Chemopreventive effects of Furan-2-yl-3-pyridin-2-yl-propenone against 7,12-dimethylbenz[a]anthracene-inducible genotoxicity.
1-Furan-2-yl-3-pyridin-2-yl-propenone (FPP-3) is an anti-inflammatory agent with a propenone moiety and chemically synthesized recently. In this study, we examined the chemopreventive effect of FPP-3 on 7,12-dimethylbenz[a]anthracene (DMBA)-induced genotoxicity in MCF-7 cells. FPP-3 reduced the formation of the DMBA-DNA adduct. DMBA-induced CYP1A1 and CYP1B1 gene expression and enzyme activity were inhibited by FPP-3. It inhibited DMBA-induced aryl hydrocarbon receptor (AhR) transactivation and DMBA-inducible nuclear localization of the AhR. Induction of detoxifying phase II genes by chemopreventive agents represents a coordinated protective response against oxidative stress and neoplastic effects of carcinogens. Transcription factor NF-E2 related factor 2 (Nrf2) regulates antioxidant response element (ARE) of phase II detoxifying and antioxidant enzymes, such as glutathione S-transferase (GST) and NAD(P)H:quinone oxidoreductase (QR). FPP-3 increased the expression and enzymatic activity of GST and QR. Moreover, FPP-3 increased transcriptional activity of GST and QR. GST and QR induction and Nrf2 translocation by FPP-3 were blocked by the PKC inhibitor Gö6983, and the p38 inhibitor SB203580. These results reflected a partial role of PKC delta and p38 signaling in FPP-3-mediated GSTA and QR induction through nuclear translocation of Nrf2. Classically, chemopreventive agents either inhibit CYP metabolizing enzyme or induce phase II detoxifying enzymes. These results suggest that FPP-3 has a potent protective effect against DMBA-induced genotoxicity through modulating phase I and II enzymes and that it has potential as a chemopreventive agent.
Hwang
Yong Pil
YP
BK21 Project Team, Department of Pharmacy, College of Pharmacy, Research Center for Proteineous Materials, Chosun University, Gwangju, Republic of Korea.
Han
Eun Hee
EH
Choi
Jae Ho
JH
Kim
Hyung Gyun
HG
Lee
Kyung Jin
KJ
Jeong
Tae Cheon
TC
Lee
Eung Seok
ES
Jeong
Hye Gwang
HG
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000378:metabolism / Q000633:toxicity*; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D018736:DNA Adducts / Q000378:metabolism; D005663:Furans / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D011407:Propane / Q000031:analogs & derivatives* / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology*; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism
C508534:1-furan-2-yl-3-pyridin-2-yl-propenone; D016588:Anticarcinogenic Agents; D018736:DNA Adducts; D005663:Furans; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D011725:Pyridines; D018336:Receptors, Aryl Hydrocarbon; D015127:9,10-Dimethyl-1,2-benzanthracene; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D016660:NAD(P)H Dehydrogenase (Quinone); D005982:Glutathione Transferase; D011493:Protein Kinase C; D011407:Propane