Alhosin et al. Journal of Experimental & Clinical Cancer Research 2011, 30:41 http://www.jeccr.com/content/30/1/41 Page 6 of 10 Epidemiological studies report that diets rich in fruits and vegetables reduce the rate of cancer mortality [83-87]. The beneficial effects of these diets are attribu- ted, at least partly, to polyphenols which have been described to have in vitro and in vivo anti-tumoral prop- erties in several types of cancer cells [88-90]. Red wine is one of the most abundant source of polyphenols and represents an important occidental dietary component. In recent years, epidemiological studies have demon- strated the cancer chemopreventive effects of red wine polyphenols (RWPs) [91,92]. In this context, we found that a whole extract of RWPs dose-dependently inhibits the proliferation of various cancer cell lines, including the acute lymphoblastic leukemia Jurkat and the P19 teratocarcinoma cell lines [93,94]. This growth inhibi- tion was correlated with an arrest of cell cycle progres- sion in G1 and to subsequent apoptosis. Further investigations allowed us to observe that RWPs-exposed leukemia cells exhibit a sharp increase of p73 level asso- ciated with a significant decrease in UHRF1 expression, in agreement with Alhosin et al., [67]. These findings indicate, therefore, that RWPs extract likely triggers cell cycle arrest and apoptosis by targeting UHRF1 through a p73-dependent pathway and a ROS-dependent pro- cess. Interestingly we have also observed that a RWPs extract significantly increased the formation of ROS (Figure 3A). Consistently, it has been recently shown that saikosaponins sensitize cancer cells to cisplatin through ROS-mediated apoptosis, and the combination of saikosaponins with cisplatin could be an effective therapeutic strategy [95]. An in vivo study has demonstrated that RWPs admini- strated with diet to rats inhibited azoxymethane-induced colon carcinogenesis [96], but the involved molecular mechanism remains unclear. Thus, to confirm in vivo the pathways involved in the protective effects of RWPs, we used a mouse model of colorectal cancer, by sub- cutaneously injecting C26 cells [97]. By using micro- angiography and immunohistochemistry approaches, we showed that regular consumption of RWPs in the drink- ing water decreased C26 tumour vascularization in BALB/C mice as a consequence of decreased expression of major proangiogenic factors including VEGF, matrix metalloproteinase 2 and 9, and cyclooxygenase-2 [97]. The RWPs-induced down-regulation of proangiogenic factors was associated with an activation of various TSGs such as p53, p73, p16INK4A and the cell cycle reg- ulator p21Waf1/Cip1. Interestingly, a strong immunostain- ing for UHRF1 was observed in the tumours from the control group, whereas low staining was found in those from RWPs-treated group. These results suggest a speci- fic role of this epigenetic actor in the progression of col- orectal tumor. Therefore, UHRF1 abundance is likely a preferred target of RWPs in C26 cells-induced Figure 3 Schematic representation of RWPs-induced apoptosis involving p73 and UHRF1 deregulation in Jurkat cells and in an in vivo colorectal cancer model. A. Schematic representation of RWPs-induced apoptosis involving p73 and UHRF1 deregulation in Jurkat cells. RWPs triggers production of reactive oxygen species (ROS) and putatively DNA damage. The activation of the p73 gene results in enhanced caspase 3 level inducing UHRF1 decrease with subsequent G1/S arrest and apoptosis. B. The pathway involved in vivo is similar to that observed in Jurkat cells by involving a down- regulation of UHRF1 with subsequent increase of p16INK4A gene expression. The down-regulation of UHRF1 is probably driven by p53 and/or p53. This is leading to an inhibition of tumor vascularization as a consequence of the down-regulation of the VEGF gene expression. tumorigenesis mouse model. However, the precise mechanism by which RWPs induce the up-regulation of TSGs in colorectal cancer models is presently unclear. Recently, it has been shown that apple polyphenols has potent DNA demethylation activity in colorectal cancers by reducing DNMT1 expression with a subsequent acti- vation of TSGs such as hMLH1, p14ARF and p16INK4A. These genes are known to be silenced through their promoter hypermethylation in colorectal cancers [98]. Consistently with this, it was recently shown that the polyphenol epigallocatechin gallate allows re-expression of p16INK4A and p21Waf1/Cip1 through a DNA demethyla- tion dependent process probably involving a down-regu- lation of DNMT1 [99]. In agreement with our previous studies [49,67], we propose two mechanisms targeting UHRF1 and underlying the antitumoral activities of RWPs in colorectal cancer. First, considering that UHRF1 binds to methylated promoters of TSGs, i.e., p16INK4A [44], and that UHRF1 interacts with DNMT1 and regulates its expression [49], it is likely that the RWPs-induced down-regulation of UHRF1, with subse- quent decrease of DNMT1, could be involved in the demethylation of the p16INK4A promoter (Figure 2B). Second, RWPs could trigger cell cycle arrest and