10, 19 Among the physiological alterations cancer cells undergo as they continue to grow are the increase

in cell proliferation and the loss of apoptotic mechanisms.20, 21 In this study, saffron demonstrated significant antiproliferative activity by causing pronounced cell cycle arrest in vitro (Fig. 5) and reducing the number of proliferative cells (Ki-67–positive cells18) in DEN-treated animals (Fig. 3; Supporting Fig. 3). The antiproliferative activity of saffron was also associated with the induction of apoptosis as evidenced in vitro by caspase-3 GSI-IX cost cleavage and the pre-G predominant fraction in PI-FACS analysis. The apoptotic induction must have resulted from DNA damage as reflected by the up-regulation of the double-stranded DNA breakage marker, p-H2XA, (Fig. 5D) suggesting an additional role of saffron in sensitizing cancer cells to the effects of other chemotherapeutics. Consistently, saffron treatment find more increased the number of TUNEL- and M30 CytoDeath–positive cells in vivo (Fig. 3; Supporting Figs. 4 and 5). These results are in agreement with previous in vitro studies showing apoptosis and antiproliferative effect of saffron in various tumor cell lines.4, 22 These results seem to indicate that the inhibition of neoplastic development

in rat liver was associated with a reduction of cell proliferation and an induction of apoptosis. Increased oxidative stress can induce a wide spectrum of cellular damage and cellular

signaling changes that has been associated with carcinogenesis.20, 21 Administration of saffron to DEN-treated rats in this study counteracted DEN-induced oxidative stress as shown by restoration of antioxidant levels of SOD, CAT, and GST in the liver and diminishing of important markers of oxidative stress, such as oxidized lipids (MDA) and proteins (P.Carbonyl). The antioxidant effect of saffron was also accompanied by a decrease in liver damage markers, namely, serum ALT and GGT levels, suggesting a concomitant protection against hepatic damage. The prevention of oxidative stress and hepatic toxicity by saffron might be attributed to its potent antioxidant capacity which was confirmed in this study. Saffron showed ABTS and DPPH radical scavenging activities Resminostat and exhibited significant reducing power as indicated by the FRAP assay. The Antioxidant property of saffron could be credited to its phenolic content and to its active ingredients (such as safranal, crocin, crocetin, and carotene) (Table 1), all of which have been reported to have antioxidant properties.23 The association between decreased oxidative damage and reduced nodular and GST-P positive foci formations suggest that the antioxidant efficacy exhibited by saffron may be an important factor for its anticarcinogenic property.