This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Song, L. L. Articles by Pezzuto, J. M. Search for Related Content PubMed PubMed Citation Articles by Song, L. L. Articles by Pezzuto, J. M.

Cancer Chemopreventive Activity Mediated by 4'-Bromoflavone, a Potent Inducer of Phase II Detoxification Enzymes¹

Program for Collaborative Research in the Pharmaceutical Sciences, and Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy [L. L. S., S. K. L., C. G., J. M. P.]; Department of Chemistry, College of Liberal Arts and Sciences [J. W. K., R. M. M.]; and Department of Surgical Oncology, College of Medicine [D. L., R. C. M., J. M. P.], University of Illinois at Chicago, Chicago, Illinois 60612

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 - and µ-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 µM. 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.

This article has been cited by other articles:

				B. Yu, B. M. Dietz, T. Dunlap, I. Kastrati, D. D. Lantvit, C. R. Overk, P. Yao, Z. Qin, J. L. Bolton, and G. R.J. Thatcher Structural modulation of reactivity/activity in design of improved benzothiophene selective estrogen receptor modulators: induction of chemopreventive mechanisms Mol. Cancer Ther., September 1, 2007; 6(9): 2418 - 2428. [Abstract] [Full Text] [PDF]

				C.-T. Yeh and G.-C. Yen Involvement of p38 MAPK and Nrf2 in phenolic acid-induced P-form phenol sulfotransferase expression in human hepatoma HepG2 cells Carcinogenesis, May 1, 2006; 27(5): 1008 - 1017. [Abstract] [Full Text] [PDF]

				Y. Zhang and G. B. Gordon A strategy for cancer prevention: Stimulation of the Nrf2-ARE signaling pathway Mol. Cancer Ther., July 1, 2004; 3(7): 885 - 893. [Abstract] [Full Text] [PDF]

				E. B. Izevbigie, J. L. Bryant, and A. Walker A Novel Natural Inhibitor of Extracellular Signal-Regulated Kinases and Human Breast Cancer Cell Growth Experimental Biology and Medicine, February 1, 2004; 229(2): 163 - 169. [Abstract] [Full Text] [PDF]

				E. M. Ellis, C. M. Slattery, and J. D. Hayes Characterization of the rat aflatoxin B1 aldehyde reductase gene, AKR7A1. Structure and chromosomal localization of AKR7A1 as well as identification of antioxidant response elements in the gene promoter Carcinogenesis, April 1, 2003; 24(4): 727 - 737. [Abstract] [Full Text] [PDF]

				K. Okada, C. Wangpoengtrakul, T. Tanaka, S. Toyokuni, K. Uchida, and T. Osawa Curcumin and Especially Tetrahydrocurcumin Ameliorate Oxidative Stress-Induced Renal Injury in Mice J. Nutr., August 1, 2001; 131(8): 2090 - 2095. [Abstract] [Full Text] [PDF]

				Q. Mi, B. Cui, G. L. Silva, D. Lantvit, E. Lim, H. Chai, M. You, M. G. Hollingshead, J. G. Mayo, A. D. Kinghorn, et al. Pervilleine A, a Novel Tropane Alkaloid that Reverses the Multidrug-resistance Phenotype Cancer Res., May 1, 2001; 61(10): 4030 - 4037. [Abstract] [Full Text]

				Prevention of Cancer in the Next Millennium: Report of the Chemoprevention Working Group to the American Association for Cancer Research Cancer Res., October 1, 1999; 59(19): 4743 - 4758. [Full Text] [PDF]