Chemopreventive Effects of Frondanol A5, a Cucumaria frondosa Extract, against Rat Colon Carcinogenesis and Inhibition of Human Colon Cancer Cell Growth

Department of Medicine, University of Oklahoma Cancer Institute, University of Oklahoma Health Sciences Center, Oklahoma City, 73104, USA.
Cancer Prevention Research (Impact Factor: 4.44). 01/2010; 3(1):82-91. DOI: 10.1158/1940-6207.CAPR-09-0112
Source: PubMed


Sea cucumber extracts have been widely used to treat individuals with inflammatory conditions in East Asia. The present study has been designed to test potential colon cancer-preventive properties of Frondanol A5, a glycolipid extract from the sea cucumber, Cucumaria frondosa, using in vivo and in vitro models of colon cancer. Chemopreventive efficacy of Frondanol A5 was evaluated on azoxymethane-induced rat colon carcinogenesis using colonic aberrant crypt foci (ACF) as efficacy marker. At 7 weeks of age, groups of rats (12 per group) were fed the AIN-76A diet, and ACFs were induced by azoxymethane (15 mg/kg body weight). Three days after azoxymethane treatment, rats were fed with the diets containing 0, 150, and 450 ppm of Frondanol A5 and continued on the diets for 8 weeks, at which time ACFs were evaluated. Expression levels of proliferating cell nuclear antigen and p21(WAF1/CIP1) were determined in ACFs. Further, Frondanol A5 (10-120 microg/mL) was studied for its growth-inhibitory and apoptotic effects in the HCT-116 cell line. Dietary administration of 150 and 450 ppm of Frondanol A5 significantly suppressed azoxymethane-induced total colonic ACF formation, approximately 34% to 55% (P < 0.01 to P < 0.0001), and multicrypt aberrant foci (48-68.5%, P < 0.0001) in a dose-dependent manner. ACFs in rats treated with Frondanol A5 showed significant upregulation of p21(WAF1/CIP1) and downregulation of proliferating cell nuclear antigen compared with control group. Frondanol A5 showed growth inhibition at S and G(2)-M phase with a decrease in Cdc25c and an increase in p21(WAF1/CIP) with significant apoptosis associated with H2AX phosphorylation and caspase-2 cleavage in HCT116 cells. Overall, Frondanol A5 exhibits potential chemopreventive properties for colon carcinogenesis, which suggests further development of this sea cucumber extract.

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    • "The IC50 concentrations (producing half-maximal inhibition) at 24 h were between 1.7 and 2.5 µM Frondoside A. These results are consistent with previously published results that low concentration of Frondoside A inhibits the growth of human pancreatic cancer cells and induced apoptosis through caspase 9/3/7, increased bax, decreased bcl-2 and mcl-1, and arrested cell cycle and up-regulated p21 [8], induced apoptosis in human leukemia cells via caspase activation [6], and significantly decreases the viability of the estrogen receptor (ER)-negative MDA-MB-231 breast cancer cells by inducing apoptosis via the Caspase9-Caspase3/7 intrinsic pathway [7]. It has also been demonstrated that Frondanol A5, an impure extract of Cucumaria frondosa skin from which Frondoside A is originally derived, induced growth inhibition at S and G2-M phase with a decrease in Cdc25c and an increase in p21WAF1/CIP1 with significant apoptosis associated with H2AX phosphorylation and caspase-2 cleavage in the colon cancer-derived HCT116 cells [4]. A second paper also demonstrated that Frondanol-A5P, a polar precipitate sub-fraction of Frondanol-A5, inhibited proliferation and induced G2/M phase cell cycle arrest in two pancreatic cancer cells with decreased expression of cyclin A, cyclin B, and cdc25c [18]. "
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    ABSTRACT: A major challenge for oncologists and pharmacologists is to develop less toxic drugs that will improve the survival of lung cancer patients. Frondoside A is a triterpenoid glycoside isolated from the sea cucumber, Cucumaria frondosa and was shown to be a highly safe compound. We investigated the impact of Frondoside A on survival, migration and invasion in vitro, and on tumor growth, metastasis and angiogenesis in vivo alone and in combination with cisplatin. Frondoside A caused concentration-dependent reduction in viability of LNM35, A549, NCI-H460-Luc2, MDA-MB-435, MCF-7, and HepG2 over 24 hours through a caspase 3/7-dependent cell death pathway. The IC50 concentrations (producing half-maximal inhibition) at 24 h were between 1.7 and 2.5 µM of Frondoside A. In addition, Frondoside A induced a time- and concentration-dependent inhibition of cell migration, invasion and angiogenesis in vitro. Frondoside A (0.01 and 1 mg/kg/day i.p. for 25 days) significantly decreased the growth, the angiogenesis and lymph node metastasis of LNM35 tumor xenografts in athymic mice, without obvious toxic side-effects. Frondoside A (0.1-0.5 µM) also significantly prevented basal and bFGF induced angiogenesis in the CAM angiogenesis assay. Moreover, Frondoside A enhanced the inhibition of lung tumor growth induced by the chemotherapeutic agent cisplatin. These findings identify Frondoside A as a promising novel therapeutic agent for lung cancer.
    PLoS ONE 01/2013; 8(1):e53087. DOI:10.1371/journal.pone.0053087 · 3.23 Impact Factor
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    • "In Malaysia, sea cucumber generally known as " Gamat " is a dietary delicacy and a traditional remedy for healing various internal and external wounds. Various bioactive compounds have recently been identified from sea cucumbers, such as, Frondanol A5 from Cucumaria frondosa for its chemo preventative effects (Janakiram et al., 2010), "
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    ABSTRACT: The body wall of sea cucumber, Bohadschia bivitatta, was studied with respect to its collagen protein. About 70% of the total body wall protein was accounted for by highly insoluble collagen fibers. Aim of this study was to isolate pepsinsolubilized collagen (PSC) from crude collagen fibres, extracted from body wall of sea cucumber Bohadschia bivitatta, and also to investigate 67 nm axial repeat D-banding of collagen fibrils, which characterizes collagen. Body wall of Bohadshia bivitatta were cut into small pieces followed by washing with distilled water and then replaced with 4 mM ethylenediaminetetraacetic acid (EDTA), 0.1 M Tris–HCl, pH 8.0, and stirred for 3 days to get precipitated crude collagen fibrils. Disaggregated insoluble crude collagen fibrils were treated with 0.1 M NaOH and 0.5 M acetic acid containing porcine pepsin to get PSC collagen. The ultra structures were analyzed by using Quanta™ Scanning Electron Microscope, Netherlands, under 130 Pa pressure, at a working distance of 6-10 mm at 4.0 to 5.0 kV from magnification 5,000X to 100,000X. Pepsin-solubilized collagen was successfully isolated from disaggregated crude collagen fibres, with 65% yield. SEM analysis of crude collagen displayed a regularly repeated striated pattern, whereas, PSC displayed non-banded sheet like fibers with twisted configuration. In conclusion high yield of Pepsin-solubilized collagen was successfully isolated, and evidence of Dperiodic bands confirms it as fibrillar collagen. This collagen could be useful as an alternative to mammalian collagen in the nutraceutical and pharmaceutical industries.
    Health & the Environment Journal 01/2013; 4(2):53-65.
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    • "Fresh or dried sea cucumbers have been a dietary delicacy of Asians for over many centuries and are also used in formulation of traditional medicine in East Asia for treatment of asthma, hypertension, rheumatism, anemia, and sinus congestion [Fredalina et al., 1999; Zhong et al., 2007]. Various bioactive molecules have recently been identified from sea cucumbers, such as anticancer compound triterpene glycoside [Lu et al., 2010], chemopreventive frondanol A5 [Janakiram et al., 2010], sulfated polysaccharides used for proliferation [Zhang et al., 2010], antihypertensive gelatin hydrolysate [Zhao et al., 2007], anti-oxidant effects [Zhong et al., 2007], and anti-angiogenic saponins [Tian et al., 2005]. A recent Food and Agriculture Organization (FAO) review suggested that at least 47 species of sea cucumber are commercially available and the majority of sea cucumbers found in Japan, Korea, and China belong to the species Stichopus japonicus. "
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    ABSTRACT: Red variants of S. Japonicas show unique ecological characteristics and are indigenous to Jeju Island in South Korea. Various biological activities of red sea cucumber extracts (RSCEs) were evaluated. In comparison with positive controls, anti-oxidant activity of RSCEs was very low. In HL-60 and HT-29 cells, chloroform and ethyl acetate (EtOAc) fractions showed higher than 80 and 60% growth inhibition, respectively. Nuclear condensation and increased pro-apoptotic signaling revealed that RSCEs triggered apoptosis. EtOAc fractions also showed strong anti-inflammatory effects at sub-lethal concentrations in lipolysaccharide-stimulated RAW264.7 cells and suppressed more than 90% of nitric oxide (NO) and prostaglandin 2 productions at 50 μg/mL by inhibiting inducible NO synthase and cydooxygenase-2. Water-soluble fractions showed good antibacterial effects against Staphylococcus aureus and Staphylococcus epidermidis.
    Journal of the Korean Society for Applied Biological Chemistry 10/2011; 54(5). DOI:10.1007/BF03253150 · 0.69 Impact Factor
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