title: Cancer chemopreventive activity mediated by 4'-bromoflavone, a potent inducer of phase II detoxification enzymes.
abstract: Induction of phase II enzymes is an important mechanism of chemoprevention. In our search for novel cancer chemopreventive agents, 4'-bromoflavone (4'BF) was found to significantly induce quinone reductase (QR) activity in cultured murine hepatoma 1c1c7 cells (concentration to double activity: 10 nM) and effectively induce the alpha- and mu-isoforms of glutathione S-transferase in cultured H4IIE rat hepatoma cells with no observed toxicity. In short-term dietary studies, 4'BF was also shown to increase QR activity and glutathione levels in rat liver, mammary gland, colon, stomach, and lung in a dose-dependent manner. Induction mediated by 4'BF was bifunctional (induction of both phase I and phase II enzymes) and regulated at the transcriptional level, as revealed by transient transfection studies with plasmid constructs (pDTD-1097CAT, XRE-CAT, and ARE-CAT) and reverse transcription-PCR-based analysis of QR mRNA. In studies conducted with female Sprague Dawley rats, the effects of 4'BF on the relative induction levels of phase I and phase II enzyme activities were investigated in liver and mammary gland. Treatment with 4'BF and 7,12-dimethylbenz[a]anthracene (DMBA) or 4'BF alone did not significantly alter DMBA-induced cytochrome P4501A1 activity (phase I enzyme), but it significantly increased QR activity (phase II enzyme), compared with the DMBA treatment group. In addition, 4'BF was found to be a potent inhibitor of cytochrome P4501A1-mediated ethoxyresorufin-O-deethylase activity, with an IC50 of 0.86 microM. Furthermore, in studies conducted with cultured HepG2 or MCF-7 cells, 4'BF significantly reduced the covalent binding of metabolically activated benzo[a]pyrene to cellular DNA. On the basis of these results, a full-term cancer chemoprevention study was conducted with DMBA-treated female Sprague Dawley rats. Dietary administration of 4'BF (2000 and 4000 mg per kg of diet, from 1 week before to 1 week after DMBA) significantly inhibited the incidence and multiplicity of mammary tumors and greatly increased tumor latency. In summary, 4'BF can be viewed as a relatively simple, readily available, inexpensive compound that is a highly effective cancer chemopreventive agent. The full mechanism of action remains to be defined, but enhancement of detoxification pathways appears to be important.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 60612, USA.
authors.forename: L L
authors.initials: LL
authors.lastname: Song
authors.forename: J W
authors.initials: JW
authors.lastname: Kosmeder
authors.forename: S K
authors.initials: SK
authors.lastname: Lee
authors.forename: C
authors.initials: C
authors.lastname: Gerhäuser
authors.forename: D
authors.initials: D
authors.lastname: Lantvit
authors.forename: R C
authors.initials: RC
authors.lastname: Moon
authors.forename: R M
authors.initials: RM
authors.lastname: Moriarty
authors.forename: J M
authors.initials: JM
authors.lastname: Pezzuto
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002273:Carcinogens; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D004790:Enzyme Induction; D005260:Female; D005419:Flavonoids / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D008658:Inactivation, Metabolic; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000517:prevention & control; D018942:Macrolides; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control; D051379:Mice; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043823:Taxoids; D014407:Tumor Cells, Cultured