A Novel Prodrug of 4′-Geranyloxy-Ferulic Acid Suppresses Colitis-Related Colon Carcinogenesis in Mice

Abstract

The inhibitory effects of a novel prodrug, 3-(4′-geranyloxy-3′-methoxyphenyl)-2-trans-propenoyl-L-alanyl-L-proline (GAP), of the secondary metabolite 4′-geranyloxy-3′-methoxyphenyl)-2-trans-propenoic acid (4′-geranyloxy-ferulic acid), on colon carcinogenesis was investigated using an azoxymetahen (AOM)/dextran sodium sulfate (DSS) model. GAP was synthetically derived from ferulic acid. Male CD-1 (ICR) mice initiated with a single intraperitoneal injection of azoxymethane (10 mg/kg body weight) were promoted by 1% (wt/vol) DSS in drinking water for 7 days. They were then given modified AIN-76A diet containing 0.01% or 0.05% GAP for 17 wk. At Week 20, the development of colonic adenocarcinoma was significantly inhibited by GAP feeding at dose levels of 0.01% [60% incidence (P = 0.0158) with a multiplicity of and 1.13 ± 1.13 (P < 0.05)] and 0.05% [53% incidence (P = 0.0057) with a multiplicity of 0.08 ± 1.08 (P < 0.01)], when compared to the AOM/DSS group (95% incidence with a multiplicity of 3.10 ± 3.06). Dietary GAP modulated the mitotic and apoptotic indexes in the crypt cells and lowered 8-hydroxy-2′-deoxyguanosine (8-OHdG)-positive cells in the colonic mucosa. Urinary level of 8-OHdG was lowered by GAP feeding. Additionally, dietary GAP elevated the immunoreactivity of an inducible form of heme oxygenase 1 in the colonic mucosa. Our results indicate that GAP is able to inhibit colitis-related colon carcinogenesis by modulating proliferation and oxidative stress in mice.

ACKNOWLEDGMENTS

This work was supported in part by a Grant-in-Aid for Cancer Research, for the Third-Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare of Japan; a Grant-in-Aid (No. 18592076 to T. Tanaka, 17015016 to T. Tanaka, and 18880030 to Y. Yasui) for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and a grant (H2007–12 to T. Tanaka and S2006–9 to Y. Yasui) for the Project Research from the High-Technology Center of Kanazawa Medical University. We also thank Italian Ministero dell'Istruzione, Università e Ricerca (MIUR) for financial support for the synthesis of the title prodrug.

Notes

^a Abbreviations are as follows: AD, adenoma; ADC, adenocarcinoma; AOM, azoxymetahen; DSS, dextran sodium sulfate; GAP, 3-(4′-geranyloxy-3′-methoxyphenyl)-2-trans-propenoyl-L-alanyl-L-proline.

^b Mean ± SD.

^c Significantly different from the AOM/DSS group by Fisher's exact probability test, P = 0.0002.

^d Significantly different from the AOM/DSS group by Fisher's exact probability test, P = 0.0057.

^e Significantly different from the AOM/DSS group by Fisher's exact probability test, P = 0.0158).

^f Significantly different from the AOM/DSS group 1-way analysis of variance (ANOVA) with Tukey–Kramer multiple comparisons test, P < 0.05.

^g Significantly different from the AOM/DSS group 1-way ANOVA with Tukey–Kramer multiple comparisons test, P < 0.01.