Colorectal cancer chemoprevention by 2 β‐cyclodextrin inclusion compounds of auraptene and 4′‐geranyloxyferulic acid

Abstract

The inhibitory effects of novel prodrugs, inclusion complexes of 3-(4 0 -geranyloxy-3 0 -methoxyphenyl)-2-trans propenoic acid (GOFA) and auraptene (AUR) with b-cyclodextrin (CD), on colon carcinogenesis were investigated using an azoxymethane (AOM)/ dextran sodium sulfate (DSS) model. Male CD-1 (ICR) mice initiated with a single intraperitoneal injection of AOM (10 mg/kg body weight) were promoted by the addition of 1.5% (w/v) DSS to their drinking water for 7 days. They were then given a basal diet containing 2 dose levels (100 and 500 ppm) of GOFA/b-CD or AUR/b-CD for 15 weeks. At Week 18, the development of colonic adenocarcinoma was significantly inhibited by feeding with GOFA/b-CD at dose levels of 100 ppm (63% reduction in multiplicity, p < 0.05) and 500 ppm (83% reduction in the multiplicity, p < 0.001), when compared with the AOM/DSS group (multiplicity: 3.36 6 3.34). In addition, feeding with 100 and 500 ppm (p < 0.01) of AUR/b-CD suppressed the development of colonic adenocarcinomas. The dietary administration with GOFA/b-CD and AUR/b-CD inhibited colonic inflammation and also modulated proliferation, apoptosis and the expression of several proinflammatory cytokines, such as nuclear factor-kappaB, tumor necrosis factor-a, Stat3, NF-E2-related factor 2, interleukin (IL)-6 and IL-1b, which were induced in the adenocarcinomas. Our findings indicate that GOFA/b-CD and AUR/b-CD, especially GOFA/b-CD, are therefore able to inhibit colitis-related colon carcinogenesis by modulating inflammation, proliferation and the expression of proinflammatory cytokines in mice.There were $1 million new cases of colorectal cancer (CRC) in 2002 (9.4% of the total cancers). 1 Globally, the mortality of CRC was reported to be 655,000 deaths per year in 2005. 2 There is at least a 25-fold variation in the occurrence of CRC worldwide.1 The highest rates of incidence are in North America, Australia/New Zealand, Western Europe and Japan, especially in Japanese men.1 These large geographic differences for CRC are probably explained by differences in environmental exposures and lifestyles.There are several types of pathogenesis of CRC. 3 Among them, inflammation is linked with CRC development. 4 The risk of CRC in patients with inflammatory bowel disease inflammatory bowel disease; IL: interleukin; iNOS: inducible nitric oxide synthase; NF-jB: nuclear factor-kappaB; Nrf2: NF-E2-related factor 2; TdT: terminal deoxynucleotidyl transferase; Tnf: tumor necrosis factor;

Auraptene Is an Inhibitor of Cholesterol Esterification and a Modulator of Estrogen Receptors

“…Auraptene induces anti-inflammatory, antioxidant, antibacterial, and immunomodulatory effects (Epifano et al, 2008). It is noteworthy that auraptene has been shown to protect rodents against chemically induced carcinogenesis (Tanaka et al, 1998(Tanaka et al, , 2000(Tanaka et al, , 2010Kohno et al, 2006;Krishnan et al, 2009). It has also been reported to exert antiproliferative and proapoptotic activities on cancer cell lines such as human hepatocellular carcinoma, colorectal adenocarcinoma, and breast adenocarcinoma cells in vitro (Zheng et al, 2002;Ohnishi et al, 2004;Krishnan et al, 2009).…”

Prenylation of Aromatic Secondary Metabolites: A New Frontier for Development of Novel Drugs

“…4-Geranyloxyferulic acid (34) (Figure 5) was isolated from the bark of Acronychia baueri Schott, an Australian plant belonging to the family of Rutaceae [32]. This compound was shown to display good antitumor properties, particularly against colon related cancers [33][34][35]. This valuable pharmacological property has not been reported in the unprenylated ferulic acid (33) (Figure 5).…”

Glucans from the edible mushroom Pleurotus pulmonarius inhibit colitis-associated colon carcinogenesis in mice

“…In the present study, we used azoxymethane (AOM)/ dextran sulfate sodium (DSS)-induced colitis and associated tumor formation as the experimental in vivo model, as previously described [15][16][17]. We show that oral administration of FBE and ME considerably attenuates weight loss, colon shortening, and severe clinical signs in the colitis-related colon carcinogenesis model.…”