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Cancer chemopreventive activity mediated by 4'-bromoflavone, a potent inducer of phase II detoxification enzymes
L L Song1, J W Kosmeder, S K Lee
1Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 60612, USA.
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.
Insights
4-bromoflavone (4'BF) is a potent cancer chemopreventive agent that effectively induces detoxification enzymes and inhibits tumor formation. This compound enhances cellular defense mechanisms, offering a promising strategy for cancer prevention.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Chemoprevention strategies are crucial for cancer control.
- Induction of phase II detoxification enzymes is a key mechanism in chemoprevention.
- Novel agents are needed to enhance cellular defense against carcinogens.
Purpose of the Study:
- To investigate the chemopreventive potential of 4'-bromoflavone (4'BF).
- To elucidate the mechanisms underlying 4'BF's chemopreventive effects, focusing on enzyme induction and carcinogen metabolism.
- To evaluate the efficacy of 4'BF in a preclinical cancer model.
Main Methods:
- In vitro studies using hepatoma cell lines to assess quinone reductase (QR) and glutathione S-transferase (GST) induction.
- Short-term dietary studies in rats to measure enzyme activities and glutathione levels in various tissues.
- Transcriptional regulation analysis using plasmid constructs and RT-PCR.
- Inhibition assays for cytochrome P4501A1 activity and benzo[a]pyrene DNA adduct formation.
- A long-term cancer chemoprevention study in DMBA-treated rats.
Main Results:
- 4'BF significantly induced QR and GST activities in cultured cells and in vivo across multiple rat tissues.
- Induction was dose-dependent, regulated at the transcriptional level, and bifunctional (affecting both phase I and phase II enzymes).
- 4'BF inhibited P4501A1-mediated ethoxyresorufin-O-deethylase activity and reduced benzo[a]pyrene DNA adducts.
- Dietary 4'BF significantly inhibited mammary tumor incidence and multiplicity and increased tumor latency in DMBA-treated rats.
Conclusions:
- 4'-bromoflavone is a highly effective, inexpensive, and readily available cancer chemopreventive agent.
- 4'BF enhances detoxification pathways, contributing to its chemopreventive efficacy.
- Further research is warranted to fully define the mechanism of action of 4'BF.