Sildenafil Inhibits the Growth of Human Colorectal Cancer in Vitro and in Vivo

Overview

Journal Am J Cancer Res

Specialty Oncology

Date 2016 Jan 26

PMID 26807313

Citations 50

Authors

Xiao-Long Mei

Yang Yang

Yao-Jun Zhang

Yong Li

Jin-Ming Zhao

Jian-Ge Qiu

Wen-Ji Zhang

Qi-Wei Jiang

You-Qiu Xue

Di-Wei Zheng

Yao Chen

Wu-Ming Qin

Meng-Ning Wei

Zhi Shi

Affiliations

Soon will be listed here.

Abstract

Colorectal cancer is the third most common human cancer with frequent overexpression of the cGMP-specific phosphodiesterase 5 (PDE5). In the present study, we investigated that the anticancer effect of sildenafil on human colorectal cancer in vitro and in vivo, which is a potent and selective inhibitor of PDE5 for the treatment of erectile dysfunction and pulmonary arterial hypertension in the clinic. Sildenafil significantly induced cell growth inhibition, cell cycle arrest and apoptosis of human colorectal cancer with increased intracellular reactive oxidative specie (ROS) levels, which were accompanied by obvious alterations of related proteins such as CDKs, Cyclins and PARP etc. Pretreatment with ROS scavenger N-acetyl-L-cysteine could reverse sildenafil-induced ROS accumulation and cell apoptosis. Inhibition of the activity of protein kinase G with KT-5823 could enhance sildenafil-induced apoptosis. Furthermore, sildenafil caused the reduction of xenograft models of human colorectal cancer in nude mice. Overall, these findings suggest that sildenafil has the potential to be used for treatment of human colorectal cancer.

Citing Articles

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References

Carson C, Lue T . Phosphodiesterase type 5 inhibitors for erectile dysfunction. BJU Int. 2005; 96(3):257-80. DOI: 10.1111/j.1464-410X.2005.05614.x. View

Cunningham D, Atkin W, Lenz H, Lynch H, Minsky B, Nordlinger B . Colorectal cancer. Lancet. 2010; 375(9719):1030-47. DOI: 10.1016/S0140-6736(10)60353-4. View

Li J, Ouyang Y, Zhang X, Zhou W, Wang F, Huang Z . Effect of HM910, a novel camptothecin derivative, on the inhibition of multiple myeloma cell growth in vitro and in vivo. Am J Cancer Res. 2015; 5(3):1000-16. PMC: 4449431. View

Reffelmann T, Kloner R . Therapeutic potential of phosphodiesterase 5 inhibition for cardiovascular disease. Circulation. 2003; 108(2):239-44. DOI: 10.1161/01.CIR.0000081166.87607.E2. View

Tinsley H, Gary B, Keeton A, Zhang W, Abadi A, Reynolds R . 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. Mol Cancer Ther. 2009; 8(12):3331-40. PMC: 2805153. DOI: 10.1158/1535-7163.MCT-09-0758. View

Whitt J, Li N, Tinsley H, Chen X, Zhang W, Li Y . A novel sulindac derivative that potently suppresses colon tumor cell growth by inhibiting cGMP phosphodiesterase and β-catenin transcriptional activity. Cancer Prev Res (Phila). 2012; 5(6):822-33. PMC: 3546530. DOI: 10.1158/1940-6207.CAPR-11-0559. View

de Melo-Diogo D, Gaspar V, Costa E, Moreira A, Oppolzer D, Gallardo E . Combinatorial delivery of Crizotinib-Palbociclib-Sildenafil using TPGS-PLA micelles for improved cancer treatment. Eur J Pharm Biopharm. 2014; 88(3):718-29. DOI: 10.1016/j.ejpb.2014.09.013. View

Tinsley H, Gary B, Thaiparambil J, Li N, Lu W, Li Y . Colon tumor cell growth-inhibitory activity of sulindac sulfide and other nonsteroidal anti-inflammatory drugs is associated with phosphodiesterase 5 inhibition. Cancer Prev Res (Phila). 2010; 3(10):1303-13. PMC: 2955813. DOI: 10.1158/1940-6207.CAPR-10-0030. View

Sarfati M, Mateo V, Baudet S, Rubio M, Fernandez C, Davi F . Sildenafil and vardenafil, types 5 and 6 phosphodiesterase inhibitors, induce caspase-dependent apoptosis of B-chronic lymphocytic leukemia cells. Blood. 2002; 101(1):265-9. DOI: 10.1182/blood-2002-01-0075. View

10.

Siegel R, DeSantis C, Jemal A . Colorectal cancer statistics, 2014. CA Cancer J Clin. 2014; 64(2):104-17. DOI: 10.3322/caac.21220. View

11.

Shi Z, Li Z, Li Z, Cheng K, Du Y, Fu H . Cables1 controls p21/Cip1 protein stability by antagonizing proteasome subunit alpha type 3. Oncogene. 2014; 34(19):2538-45. PMC: 4617825. DOI: 10.1038/onc.2014.171. View

12.

Booth L, Roberts J, Cruickshanks N, Tavallai S, Webb T, Samuel P . PDE5 inhibitors enhance celecoxib killing in multiple tumor types. J Cell Physiol. 2014; 230(5):1115-27. PMC: 4398314. DOI: 10.1002/jcp.24843. View

13.

Whitehead C, Earle K, Fetter J, Xu S, Hartman T, Chan D . Exisulind-induced apoptosis in a non-small cell lung cancer orthotopic lung tumor model augments docetaxel treatment and contributes to increased survival. Mol Cancer Ther. 2003; 2(5):479-88. View

14.

Chen X, Xie F, Zhu X, Lin F, Pan S, Gong L . Cyclin-dependent kinase inhibitor dinaciclib potently synergizes with cisplatin in preclinical models of ovarian cancer. Oncotarget. 2015; 6(17):14926-39. PMC: 4558126. DOI: 10.18632/oncotarget.3717. View

15.

Zhu B, Strada S . The novel functions of cGMP-specific phosphodiesterase 5 and its inhibitors in carcinoma cells and pulmonary/cardiovascular vessels. Curr Top Med Chem. 2007; 7(4):437-54. DOI: 10.2174/156802607779941198. View

16.

Tinsley H, Gary B, Keeton A, Lu W, Li Y, Piazza G . Inhibition of PDE5 by sulindac sulfide selectively induces apoptosis and attenuates oncogenic Wnt/β-catenin-mediated transcription in human breast tumor cells. Cancer Prev Res (Phila). 2011; 4(8):1275-84. PMC: 3151326. DOI: 10.1158/1940-6207.CAPR-11-0095. View

17.

Eggen T, Sager G, Berg T, Nergaard B, Moe B, Orbo A . Increased gene expression of the ABCC5 transporter without distinct changes in the expression of PDE5 in human cervical cancer cells during growth. Anticancer Res. 2012; 32(8):3055-61. View

18.

Mohamed H, Girgis N, Wilcken R, Bauer M, Tinsley H, Gary B . Synthesis and molecular modeling of novel tetrahydro-β-carboline derivatives with phosphodiesterase 5 inhibitory and anticancer properties. J Med Chem. 2010; 54(2):495-509. PMC: 4994518. DOI: 10.1021/jm100842v. View

19.

Di X, Gennings C, Bear H, Graham L, Sheth C, White Jr K . Influence of the phosphodiesterase-5 inhibitor, sildenafil, on sensitivity to chemotherapy in breast tumor cells. Breast Cancer Res Treat. 2010; 124(2):349-60. DOI: 10.1007/s10549-010-0765-7. View

20.

Piazza G, Thompson W, Pamukcu R, Alila H, WHITEHEAD C, Liu L . Exisulind, a novel proapoptotic drug, inhibits rat urinary bladder tumorigenesis. Cancer Res. 2001; 61(10):3961-8. View