"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2021.627229\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,26]],"date-time":"2021-02-26T06:54:15Z","timestamp":1614322455000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2021.627229\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,26]]},"references-count":105,"alternative-id":["10.3389\/fonc.2021.627229"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2021.627229","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,26]]},"article-number":"627229"}}