We determined that p73 was responsible for UHRF1 down-regulation through a caspase-3 dependent process. PF-3084014 A subsequent study allowed us to propose that down-regulation of phosphodiesterase 1A (PDE1A), a modulator of cAMP and cGMP cyclic nucleotides, could be the key event to explain the TQ-induced down-regulation of UHRF1 and the occurrence of apoptosis [82]. All these findings showed for the first time that a natural compound induces apoptosis by acting on the epigenetic integrator UHRF1 through a p73-dependent mitochondrial pathway. 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 attributed, at least partly, to polyphenols which
have been described to have in vitro and in vivo anti-tumoral properties in several types of cancer cells [88–90]. Red wine is one of the most HDAC inhibitor drugs abundant source of polyphenols and represents an important occidental dietary component. In recent years, epidemiological studies have demonstrated the cancer chemopreventive effects of red wine polyphenols (RWPs) [91, 92]. In this context, we found that a whole HSP990 in vivo 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 inhibition was correlated with an arrest of cell cycle progression in G1 and to subsequent apoptosis. Further investigations allowed us to observe that RWPs-exposed leukemia cells exhibit a sharp increase of p73 level associated 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 process. 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]. Figure 3 Schematic representation of RWPs-induced apoptosis involving p73 and UHRF1 Galeterone 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 p16 INK4A gene expression. The down-regulation of UHRF1 is probably driven by p53 and/or p53.