Sildenafil suppresses inflammation-driven colorectal cancer in mice

Bianca N. Islam, Sarah K. Sharman, Yali Hou, Allison E. Bridges, Nagendra Singh, Sangmi Kim, Ravindra Bharat Kolhe, Jimena Trillo-Tinoco, Paulo C. Rodriguez, Franklin G. Berger, Subbaramiah Sridhar, Darren D Browning

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Intestinal cyclic guanosine monophosphate (cGMP) signalingregulatesepithelialhomeostasisandhasbeenimplicated in the suppression of colitis and colon cancer. In this study, we investigated the cGMP-elevating ability of the phosphodiesterase-5(PDE5)inhibitorsildenafiltoprevent disease in the azoxymethane/dextran sulfate sodium (AOM/DSS)inflammation-drivencolorectalcancermodel. Treatment of mice with sildenafil activated cGMP signaling in the colon mucosa and protected against dextran-sulfate sodium (DSS)-induced barrierdysfunction. In micetreated with AOM/DSS, oral administration of sildenafil throughout the disease course reduced polyp multiplicity by 50% compared with untreated controls. Polyps that did form in sildenafil treated mice were less proliferative and more differentiated compared with polyps from untreated mice, but apoptosis was unaffected. Polyps in sildenafil treated mice were also less inflamed; they exhibited reduced myeloid-cellinfiltration and reduced expression of iNOS, IFNg, and IL6 compared with untreated controls. Most of the protection conferred by sildenafil was during the initiation stage of carcinogenesis (38% reduction in multiplicity). Administration of sildenafil during the later promotion stages did not affect multiplicity but had a similar effect on the polyp phenotype, including increased mucus production, and reduced proliferation and inflammation. In summary, the results demonstrate that oral administration ofsildenafilsuppressespolypformationandinflammation in mice treated with AOM/DSS. This validation of PDE5 as a target highlights the potential therapeutic value of PDE5 inhibitors for the prevention of colitis-driven colon cancer in humans.

Original languageEnglish (US)
Pages (from-to)377-388
Number of pages12
JournalCancer Prevention Research
Volume10
Issue number7
DOIs
StatePublished - Jul 1 2017

Fingerprint

Polyps
Colorectal Neoplasms
Dextran Sulfate
Azoxymethane
Inflammation
Cyclic GMP
Type 5 Cyclic Nucleotide Phosphodiesterases
Colitis
Colonic Neoplasms
Oral Administration
Phosphodiesterase 5 Inhibitors
Mucus
Sildenafil Citrate
Interleukin-6
Colon
Carcinogenesis
Mucous Membrane
Apoptosis
Phenotype
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Sildenafil suppresses inflammation-driven colorectal cancer in mice. / Islam, Bianca N.; Sharman, Sarah K.; Hou, Yali; Bridges, Allison E.; Singh, Nagendra; Kim, Sangmi; Kolhe, Ravindra Bharat; Trillo-Tinoco, Jimena; Rodriguez, Paulo C.; Berger, Franklin G.; Sridhar, Subbaramiah; Browning, Darren D.

In: Cancer Prevention Research, Vol. 10, No. 7, 01.07.2017, p. 377-388.

Research output: Contribution to journalArticle

Islam, BN, Sharman, SK, Hou, Y, Bridges, AE, Singh, N, Kim, S, Kolhe, RB, Trillo-Tinoco, J, Rodriguez, PC, Berger, FG, Sridhar, S & Browning, DD 2017, 'Sildenafil suppresses inflammation-driven colorectal cancer in mice', Cancer Prevention Research, vol. 10, no. 7, pp. 377-388. https://doi.org/10.1158/1940-6207.CAPR-17-0015
Islam, Bianca N. ; Sharman, Sarah K. ; Hou, Yali ; Bridges, Allison E. ; Singh, Nagendra ; Kim, Sangmi ; Kolhe, Ravindra Bharat ; Trillo-Tinoco, Jimena ; Rodriguez, Paulo C. ; Berger, Franklin G. ; Sridhar, Subbaramiah ; Browning, Darren D. / Sildenafil suppresses inflammation-driven colorectal cancer in mice. In: Cancer Prevention Research. 2017 ; Vol. 10, No. 7. pp. 377-388.
@article{e078deec0b5741cc8acece11b84aa1a3,
title = "Sildenafil suppresses inflammation-driven colorectal cancer in mice",
abstract = "Intestinal cyclic guanosine monophosphate (cGMP) signalingregulatesepithelialhomeostasisandhasbeenimplicated in the suppression of colitis and colon cancer. In this study, we investigated the cGMP-elevating ability of the phosphodiesterase-5(PDE5)inhibitorsildenafiltoprevent disease in the azoxymethane/dextran sulfate sodium (AOM/DSS)inflammation-drivencolorectalcancermodel. Treatment of mice with sildenafil activated cGMP signaling in the colon mucosa and protected against dextran-sulfate sodium (DSS)-induced barrierdysfunction. In micetreated with AOM/DSS, oral administration of sildenafil throughout the disease course reduced polyp multiplicity by 50{\%} compared with untreated controls. Polyps that did form in sildenafil treated mice were less proliferative and more differentiated compared with polyps from untreated mice, but apoptosis was unaffected. Polyps in sildenafil treated mice were also less inflamed; they exhibited reduced myeloid-cellinfiltration and reduced expression of iNOS, IFNg, and IL6 compared with untreated controls. Most of the protection conferred by sildenafil was during the initiation stage of carcinogenesis (38{\%} reduction in multiplicity). Administration of sildenafil during the later promotion stages did not affect multiplicity but had a similar effect on the polyp phenotype, including increased mucus production, and reduced proliferation and inflammation. In summary, the results demonstrate that oral administration ofsildenafilsuppressespolypformationandinflammation in mice treated with AOM/DSS. This validation of PDE5 as a target highlights the potential therapeutic value of PDE5 inhibitors for the prevention of colitis-driven colon cancer in humans.",
author = "Islam, {Bianca N.} and Sharman, {Sarah K.} and Yali Hou and Bridges, {Allison E.} and Nagendra Singh and Sangmi Kim and Kolhe, {Ravindra Bharat} and Jimena Trillo-Tinoco and Rodriguez, {Paulo C.} and Berger, {Franklin G.} and Subbaramiah Sridhar and Browning, {Darren D}",
year = "2017",
month = "7",
day = "1",
doi = "10.1158/1940-6207.CAPR-17-0015",
language = "English (US)",
volume = "10",
pages = "377--388",
journal = "Cancer Prevention Research",
issn = "1940-6207",
publisher = "American Association for Cancer Research Inc.",
number = "7",

}

TY - JOUR

T1 - Sildenafil suppresses inflammation-driven colorectal cancer in mice

AU - Islam, Bianca N.

AU - Sharman, Sarah K.

AU - Hou, Yali

AU - Bridges, Allison E.

AU - Singh, Nagendra

AU - Kim, Sangmi

AU - Kolhe, Ravindra Bharat

AU - Trillo-Tinoco, Jimena

AU - Rodriguez, Paulo C.

AU - Berger, Franklin G.

AU - Sridhar, Subbaramiah

AU - Browning, Darren D

PY - 2017/7/1

Y1 - 2017/7/1

N2 - Intestinal cyclic guanosine monophosphate (cGMP) signalingregulatesepithelialhomeostasisandhasbeenimplicated in the suppression of colitis and colon cancer. In this study, we investigated the cGMP-elevating ability of the phosphodiesterase-5(PDE5)inhibitorsildenafiltoprevent disease in the azoxymethane/dextran sulfate sodium (AOM/DSS)inflammation-drivencolorectalcancermodel. Treatment of mice with sildenafil activated cGMP signaling in the colon mucosa and protected against dextran-sulfate sodium (DSS)-induced barrierdysfunction. In micetreated with AOM/DSS, oral administration of sildenafil throughout the disease course reduced polyp multiplicity by 50% compared with untreated controls. Polyps that did form in sildenafil treated mice were less proliferative and more differentiated compared with polyps from untreated mice, but apoptosis was unaffected. Polyps in sildenafil treated mice were also less inflamed; they exhibited reduced myeloid-cellinfiltration and reduced expression of iNOS, IFNg, and IL6 compared with untreated controls. Most of the protection conferred by sildenafil was during the initiation stage of carcinogenesis (38% reduction in multiplicity). Administration of sildenafil during the later promotion stages did not affect multiplicity but had a similar effect on the polyp phenotype, including increased mucus production, and reduced proliferation and inflammation. In summary, the results demonstrate that oral administration ofsildenafilsuppressespolypformationandinflammation in mice treated with AOM/DSS. This validation of PDE5 as a target highlights the potential therapeutic value of PDE5 inhibitors for the prevention of colitis-driven colon cancer in humans.

AB - Intestinal cyclic guanosine monophosphate (cGMP) signalingregulatesepithelialhomeostasisandhasbeenimplicated in the suppression of colitis and colon cancer. In this study, we investigated the cGMP-elevating ability of the phosphodiesterase-5(PDE5)inhibitorsildenafiltoprevent disease in the azoxymethane/dextran sulfate sodium (AOM/DSS)inflammation-drivencolorectalcancermodel. Treatment of mice with sildenafil activated cGMP signaling in the colon mucosa and protected against dextran-sulfate sodium (DSS)-induced barrierdysfunction. In micetreated with AOM/DSS, oral administration of sildenafil throughout the disease course reduced polyp multiplicity by 50% compared with untreated controls. Polyps that did form in sildenafil treated mice were less proliferative and more differentiated compared with polyps from untreated mice, but apoptosis was unaffected. Polyps in sildenafil treated mice were also less inflamed; they exhibited reduced myeloid-cellinfiltration and reduced expression of iNOS, IFNg, and IL6 compared with untreated controls. Most of the protection conferred by sildenafil was during the initiation stage of carcinogenesis (38% reduction in multiplicity). Administration of sildenafil during the later promotion stages did not affect multiplicity but had a similar effect on the polyp phenotype, including increased mucus production, and reduced proliferation and inflammation. In summary, the results demonstrate that oral administration ofsildenafilsuppressespolypformationandinflammation in mice treated with AOM/DSS. This validation of PDE5 as a target highlights the potential therapeutic value of PDE5 inhibitors for the prevention of colitis-driven colon cancer in humans.

UR - http://www.scopus.com/inward/record.url?scp=85023749360&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85023749360&partnerID=8YFLogxK

U2 - 10.1158/1940-6207.CAPR-17-0015

DO - 10.1158/1940-6207.CAPR-17-0015

M3 - Article

C2 - 28468928

AN - SCOPUS:85023749360

VL - 10

SP - 377

EP - 388

JO - Cancer Prevention Research

JF - Cancer Prevention Research

SN - 1940-6207

IS - 7

ER -