Abstract
Abstract Ellagitannins are the most abundant polyphenols present in pomegranate (Punica granatum) peel and black raspberry and contribute greatly towards reported biological properties. In this study, we report on i) the bulk isolation of punicalagins from pomegranate peel, and ii) various chemopreventive/chemotherapeutic activities. The pre-enriched pomegranate peel powder was extracted repeatedly with water. The pooled extract was concentrated using rotovapor and then further purified by an amberlite XAD-16 column. Punicalagins were eluted using a gradient of methanol. Fractions eluted with 20-25% methanol yielded 1.2 g light brown powder from a total of 40 g extract. This fraction was identified as punicalagins by HPLC using reference compounds and confirmed by LC/MS analysis. The punicalagins (40 µM) were found to inhibit oxidative DNA products (70% inhibition; p=0.0017) from Cu2+-catalyzed redox cycling of 4-hydroxy-17ß-estradiol as analyzed by 32P-postlabeling. Evidence of high antioxidant activity of punicalagins was also obtained based on ORAC assay (1556 ± 79 μmol of TE/mg), as well as by 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid (ABTS)- and 2,2-diphenyl-1-picrylhydrazyl (DPPH)-scavenging, and ferrous ions-chelating activities (IC50 1.2 µg/ml, 19 µg/ml, and 46.5 µg/ml respectively). We further investigated the effect of punicalagins on benzo[a]pyrene (BP)-induced DNA adducts in vitro and in vivo: Incubation of BP (1 µM) with rat liver microsomes, appropriate co-factors and DNA in the presence of vehicle or punicalagins (1-40 µM) showed dose-dependent inhibition of the resultant DNA adducts, with essentially complete (97%) inhibition at 40 µM. To determine its efficacy in vivo, female S/D rats were treated with punicalagins via diet (1,500 ppm) or by subcutaneous polymeric implants (two 2-cm implants; 20% drug load) and then challenged with BP by subcutaneous polymeric implants (2-cm; 10% load) and euthanized after 1 week. Analysis of the lung DNA by 32P-postlabeling showed significant (60%; p = 0.029) inhibition of DNA adducts by punicalagins administered by the implants; the dietary administration of punicalagins also showed modest but statistically insignificant inhibition (34%). Measurement of the residual compound in the implants recovered from the animals showed that the total dose administered by the implants was 40-fold lower than the oral route. Together, our data show that punicalagins isolated from pomegranate peel had significant antioxidant activity and was highly effective against BP-induced DNA adducts in vivo only when administered by sustained-release polymeric implants (Supported from the USPHS grants CA-118114 and CA-125152 and the Duggan Endowment). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3711. doi:10.1158/1538-7445.AM2011-3711
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