Keap1 eye on the target: chemoprevention of liver cancer.
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, causing nearly 600,000 deaths each year. Increased risk of HCC due to chronic infection with hepatitis B virus (HBV) and exposure to dietary aflatoxins is responsible for many of these deaths. Prevention strategies targeting HBV infection and aflatoxin exposure could dramatically impact the rates of HCC. Universal HBV vaccination programs have begun in some high-risk areas. Strategies to reduce aflatoxin contamination in food stores have also been implemented. However, complete elimination of aflatoxin contamination might not be possible. For this reason, chemoprevention strategies which alter aflatoxin disposition are a practical strategy to reduce the incidence of HCC in populations with high dietary aflatoxin exposure. The mechanisms of aflatoxin-induced hepatocarcinogenesis are well known. This knowledge provides the basis for evaluation of both exposures to aflatoxin, as well as modulation of aflatoxin disposition by chemopreventive agents. Products of aflatoxin DNA damage and toxicity as well as other metabolites can be used as biomarkers to evaluate modulation of aflatoxin disposition. Modulation of aflatoxin disposition can be achieved through induction of conjugating and cytoprotective enzymes. Many of these enzymes are regulated through Kelch ECH-associating protein 1 (Keap1)-NF-E2-related factor 2(Nrf2)-antioxidant response element (ARE) signaling, making this pathway an important molecular target for chemoprevention. Rodent studies have identified several classes of chemopreventive agents which induce cytoprotective genes. These inducers include phenolic antioxidants, dithiolethiones, isothiocyanates, and triterpenoids. Furthermore, clinical interventions have shown that inducers of Keap1-Nrf2- ARE signaling increase cytoprotective enzyme expression, resulting in modulation of aflatoxin disposition. Much work remains to be done in order to take promising chemopreventive agents from preclinical evaluation to application in at-risk populations. However, appropriately designed clinical trials will aid in this process, which can have profound impact on the incidence of HCC.
Yates
Melinda Sue
MS
Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA.
Kensler
Thomas Wells
TW
D000348:Aflatoxins / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000178:diet therapy / Q000188:drug therapy / Q000517:prevention & control*; D002986:Clinical Trials as Topic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D017879:Isothiocyanates; D000072019:Kelch-Like ECH-Associated Protein 1; D008113:Liver Neoplasms / Q000178:diet therapy / Q000188:drug therapy / Q000517:prevention & control*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology / Q000627:therapeutic use; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology / Q000627:therapeutic use; D013871:Thiones; D013876:Thiophenes; D014315:Triterpenes / Q000494:pharmacology / Q000627:therapeutic use
D000348:Aflatoxins; D016588:Anticarcinogenic Agents; D000975:Antioxidants; D047908:Intracellular Signaling Peptides and Proteins; D017879:Isothiocyanates; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D010636:Phenols; D011719:Pyrazines; D013454:Sulfoxides; D013861:Thiocyanates; D013871:Thiones; D013876:Thiophenes; D014315:Triterpenes; C026209:oltipraz; C016766:sulforaphane