Pomegranate-mediated chemoprevention of experimental hepatocarcinogenesis involves Nrf2-regulated antioxidant mechanisms

Abstract

Hepatocellular carcinoma (HCC), one of the most prevalent and lethal cancers, has shown an alarming rise in the USA. Without effective therapy for HCC, novel chemopreventive strategies may effectively circumvent the current morbidity and mortality. Oxidative stress predisposes to hepatocarcinogenesis and is the major driving force of HCC. Pomegranate, an ancient fruit, is gaining tremendous attention due to its powerful antioxidant properties. Here, we examined mechanism-based chemopreventive potential of a pomegranate emulsion (PE) against dietary carcinogen diethylnitrosamine (DENA)-induced rat hepatocarcinogenesis that mimics human HCC. PE treatment (1 or 10 g/kg), started 4 weeks prior to the DENA challenge and continued for 18 weeks thereafter, showed striking chemopreventive activity demonstrated by reduced incidence, number, multiplicity, size and volume of hepatic nodules, precursors of HCC. Both doses of PE significantly attenuated the number and area of γ-glutamyl transpeptidase-positive hepatic foci compared with the DENA control. PE also attenuated DENA-induced hepatic lipid peroxidation and protein oxidation. Mechanistic studies revealed that PE elevated gene expression of an array of hepatic antioxidant and carcinogen detoxifying enzymes in DENA-exposed animals. PE elevated protein and messenger RNA expression of the hepatic nuclear factor E2-related factor 2 (Nrf2). Our results provide substantial evidence, for the first time, that pomegranate constituents afford chemoprevention of hepatocarcinogenesis possibly through potent antioxidant activity achieved by upregulation of several housekeeping genes under the control of Nrf2 without toxicity. The outcome of this study strongly supports the development of pomegranate-derived products in the prevention and treatment of human HCC, which remains a devastating disease.

Effect of Punica Granatum (Pomegranate) on serum ALT and AST in Carbon tetrachloride induced liver damage in Wistar Albino Rats

“…Pomegranate has been known to posses considerable pharmacological properties as pomegranate peel is a rich source of antioxidants, especially polyphenols. In some recent studies, pomegranate fruit and flower extracts exhibited free-radicals scavenging properties with simultaneous potent hepatoprotection against chemically induced liver damage in rodents 10,11 .…”

Pharmacological Evaluation of Gatifloxacin in Chemically Induced Hepatocarcinogenesis: A New Tool for Hepatocellularcarcinoma Treatment

“…DENA is reported to be hepatotoxin and the hepatocarcinogenic agent [12]. In the present study, DENA induced hepatocellular damage is clearly evidenced by the marked elevation in serum SGPT, SGOT, GGTP, ALP and decrease level of glucose in the liver tissue, These biochemical marker enzymes are indicators of tumor response [13].…”

Punica granatum L. protects mice against hexavalent chromium-induced genotoxicity

“…The best results were observed with the 50mg/kg/day dose. In this respect, Bishayee et al (2011) found that pomegranate may act through the induction of Nrf2-regulated cytoprotective enzymes, which results in enhancing the excretion of the electrophilic carcinogen and reducing the formation of free radicals inductors of tumorigenesis. In contrast, the 75 mg/kg dose of PGE did not affect the bioavailability of this xenobiotic.…”

“…Moreover certain reports have shown considerable antioxidant activities of Punica granatum in several in vitro and in vivo experimental models (Chidambara et al, 2002;Cerda et al, 2003;Ricci et al, 2006;Bishayee et al, 2011). Such effects have been attributed to its effective action against ROS (Ozgen et al, 2008).…”