Chemopreventive effects of diverse dietary phytochemicals against DMBA-induced hamster buccal pouch carcinogenesis via the induction of Nrf2-mediated cytoprotective antioxidant, detoxification, and DNA repair enzymes.

Abstract

Identifying agents that activate nuclear factor erythroid-2 related factor-2 (Nrf2), a key regulator of various cytoprotective antioxidant, and detoxifying enzymes has evolved as a promising strategy for cancer chemoprevention. In the present study, we investigated the effect of dietary supplementation of structurally diverse phytochemicals- astaxanthin, blueberry, chlorophyllin, ellagic acid, and theaphenon-E on Nrf2 signaling, and xenobiotic-metabolizing and antioxidant enzymes in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis model. We observed that these phytochemicals induce nuclear accumulation of Nrf2 while downregulating its negative regulator, Keap-1. This was associated with reduced expression of CYP1A1 and CYP1B1, the cytochrome P450 isoforms involved in the activation of DMBA, and the oxidative stress marker 8-hydroxy-2'-deoxyguanosine coupled with upregulation of the phase II detoxification enzymes glutathione S-transferases and NAD(P)H:quinone oxidoreductase 1 and the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase. In addition, these dietary phytochemicals also enhanced the DNA repair enzymes 8-oxoguanine glycosylase 1 (OGG1), xeroderma pigmentosum D (XPD), xeroderma pigmentosum G (XPG), and x-ray repair cross complementing group 1 (XRCC1). Our data provide substantial evidence that the dietary phytochemicals inhibit the development of HBP carcinomas through the activation of Nrf2/Keap-1 signaling and by upregulating cytoprotective enzymes. The extent of the chemopreventive effects of the phytochemicals was in the order: chlorophyllin > blueberry > ellagic acid > astaxanthin > theaphenon-E. Thus these dietary phytochemicals that function as potent activators of Nrf2 and its orchestrated response are novel candidates for cancer chemoprevention.

• Authors: K Kavitha, P Thiyagarajan, J Rathna Nandhini, Rajakishore Mishra, S Nagini
• Journal: Biochimie (Biochimie) Vol. 95 Issue 8 Pg. 1629-39 (Aug 2013) ISSN: 1638-6183 [Electronic] France
• PMID: 23707664 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• NF-E2-Related Factor 2
• Phytochemicals
• 9,10-Dimethyl-1,2-benzanthracene
• DNA Repair Enzymes

Topics

• 9,10-Dimethyl-1,2-benzanthracene
• Animals
• Antineoplastic Agents (pharmacology)
• Blotting, Western
• Carcinogenesis (drug effects)
• Cricetinae
• DNA Repair Enzymes (metabolism)
• Male
• Mouth Neoplasms (chemically induced, prevention & control)
• NF-E2-Related Factor 2 (metabolism)
• Phytochemicals (pharmacology)
• Polymerase Chain Reaction
• Signal Transduction (drug effects)