Geranylgeranylacetone suppresses colitis‑related mouse colon carcinogenesis

Inoue,Takuya; Yorifuji,Naoki; Iguchi,Munetaka; Fujiwara,Kaori; Kakimoto,Kazuki; Nouda,Sadaharu; Okada,Toshihiko; Kawakami,Ken; Abe,Yosuke; Takeuchi,Toshihisa; Higuchi,Kazuhide

doi:10.3892/or.2015.3794

Geranylgeranylacetone suppresses colitis‑related mouse colon carcinogenesis

Authors:
- Takuya Inoue
- Naoki Yorifuji
- Munetaka Iguchi
- Kaori Fujiwara
- Kazuki Kakimoto
- Sadaharu Nouda
- Toshihiko Okada
- Ken Kawakami
- Yosuke Abe
- Toshihisa Takeuchi
- Kazuhide Higuchi
View Affiliations

Affiliations: Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
Published online on: February 10, 2015 https://doi.org/10.3892/or.2015.3794
Pages: 1769-1774

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Geranylgeranylacetone (GGA), an isoprenoid compound, is an anti-ulcer drug developed in Japan. GGA protects a variety of cells and tissues against numerous stresses via induction of heat shock protein (HSP) 70, and it has recently been reported to protect mice from experimental ulcerative colitis (UC). However, it is unknown whether GGA exhibits a preventive effect on UC-associated neoplasia. In the present study, we evaluated the preventive effects of GGA on colitis-related carcinogenesis in the mouse colon. Mice were administered 1,2-dimethylhydrazine (DMH) subcutaneously three times within a week, followed by 2 cycles of dextran sulfate sodium (DSS) (each cycle, 3% DSS for 7 days and then distilled water for 14 days) and they were sacrificed 28 days after the completion of the 2 cycles. The mice were divided into the following groups according to the diet received during the experiment: group A, which received a standard diet and served as a disease control; group B, which received a diet mixed with 0.25% GGA; group C, which received a diet mixed with 0.5% GGA; group D, which received a diet mixed with 1.0% GGA; group E, which received a diet mixed with 2.0% GGA; and group F, which received a diet containing no agents, including DSS and served as a normal control. The incidence of neoplasia was assessed. The expression of inducible nitric oxide synthase (iNOS) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) was also determined. In addition, the expression of HSP70 in the colon tissues was determined by immunohistochemistry and western blot analysis. The mean number of tumors was 16.6, 11.0, 9.4, 5.8, 5.4 and 0 in groups A-F, respectively. GGA significantly suppressed the occurrence of neoplasia in a dose-dependent manner. GGA treatment enhanced the expression of HSP70 and suppressed the oxidative damage in the background mucosa (i.e. lesion-free colon). These results suggest that GGA could be useful in the prevention of UC-associated neoplasia.

View Figures

View References

1	Watanabe T, Konishi T, Kishimoto J, Kotake K, Muto T and Sugihara K: Japanese Society for Cancer of the Colon and Rectum: Ulcerative colitis-associated colorectal cancer shows a poorer survival than sporadic colorectal cancer: a nationwide Japanese study. Inflamm Bowel Dis. 3:802–808. 2011. View Article : Google Scholar
2	Lyakhovich A and Gasche C: Systematic review: molecular chemoprevention of colorectal malignancy by mesalazine. Aliment Pharmacol Ther. 31:202–209. 2010.
3	Herfarth H: The role of chemoprevention of colorectal cancer with 5-aminosalicylates in ulcerative colitis. Dig Dis. 30(Suppl 2): 55–59. 2012. View Article : Google Scholar : PubMed/NCBI
4	Lopez A and Peyrin-Biroulet L: 5-Aminosalicylic acid and chemoprevention: does it work? Dig Dis. 31:248–253. 2013. View Article : Google Scholar : PubMed/NCBI
5	Ekbom A, Helmick C, Zack M and Adami HO: Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med. 323:1228–1233. 1990. View Article : Google Scholar : PubMed/NCBI
6	Mizushima T: RETRACTED: protective role of HSP70 against various gastrointestinal diseases. Curr Opin Pharmacol. 19:1–5. 2014. View Article : Google Scholar
7	Hauser GJ, Dayao EK, Wasserloos K, Pitt BR and Wong HR: HSP induction inhibits iNOS mRNA expression and attenuates hypotension in endotoxin-challenged rats. Am J Physiol. 271:H2529–H2535. 1996.PubMed/NCBI
8	Chan JY, Ou CC, Wang LL and Chan SH: Heat shock protein 70 confers cardiovascular protection during endotoxemia via inhibition of nuclear factor-κB activation and inducible nitric oxide synthase expression in the rostral ventrolateral medulla. Circulation. 110:3560–3566. 2004. View Article : Google Scholar : PubMed/NCBI
9	Tao Y, Hart J, Lichtenstein L, Joseph LJ, Ciancio MJ, Hu S, Chang EB and Bissonnette M: Inducible heat shock protein 70 prevents multifocal flat dysplastic lesions and invasive tumors in an inflammatory model of colon cancer. Carcinogenesis. 30:175–182. 2009. View Article : Google Scholar :
10	Ohkawara T, Nishihira J, Takeda H, Miyashita K, Kato K, Kato M, Sugiyama T and Asaka M: Geranylgeranylacetone protects mice from dextran sulfate sodium-induced colitis. Scand J Gastroenterol. 40:1049–1057. 2005. View Article : Google Scholar : PubMed/NCBI
11	Ohkawara T, Nishihira J, Takeda H, Katsurada T, Kato K, Yoshiki T, Sugiyama T and Asaka M: Protective effect of geranylgeranylacetone on trinitrobenzene sulfonic acid-induced colitis in mice. Int J Mol Med. 17:229–234. 2006.PubMed/NCBI
12	Inoue T, Murano M, Yoda Y, et al: R-etodolac induces E-cadherin and suppresses colitis-related mouse colon tumorigenesis. Oncol Rep. 24:1487–1492. 2010.PubMed/NCBI
13	Inoue T, Murano M, Abe Y, et al: Therapeutic effect of nimesulide on colorectal carcinogenesis in experimental murine ulcerative colitis. J Gastroenterol Hepatol. 22:1474–1481. 2007. View Article : Google Scholar : PubMed/NCBI
14	Wedemeyer J and Galli SJ: Decreased susceptibility of mast cell-deficient Kit^W/Kit^W-v mice to the development of 1,2-dimeth-ylhydrazine-induced intestinal tumors. Lab Invest. 85:388–396. 2005. View Article : Google Scholar : PubMed/NCBI
15	Riddell RH, Goldman H, Ransohof DF, et al: Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical application. Human Pathol. 14:931–968. 1983. View Article : Google Scholar
16	Murthy SN, Cooper HS, Shim H, Shah RS, Ibrahim SA and Sedergran DJ: Treatment of dextran sulfate sodium-induced murine colitis by intracolonic cyclosporine. Dig Dis Sci. 38:1722–1734. 1993. View Article : Google Scholar : PubMed/NCBI
17	Suemasu S, Tanaka K, Namba T, et al: A role for HSP70 in protecting against indomethacin-induced gastric lesions. J Biol Chem. 284:19705–19715. 2009. View Article : Google Scholar : PubMed/NCBI
18	Asano T, Tanaka K, Yamakawa N, Adachi H, Sobue G, Goto H, Takeuchi K and Mizushima T: HSP70 confers protection against indomethacin-induced lesions of the small intestine. J Pharmacol Exp Ther. 330:458–467. 2009. View Article : Google Scholar : PubMed/NCBI
19	Umegaki E, Kuramoto T, Kojima Y, Nouda S, Ishida K, Takeuchi T, Inoue T, Tokioka S and Higuchi K: Geranylgeranylacetone, a gastromucoprotective drug, protects against NSAID-induced esophageal, gastroduodenal and small intestinal mucosal injury in healthy subjects: a prospective randomized study involving a comparison with famotidine. Intern Med. 53:283–290. 2014. View Article : Google Scholar : PubMed/NCBI
20	Yanaka A, Zhang S, Sato D, Tauchi M, Suzuki H, Shibahara T, Matsui H, Nakahara A and Hyodo I: Geranylgeranylacetone protects the human gastric mucosa from diclofenac-induced injury via induction of heat shock protein 70. Digestion. 75:148–155. 2007. View Article : Google Scholar : PubMed/NCBI
21	Chan AT, Ogino S and Fuchs CS: Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Eng J Med. 356:2131–2142. 2007. View Article : Google Scholar
22	Tardieu D, Jaeg JP, Deloly A, Corpet DE, Cadet J and Petit CR: The COX-2 inhibitor nimesulide suppresses superoxide and 8-hydroxy-deoxyguanosine formation, and stimulates apoptosis in mucosa during early colonic inflammation in rats. Carcinogenesis. 21:973–976. 2000. View Article : Google Scholar : PubMed/NCBI
23	Forrest K, Symmons D and Foster P: Systematic review: is ingestion of paracetamol or non-steroidal anti-inflammatory drugs associated with exacerbations of inflammatory bowel disease? Aliment Pharmacol Ther. 20:1035–1043. 2004. View Article : Google Scholar : PubMed/NCBI
24	Nishida T, Yabe Y, Fu HY, Hayashi Y, Asahi K, Eguchi H, Tsuji S, Tsujii M, Hayashi N and Kawano S: Geranylgeranylacetone induces cyclooxygenase-2 expression in cultured rat gastric epithelial cells through NF-κB. Dig Dis Sci. 52:1890–1896. 2007. View Article : Google Scholar : PubMed/NCBI
25	Ashburn TT and Thor KB: Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov. 3:673–683. 2004. View Article : Google Scholar : PubMed/NCBI
26	Hoshino T, Suzuki K, Matsushima T, Yamakawa N, Suzuki T and Mizushima T: Suppression of Alzheimer’s disease-related phenotypes by geranylgeranylacetone in mice. PLoS One. 8:e763062013. View Article : Google Scholar
27	Namba T, Tanaka K, Hoshino T, Azuma A and Mizushima T: Suppression of expression of heat shock protein 70 by gefitinib and its contribution to pulmonary fibrosis. PLoS One. 6:e272962011. View Article : Google Scholar : PubMed/NCBI