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Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

Sildenafil in Combination Therapy against Cancer: A Literature Review

Author(s): Rabah Iratni* and Mohammed Akli Ayoub*

Volume 28, Issue 11, 2021

Published on: 30 July, 2020

Page: [2248 - 2259] Pages: 12

DOI: 10.2174/0929867327666200730165338

Price: $65


The concepts of drug repurposing and Sildenafil or blue pill are tightly linked over the years. Indeed, in addition to its initial clinical application as an anti-hypertensive drug in the pulmonary system, Sildenafil is also known for its beneficial effects in erectile dysfunction. Moreover, evidence has been accumulated to support its value in anti-cancer therapy, either alone or in combination with other clinically efficient chemotherapy drugs. In this review, we focused on the old and recent in vitro and in vivo studies demonstrating the cellular and molecular rationale for the application of Sildenafil in combination therapy in various types of cancer. We emphasized on the different molecular targets as well as the different signaling pathways involved in cancer cells. The pro-apoptotic effect of Sildenafil through nitric oxide (NO)/ phosphodiesterase type 5 (PDE5)-dependent manner seems to be one of the most common mechanisms. However, the activation of autophagy, as well as the modulation of the anti-tumor immunity, constitutes the other pathways triggered by Sildenafil. Overall, the studies converged to reveal the complexity of the anti-cancer potential of Sildenafil. Thus, through our review, we aimed to present an updated and simplified picture of such repurposing of Sildenafil in the field of oncology.

Keywords: Sildenafil, drug repurposing, PDE-5 inhibitor, cancer, combination therapy, cancer therapy.

Ashburn, T.T.; Thor, K.B. Drug repositioning: identifying and developing new uses for existing drugs. Nat. Rev. Drug Discov., 2004, 3(8), 673-683.
[] [PMID: 15286734]
Pushpakom, S.; Iorio, F.; Eyers, P.A.; Escott, K.J.; Hopper, S.; Wells, A.; Doig, A.; Guilliams, T.; Latimer, J.; McNamee, C.; Norris, A.; Sanseau, P.; Cavalla, D.; Pirmohamed, M. Drug repurposing: progress, challenges and recommendations. Nat. Rev. Drug Discov., 2019, 18(1), 41-58.
[] [PMID: 30310233]
Langedijk, J.; Mantel-Teeuwisse, A.K.; Slijkerman, D.S.; Schutjens, M-H.D.B. Drug repositioning and repurposing: terminology and definitions in literature. Drug Discov. Today, 2015, 20(8), 1027-1034.
[] [PMID: 25975957]
Jourdan, J-P.; Bureau, R.; Rochais, C.; Dallemagne, P. Drug repositioning: a brief overview. J. Pharm. Pharmacol., 2020, 72(9), 1145-1151.
[] [PMID: 32301512]
Naylor, S.; Schonfeld, J. Therapeutic drug repurposing, repositioning and rescue., Drug Discov. World Spring, 2014, 50-63..
Ghofrani, H.A.; Osterloh, I.H.; Grimminger, F. Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond. Nat. Rev. Drug Discov., 2006, 5(8), 689-702.
[] [PMID: 16883306]
Morales, A.; Gingell, C.; Collins, M.; Wicker, P.A.; Osterloh, I.H. Clinical safety of oral sildenafil citrate (VIAGRA) in the treatment of erectile dysfunction. Int. J. Impot. Res., 1998, 10(2), 69-73.
[] [PMID: 9647940]
Worldwide revenue of Pfizer's Viagra from 2003 to 2019. Available at:; (Accessed date: April 2020)..
Langtry, H.D.; Markham, A. Sildenafil: a review of its use in erectile dysfunction. Drugs, 1999, 57(6), 967-989.
[] [PMID: 10400408]
Corbin, J.D.; Francis, S.H. Cyclic GMP phosphodiesterase-5: target of sildenafil. J. Biol. Chem., 1999, 274(20), 13729-13732.
[] [PMID: 10318772]
Kosier, J.H.; Newton, M.; Smith, D. Sildenafil citrate (Viagra): oral medication for treating erectile dysfunction. Urol. Nurs., 1999, 19(2), 158-160.
[PMID: 10633767]
Krishnappa, P.; Fernandez-Pascual, E.; Carballido, J.; Martinez-Salamanca, J.I. Sildenafil/Viagra in the treatment of premature ejaculation. Int. J. Impot. Res., 2019, 31(2), 65-70.
[] [PMID: 30837718]
Pantziarka, P.; Sukhatme, V.; Crispino, S.; Bouche, G.; Meheus, L.; Sukhatme, V.P. Repurposing drugs in oncology (ReDO)-selective PDE5 inhibitors as anti-cancer agents. Ecancermedicalscience, 2018, 12, 824.
[] [PMID: 29743944]
Das, A.; Durrant, D.; Salloum, F.N.; Xi, L.; Kukreja, R.C. PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer. Pharmacol. Ther., 2015, 147, 12-21.
[] [PMID: 25444755]
Kouvelas, D.; Goulas, A.; Papazisis, G.; Sardeli, C.; Pourzitaki, C. PDE5 inhibitors: in vitro and in vivo pharmacological profile. Curr. Pharm. Des., 2009, 15(30), 3464-3475.
[] [PMID: 19860692]
Keats, T.; Rosengren, R.J.; Ashton, J.C. The rationale for repurposing sildenafil for lung cancer treatment. Anticancer. Agents Med. Chem., 2018, 18(3), 367-374.
[] [PMID: 29110626]
Booth, L.; Roberts, J.L.; Rais, R.; Cutler, R.E. Jr.; Diala, I.; Lalani, A.S.; Hancock, J.F.; Poklepovic, A.; Dent, P. Neratinib augments the lethality of. [regorafenib + sildenafil]. J. Cell. Physiol., 2019, 234(4), 4874-4887.
[] [PMID: 30203445]
Booth, L.; Roberts, J.L.; Poklepovic, A.; Gordon, S.; Dent, P. PDE5 inhibitors enhance the lethality of pemetrexed through inhibition of multiple chaperone proteins and via the actions of cyclic GMP and nitric oxide. Oncotarget, 2017, 8(1), 1449-1468.
[] [PMID: 27903966]
Domankevich, V.; Cohen, A.; Efrati, M.; Schmidt, M.; Rammensee, H-G.; Nair, S.S.; Tewari, A.; Kelson, I.; Keisari, Y. Combining alpha radiation-based brachytherapy with immunomodulators promotes complete tumor regression in mice via tumor-specific long-term immune response. Cancer Immunol. Immunother., 2019, 68(12), 1949-1958.
[] [PMID: 31637474]
Tavallai, M.; Hamed, H.A.; Roberts, J.L.; Cruickshanks, N.; Chuckalovcak, J.; Poklepovic, A.; Booth, L.; Dent, P. Nexavar/Stivarga and viagra interact to kill tumor cells. J. Cell. Physiol., 2015, 230(9), 2281-2298.
[] [PMID: 25704960]
Islam, B.N.; Sharman, S.K.; Hou, Y.; Bridges, A.E.; Singh, N.; Kim, S.; Kolhe, R.; Trillo-Tinoco, J.; Rodriguez, P.C.; Berger, F.G.; Sridhar, S.; Browning, D.D. Sildenafil suppresses inflammation-driven colorectal cancer in mice. Cancer Prev. Res. (Phila.), 2017, 10(7), 377-388.
[] [PMID: 28468928]
Dhayade, S.; Kaesler, S.; Sinnberg, T.; Dobrowinski, H.; Peters, S.; Naumann, U.; Liu, H.; Hunger, R.E.; Thunemann, M.; Biedermann, T.; Schittek, B.; Simon, H.U.; Feil, S.; Feil, R. Sildenafil potentiates a cGMP-dependent pathway to promote melanoma growth. Cell Rep., 2016, 14(11), 2599-2610.
[] [PMID: 26971999]
Loeb, S.; Ventimiglia, E.; Salonia, A.; Folkvaljon, Y.; Stattin, P. Meta-analysis of the association between phosphodiesterase inhibitors (PDE5Is) and risk of melanoma. J. Natl. Cancer Inst., 2017, 109(8)djx086
[] [PMID: 29117385]
Loeb, S.; Folkvaljon, Y.; Lambe, M.; Robinson, D.; Garmo, H.; Ingvar, C.; Stattin, P. Use of phosphodiesterase type 5 inhibitors for erectile dysfunction and risk of malignant melanoma. JAMA, 2015, 313(24), 2449-2455.
[] [PMID: 26103029]
Adjei, A.A. Pharmacology and mechanism of action of pemetrexed. Clin. Lung Cancer, 2004, 5(Suppl. 2), S51-S55.
[] [PMID: 15117425]
Park, J-H.; Lee, Y-R.; So, H-S.; Lee, K-K.; Lee, S-Y.; Moon, S-R.; Jo, H-J.; Lee, S.; Jeong, K.; Kwon, K-B.; Yang, S.H. The role of autophagy induced by pemetrexed in lung adenocarcinoma cells. Oncol. Rep., 2014, 31(5), 2365-2370.
[] [PMID: 24626722]
Booth, L.; Roberts, J.L.; Poklepovic, A.; Dent, P. PDE5 inhibitors enhance the lethality of.[pemetrexed + sorafenib]. Oncotarget, 2017, 8(8), 13464-13475.
[] [PMID: 28088782]
Booth, L.; Roberts, J.L.; Poklepovic, A.; Dent, P. [pemetrexed + sildenafil], via autophagy-dependent HDAC downregulation, enhances the immunotherapy response of NSCLC cells. Cancer Biol. Ther., 2017, 18(9), 705-714.
[] [PMID: 28812434]
Nowicki, T.S.; Hu-Lieskovan, S.; Ribas, A. Mechanisms of resistance to PD-1 and PD-L1 blockade. Cancer J., 2018, 24(1), 47-53.
[] [PMID: 29360728]
Heqing, Y.; Bin, L.; Xuemei, Y.; Linfa, L. The role and mechanism of autophagy in sorafenib targeted cancer therapy. Crit. Rev. Oncol. Hematol., 2016, 100, 137-140.
[] [PMID: 26920575]
Domvri, K.; Zarogoulidis, K.; Zogas, N.; Zarogoulidis, P.; Petanidis, S.; Porpodis, K.; Kioseoglou, E.; Hohenforst-Schmidt, W. Potential synergistic effect of phosphodiesterase inhibitors with chemotherapy in lung cancer. J. Cancer, 2017, 8(18), 3648-3656.
[] [PMID: 29151951]
de Melo-Diogo, D.; Gaspar, V.M.; Costa, E.C.; Moreira, A.F.; Oppolzer, D.; Gallardo, E.; Correia, I.J. Combinatorial delivery of Crizotinib-Palbociclib-Sildenafil using TPGS-PLA micelles for improved cancer treatment. Eur. J. Pharm. Biopharm., 2014, 88(3), 718-729.
[] [PMID: 25308930]
Xie, Y-H.; Chen, Y-X.; Fang, J-Y. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct. Target. Ther., 2020, 5(1), 22.
[] [PMID: 32296018]
Roberts, J.L.; Poklepovic, A.; Booth, L. Curcumin interacts with sildenafil to kill GI tumor cells via endoplasmic reticulum stress and reactive oxygen/nitrogen species. Oncotarget, 2017, 8(59), 99451-99469.
[] [PMID: 29245915]
Zhu, J.; Zhao, B.; Xiong, P.; Wang, C.; Zhang, J.; Tian, X.; Huang, Y. Curcumin induces autophagy via inhibition of yes-associated protein (YAP) in human colon cancer cells. Med. Sci. Monit., 2018, 24, 7035-7042.
[] [PMID: 30281585]
Dent, P.; Booth, L.; Roberts, J.L.; Poklepovic, A.; Hancock, J.F. (Curcumin+sildenafil) enhances the efficacy of 5FU and anti-PD1 therapies in vivo. J. Cell. Physiol., 2020, 235(10), 6862-6874.
[] [PMID: 31985048]
Mei, X-L.; Yang, Y.; Zhang, Y-J.; Li, Y.; Zhao, J-M.; Qiu, J-G.; Zhang, W-J.; Jiang, Q-W.; Xue, Y-Q.; Zheng, D-W.; Chen, Y.; Qin, W.M.; Wei, M.N.; Shi, Z. Sildenafil inhibits the growth of human colorectal cancer in vitro and in vivo. Am. J. Cancer Res., 2015, 5(11), 3311-3324.
[PMID: 26807313]
Booth, L.; Roberts, J.L.; Cruickshanks, N.; Grant, S.; Poklepovic, A.; Dent, P. Regulation of OSU-03012 toxicity by ER stress proteins and ER stress-inducing drugs. Mol. Cancer Ther., 2014, 13(10), 2384-2398.
[] [PMID: 25103559]
Das, A.; Durrant, D.; Mitchell, C.; Mayton, E.; Hoke, N.N.; Salloum, F.N.; Park, M.A.; Qureshi, I.; Lee, R.; Dent, P.; Kukreja, R.C. Sildenafil increases chemotherapeutic efficacy of doxorubicin in prostate cancer and ameliorates cardiac dysfunction. Proc. Natl. Acad. Sci. USA, 2010, 107(42), 18202-18207.
[] [PMID: 20884855]
Das, A.; Durrant, D.; Mitchell, C.; Dent, P.; Batra, S.K.; Kukreja, R.C. Sildenafil (Viagra) sensitizes prostate cancer cells to doxorubicin-mediated apoptosis through CD95. Oncotarget, 2016, 7(4), 4399-4413.
[] [PMID: 26716643]
Poklepovic, A.; Qu, Y.; Dickinson, M.; Kontos, M.C.; Kmieciak, M.; Schultz, E.; Bandopadhyay, D.; Deng, X.; Kukreja, R.C. Randomized study of doxorubicin-based chemotherapy regimens, with and without sildenafil, with analysis of intermediate cardiac markers. Cardiooncology, 2018, 4(1), 7.
[] [PMID: 30221011]
Webb, T.; Carter, J.; Roberts, J.L.; Poklepovic, A.; McGuire, W.P.; Booth, L.; Dent, P. Celecoxib enhances [sorafenib + sildenafil] lethality in cancer cells and reverts platinum chemotherapy resistance. Cancer Biol. Ther., 2015, 16(11), 1660-1670.
[] [PMID: 26417912]
World Health Organization. World Health Statistics 2014 World Health Organization: Geneve, 2014. Available at:. date: April 2020).
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2015. CA Cancer J. Clin., 2015, 65(1), 5-29.
[] [PMID: 25559415]
Di, X.; Gennings, C.; Bear, H.D.; Graham, L.J.; Sheth, C.M.; White, K.L., Jr; Gewirtz, D.A. Influence of the phosphodiesterase-5 inhibitor, sildenafil, on sensitivity to chemotherapy in breast tumor cells. Breast Cancer Res. Treat., 2010, 124(2), 349-360.
[] [PMID: 20155316]
Greish, K.; Fateel, M.; Abdelghany, S.; Rachel, N.; Alimoradi, H.; Bakhiet, M.; Alsaie, A. Sildenafil citrate improves the delivery and anticancer activity of doxorubicin formulations in a mouse model of breast cancer. J. Drug Target., 2018, 26(7), 610-615.
[] [PMID: 29148852]
El-Naa, M.M.; Othman, M.; Younes, S. Sildenafil potentiates the antitumor activity of cisplatin by induction of apoptosis and inhibition of proliferation and angiogenesis. Drug Des. Devel. Ther., 2016, 10, 3661-3672.
[] [PMID: 27895461]
Kaaijk, P.; Schouten-van Meeteren, A.Y.N.; Slotman, B.J.; Kaspers, G.J.L. Past, current and future protocols for combined modality therapy in childhood medulloblastoma. Expert Rev. Anticancer Ther., 2003, 3(1), 79-90.
[] [PMID: 12597352]
Roberts, J.L.; Booth, L.; Conley, A.; Cruickshanks, N.; Malkin, M.; Kukreja, R.C.; Grant, S.; Poklepovic, A.; Dent, P. PDE5 inhibitors enhance the lethality of standard of care chemotherapy in pediatric CNS tumor cells. Cancer Biol. Ther., 2014, 15(6), 758-767.
[] [PMID: 24651037]
Booth, L.; Roberts, J.L.; Cruickshanks, N.; Conley, A.; Durrant, D.E.; Das, A.; Fisher, P.B.; Kukreja, R.C.; Grant, S.; Poklepovic, A.; Dent, P. Phosphodiesterase 5 inhibitors enhance chemotherapy killing in gastrointestinal/genitourinary cancer cells. Mol. Pharmacol., 2014, 85(3), 408-419.
[] [PMID: 24353313]
Shi, Z.; Tiwari, A.K.; Patel, A.S.; Fu, L-W.; Chen, Z-S. Roles of sildenafil in enhancing drug sensitivity in cancer. Cancer Res., 2011, 71(11), 3735-3738.
[] [PMID: 21610107]
Szakács, G.; Paterson, J.K.; Ludwig, J.A.; Booth-Genthe, C.; Gottesman, M.M. Targeting multidrug resistance in cancer. Nat. Rev. Drug Discov., 2006, 5(3), 219-234.
[] [PMID: 16518375]
Fletcher, J.I.; Haber, M.; Henderson, M.J.; Norris, M.D. ABC transporters in cancer: more than just drug efflux pumps. Nat. Rev. Cancer, 2010, 10(2), 147-156.
[] [PMID: 20075923]
Robey, R.W.; Pluchino, K.M.; Hall, M.D.; Fojo, A.T.; Bates, S.E.; Gottesman, M.M. Revisiting the role of ABC transporters in multidrug-resistant cancer. Nat. Rev. Cancer, 2018, 18(7), 452-464.
[] [PMID: 29643473]
Shi, Z.; Tiwari, A.K.; Shukla, S.; Robey, R.W.; Singh, S.; Kim, I-W.; Bates, S.E.; Peng, X.; Abraham, I.; Ambudkar, S.V.; Talele, T.T.; Fu, L.W.; Chen, Z.S. Sildenafil reverses ABCB1- and ABCG2-mediated chemotherapeutic drug resistance. Cancer Res., 2011, 71(8), 3029-3041.
[] [PMID: 21402712]
Chen, J-J.; Sun, Y-L.; Tiwari, A.K.; Xiao, Z-J.; Sodani, K.; Yang, D-H.; Vispute, S.G.; Jiang, W-Q.; Chen, S-D.; Chen, Z-S. PDE5 inhibitors, sildenafil and vardenafil, reverse multidrug resistance by inhibiting the efflux function of multidrug resistance protein 7 (ATP-binding Cassette C10) transporter. Cancer Sci., 2012, 103(8), 1531-1537.
[] [PMID: 22578167]
Ding, P-R.; Tiwari, A.K.; Ohnuma, S.; Lee, J.W.K.K.; An, X.; Dai, C-L.; Lu, Q-S.; Singh, S.; Yang, D-H.; Talele, T.T.; Ambudkar, S.V.; Chen, Z.S. The phosphodiesterase-5 inhibitor vardenafil is a potent inhibitor of ABCB1/P-glycoprotein transporter. PLoS One, 2011, 6(4)e19329
[] [PMID: 21552528]
Lin, F.; Hoogendijk, L.; Buil, L.; Beijnen, J.H.; van Tellingen, O. Sildenafil is not a useful modulator of ABCB1 and ABCG2 mediated drug resistance in vivo. Eur. J. Cancer, 2013, 49(8), 2059-2064.
[] [PMID: 23422148]
Chatterjee, K.; Zhang, J.; Honbo, N.; Karliner, J.S. Doxorubicin cardiomyopathy. Cardiology, 2010, 115(2), 155-162.
[] [PMID: 20016174]
Kalivendi, S.V.; Kotamraju, S.; Zhao, H.; Joseph, J.; Kalyanaraman, B. Doxorubicin-induced apoptosis is associated with increased transcription of endothelial nitric-oxide synthase. Effect of antiapoptotic antioxidants and calcium. J. Biol. Chem., 2001, 276(50), 47266-47276.
[] [PMID: 11579094]
Wang, L.; Ma, W.; Markovich, R.; Chen, J.W.; Wang, P.H. Regulation of cardiomyocyte apoptotic signaling by insulin-like growth factor I. Circ. Res., 1998, 83(5), 516-522.
[] [PMID: 9734474]
Zhao, L.; Zhang, B. Doxorubicin induces cardiotoxicity through upregulation of death receptors mediated apoptosis in cardiomyocytes. Sci. Rep., 2017, 7, 44735.
[] [PMID: 28300219]
Fisher, P.W.; Salloum, F.; Das, A.; Hyder, H.; Kukreja, R.C. Phosphodiesterase-5 inhibition with sildenafil attenuates cardiomyocyte apoptosis and left ventricular dysfunction in a chronic model of doxorubicin cardiotoxicity. Circulation, 2005, 111(13), 1601-1610.
[] [PMID: 15811867]
Sastry, J.; Kellie, S.J. Severe neurotoxicity, ototoxicity and nephrotoxicity following high-dose cisplatin and amifostine. Pediatr. Hematol. Oncol., 2005, 22(5), 441-445.
[] [PMID: 16020136]
Volarevic, V.; Djokovic, B.; Jankovic, M.G.; Harrell, C.R.; Fellabaum, C.; Djonov, V.; Arsenijevic, N. Molecular mechanisms of cisplatin-induced nephrotoxicity: a balance on the knife edge between renoprotection and tumor toxicity. J. Biomed. Sci., 2019, 26(1), 25.
[] [PMID: 30866950]
Ali, B.H.; Abdelrahman, A.M.; Al-Salam, S.; Sudhadevi, M.; AlMahruqi, A.S.; Al-Husseni, I.S.; Beegam, S.; Dhanasekaran, S.; Nemmar, A.; Al-Moundhri, M. The effect of sildenafil on cisplatin nephrotoxicity in rats. Basic Clin. Pharmacol. Toxicol., 2011, 109(4), 300-308.
[] [PMID: 21575139]
Lee, K.W.; Jeong, J.Y.; Lim, B.J.; Chang, Y.K.; Lee, S.J.; Na, K.R.; Shin, Y.T.; Choi, D.E. Sildenafil attenuates renal injury in an experimental model of rat cisplatin-induced nephrotoxicity. Toxicology, 2009, 257(3), 137-143.
[] [PMID: 19152827]
Morgan, S.; Lopes, F.; Gourley, C.; Anderson, R.A.; Spears, N. Cisplatin and doxorubicin induce distinct mechanisms of ovarian follicle loss; imatinib provides selective protection only against cisplatin. PLoS One, 2013, 8(7)e70117
[] [PMID: 23922929]
Taskin, M.I.; Yay, A.; Adali, E.; Balcioglu, E.; Inceboz, U. Protective effects of sildenafil citrate administration on cisplatin-induced ovarian damage in rats. Gynecol. Endocrinol., 2015, 31(4), 272-277.
[] [PMID: 25483005]

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