A. When the SRA domain of UHRF1 meets hemi-methylated DNA present in the p16 INK4A promoter, UHRF1 acts as a guide for DNMT1 to methylate the complementary DNA strand. Subsequently a p16 INK4A gene repression and VEGF gene activation are maintained on the DNA daughter strands, i.e., in the daughter cancer cells. B. The UHRF1 down-regulation, by natural compounds such as TQ or polyphenols, induces the DNMT1

abundance decrease, that is accompanied by a p16 INK4A gene re-expression and a down-regulation of VEGF gene expression. Over the last millenium, herbal products have been commonly used for prevention and treatment of various diseases including cancer [69–71]. One of these natural products is curcumin which has potent anti-cancer properties in experimental

systems. Curcumin is consumed in high quantities SRT1720 chemical structure in Asian countries and epidemiological studies have attributed the lower rate of colon cancer in these countries to its consumption [72]. Green tea is also widely consumed in Asia countries. This natural product, which is rich in polyphenols, has been shown to significantly decrease the risk of Crenigacestat breast and ovarian cancers in women in Asian countries [73]. Black seed (nigella sativia) belongs to the Ranunculaceae family which grows in the Mediterranean sea and Western Asia countries, including Pakistan, India and China [74]. This plant is used in traditional folk medicine for the prevention and the treatment of numerous diseases such as eczema, cough, bacterial and viral infections, hypertension and diabetes [75]. The chemotherapeutic and chemopreventive activities of black cumin oil are attributed to thymoquinone (TQ). Several in vitro and in vivo studies have shown that TQ has potent cytotoxic and genotoxic activities on

a wide range of cancer cells [76–80]. TQ exerts its anti-cancer effects by inhibiting cell proliferation, arresting cell cycle progression and inducing subsequently apoptosis by p53- AZD1480 cell line dependent or -independent pathways. By using the acute lymphoblastic leukemia jurkat cell model (p53 mutated cell line), we have demonstrated that TQ triggers apoptosis through the production of reactive oxygen species (ROS) and the activation Carnitine dehydrogenase of the p73 gene [67]. This tumor suppressor gene seems to act as a cellular gatekeeper by preventing the proliferation of TQ-exposed Jurkat cells [67]. Obviously, the observed p73 activation triggers G1 cell cycle arrest and apoptosis. Interestingly, a transient TQ concentration-dependent up-regulation of caspase 3 cleaved subunits was also observed, suggesting that TQ exerts its apoptotic activity through a p73-dependent caspase-dependent cell death pathway. Consistently with our study, it was recently reported that catechin, a natural polyphenolic compound, induces apoptosis, in a similar way as does TQ, by its ability to increase the expression of pro-apoptotic genes such as caspase-3, -8, and -9 and p53 [81].