Abstract 2145: Chemopreventive and immune-modulatory effects of the Cucumaria frondosa extract, Frondanol A5 in the APCMin/+ mice intestinal tumorigenesis

Abstract

Abstract Sea cucumbers have been used widely as a food source and for their health benefits, which include treatment of various chronic inflammatory conditions. We have shown previously that Cucumaria frondosa extract, Frondanol A5 inhibits azoxymethane -induced colonic precursor lesions in F344 rats. Experiments were designed to assess the chemopreventive efficacy of Frondanol A5, for suppression of intestinal tumorigenesis in male and female APCMin/+ mice. Six-week-old APCMin/+ mice were fed the modified AIN-76A diets containing 0, 250 or 500 ppm Frondanol A5 for 14 weeks. To understand molecular mechanisms, we analyzed levels of proliferation, inflammatory and angiogenesis makers; PCNA, inflammatory cytokines, 5-lipoxygenase (5-LOX), Five Lox Activating Protein (FLAP) and vascular endothelial growth factor (VEGF) expressions by IHC, IHF, and/or RT-PCR methods. To determine immuno-modulatory effects of Fondanol A5 on intestinal tumorigenesis, number of macrophages was evaluated in the blood, SI polyps and colon tumors by Giemsa staining, ex-vivo phagocytic assay was performed on the peritoneal macrophages isolated from the control and treated mice. Further, γ-interferon-inducible lysosomal thiolreductase (GILT) mRNA expression was analyzed in the peritoneal macrophages, SI polyps and colonic tumors. Dietary administration of 250 and 500 ppm of Frondanol A5 suppressed small intestinal polyp formation up to 28 % (p<0.02) in males and up to 50 % (p<0.01) in females; and significantly decreased polyp size in both genders. Importantly, 250 and 500 ppm Frondanol A5 diet suppressed colon tumors multiplicities by 65% (p<0.007) and 75% (p<0.0001) as compared to control diet fed male APCMin/+ mice. Similarly, in female APCMin/+ mice, dietary Frondanol A5 at both dose levels suppressed colon tumor multiplicities up to 80% (p<0.0001). Frondanol A5 showed significant colon tumor inhibitory dose-response effects in male APCMin/+ mice. Intestinal tumors of Frondanol A5-fed mice showed significantly reduced expression of PCNA, 5-LOX, its regulator molecule, FLAP and angiogenic marker VEGF. Frondanol A5-fed-mice showed suppression of serum inflammatory cytokines and increased expression of granulocyte-colony stimulating factor (G-CSF) by ELISA. Importantly, mice treated with Frondanol A5 diet showed enhanced phagocytic activity and increase in number of macrophages (Control 24% Vs treated 50%; p<0.01) and caused a significant increase in GILT mRNA expression, in both peritoneal macrophages as well as colonic tumors. These results suggest that Frondanol A5 exhibits significant chemopreventive potential in FAP model of SI and colon tumorigenesis. Frondanol A5 induced antitumor activities in part mediated through modulation of inflammatory molecules and stimulation of macrophage activity. Supported by NIH Grant N01-CN-53300 and R01CA094962. Citation Format: Naveena B. Janakiram, Altaf Mohammed, Misty Brewer, Peter D. Collin, Vernon E. Steele, Chinthalapally V. Rao. Chemopreventive and immune-modulatory effects of the Cucumaria frondosa extract, Frondanol A5 in the APCMin/+ mice intestinal tumorigenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2145. doi:10.1158/1538-7445.AM2014-2145