Cancer-preventive anti-oxidants that attenuate free radical generation by inflammatory cells.
Active inflammatory leukocytes are a major endogenous source of reactive oxygen and nitrogen oxide species (RONS). We have recently established novel bioassay systems, in which either phorbol ester-stimulated, differentiated HL-60 human leukemia cells or lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophages were co-cultured with AS52 Chinese hamster ovary cells. Extensive screening of extracts from Asian vegetables and fruits led to the identification of 1'-acetoxychavicol acetate (ACA), auraptene, nobiletin, and zerumbone, all of which were found to be highly anti-mutagenic in the above co-culture systems. Pretreatment of RAW264.7 macrophages with LPS led to the activation of mitogen-activated protein kinases (MAPKs) and Akt, together with the degradation of IkappaB-alpha protein, and the resultant activation of the AP-1, NF-kappaB, and CREB transcription factors. ACA abrogated ERK1/2 and JNK1/2, but not p38 activation, as well as the activation and transcriptional activation of NF-kappaB and CREB, whereas nobiletin allowed phosphorylation of these MAPKs, while it suppressed AP-1, NF-kappaB, and CREB activation. Interestingly, zerumbone did not have any effects on the latter transcription factors, although it did attenuate iNOS mRNA expression. In addition, auraptene suppressed iNOS protein production, but not mRNA expression, implying that it targets the translation step. Our model systems may be useful for identifying potentially anti-carcinogenic inhibitors of RONS generation.
Murakami
Akira
A
Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan. cancer@kais.kyoto-u.ac.jp
Ohigashi
Hajime
H
D000818:Animals; D016588:Anticarcinogenic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D018920:Coculture Techniques; D006224:Cricetinae; D005609:Free Radicals / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism
D016588:Anticarcinogenic Agents; D000975:Antioxidants; D005609:Free Radicals; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse