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

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

Bishayee Anupam; Bhatia Deepak; Thoppil Roslin J; Darvesh Altaf S; Nevo Eviatar; Lansky Ephraim P

Carcinogenesis

2011

2011-06

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 gamma-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

*Phytotherapy; Alkylating Agents/toxicity; Animals; Antioxidants/*therapeutic use; Blotting; Carcinoma; Diethylnitrosamine/toxicity; Experimental/chemically induced/*drug therapy/metabolism; GA-Binding Protein Transcription Factor/*metabolism; gamma-Glutamyltransferase/metabolism; Hepatocellular/chemically induced/*drug therapy/metabolism; Immunoenzyme Techniques; Lipid Peroxidation/drug effects; Liver Neoplasms; Male; Oxidative Stress; Plant Extracts/*therapeutic use; Punicaceae/*chemistry; Rats; Sprague-Dawley; Western

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