Title: Differential in vivo mechanism of chemoprevention of tumor formation in azoxymethane/dextran sodium sulfate mice by PEITC and DBM.

Authors: Cheung, Ka Lung; Khor, Tin Oo; Huang, Mou-Tuan; Kong, Ah-Ng

Published In Carcinogenesis, (2010 May)

Abstract: Previously, phenethyl isothiocyanate (PEITC) and dibenzoylmethane (DBM) had been shown to inhibit intestinal carcinogenesis in Apc(Min/+) mice. In this study, we investigated the chemopreventive efficacy of PEITC and DBM in the azoxymethane (AOM)-initiated and dextran sodium sulfate (DSS)-promoted colon cancer mouse model and to compare their potential in vivo mechanisms leading to chemoprevention. The mice were fed with diet supplemented with 0.05% PEITC or 1% DBM before or after AOM initiation. Our results showed that AOM/DSS mice fed with PEITC- or DBM-supplemented diet had lower tumor incidence, lower colon tumor multiplicities and smaller polyps as compared with mice fed with the standard AIN-76A diet. PEITC was effective even after AOM initiation, whereas DBM was not as effective when fed after AOM initiation. Hematoxylin and eosin staining showed that mice fed with PEITC or DBM had attenuated loss of crypt, a marker of inflammation. To examine potential in vivo mechanisms involved in chemoprevention, western blotting was performed and showed that inhibition of growth of adenomas by PEITC was associated with an increase of apoptosis (increased cleaved caspase-3 and-7) and cell cycle arrest (increased p21). In contrast DBM's effect on cell cycle arrest and apoptosis markers was not as substantial as PEITC. Instead, DBM showed increased induction of NF-E2-related factor-2 (Nrf2) transcription factor and phase II detoxifying enzymes, which appears to correlate with in vitro cell lines results that DBM is a more potent Nrf2 activator than PEITC. In summary, our present study shows that PEITC and DBM are potent natural dietary compounds for chemoprevention of colon cancer induced by AOM/DSS and appears to be associated with different in vivo mechanism of actions. PEITC's chemopreventive effect appears to be due to induction of apoptosis and cell cycle arrest, whereas DBM's effect is due to prevention of AOM initiation via induction of Nrf2 and phase II detoxifying enzymes.

PubMed ID: 19959557

MeSH Terms: Animals; Anticarcinogenic Agents/pharmacology*; Apoptosis/drug effects; Azoxymethane/toxicity*; Body Weight/drug effects; Cell Cycle/drug effects; Chalcones/pharmacology*; Colorectal Neoplasms/chemically induced; Colorectal Neoplasms/pathology; Colorectal Neoplasms/prevention & control*; Dextran Sulfate/toxicity*; Intestinal Mucosa/pathology; Intestinal Polyps/pathology; Isothiocyanates/pharmacology*; Male; Mice; Mice, Inbred C57BL