Abstract
Falcarinol (FaOH) and falcarindiol (FaDOH) are cytotoxic and anti-inflammatory polyacetylenic oxylipins, which are commonly found in the carrot family (Apiaceae). FaOH and FaDOH have previously demonstrated a chemopreventive effect on precursor lesions of colorectal cancer (CRC) in azoxymethane (AOM)-induced rats. The purpose of the present study was to elucidate possible mechanisms of action for the preventive effect of FaOH and FaDOH on colorectal precancerous lesions and to determine how this effect was dependent on dose. Gene expression studies performed by RT-qPCR of selected cancer biomarkers in tissue from biopsies of neoplastic tissue revealed that FaOH and FaDOH downregulated NF-κβ and its downstream inflammatory markers TNFα, IL-6, and COX-2. The dose-dependent anti-neoplastic effect of FaOH and FaDOH in AOM-induced rats was investigated in groups of 20 rats receiving a standard rat diet (SRD) supplemented with 0.16, 0.48, 1.4, 7 or 35 µg FaOH and FaDOH g−1 feed in the ratio 1:1 and 20 rats were controls receiving only SRD. Analysis of aberrant crypt foci (ACF) showed that the average number of small ACF (<7 crypts) and large ACF (>7 crypts) decreased with increasing dose of FaOH and FaDOH and that this inhibitory effect on early neoplastic formation of ACF was dose-dependent, which was also the case for the total number of macroscopic neoplasms. The CRC protective effects of apiaceous vegetables are mainly due to the inhibitory effect of FaOH and FaDOH on NF-κB and its downstream inflammatory markers, especially COX-2.
Highlights
Colorectal cancer (CRC) is a major worldwide health problem and is the third most frequent cause of cancer-related death in developed countries [1]
We show that FaOH and FaDOH have an inhibitory effect on certain inflammatory markers neoplastic lesions of and that aand possible mechanism action in to colorectal cancer (CRC)
Analyses of randomly selected batches of feed of the active arm during the feeding experiments showed no sign of degradation, oxidation or isomerization of FaOH and FaDOH in accordance with the fact that no significant changes in the content of these polyacetylenes were observed duringNutrients the feeding which is in accordance with our previous investigation
Summary
Colorectal cancer (CRC) is a major worldwide health problem and is the third most frequent cause of cancer-related death in developed countries [1]. The growing incidence of CRC is probably associated with a modern lifestyle typified by limited physical activity, alcohol consumption and dietary changes [2]. In order to reduce the incidence of CRC, effective prevention and treatment strategies need to be identified. Due to the long precancerous stage of this disease, dietary intervention may exert a favorable effect on polyp formation and/or inhibition of the transformation of adenomas to CRC. Recent findings indicate that long-term consumption of a diet rich in vegetables may prevent the development of CRC [5]. Vegetables contain a wide variety of bioactive secondary metabolites such as glucosinolates, polyphenols and/or polyacetylenic oxylipins, some of which have shown bioactivities that may contribute to their CRC protective effects [6,7,8]
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