Quinone reductase induction as a biomarker for cancer chemoprevention.
Chemoprevention involves the use of natural or synthetic substances to reduce the risk of developing cancer. Strategies for protecting cells from initiation events include decreasing metabolic enzymes responsible for generating reactive species (phase I enzymes) while increasing phase II enzymes that can deactivate radicals and electrophiles known to intercede in normal cellular processes. Reduction of electrophilic quinones by quinone reductase is an important detoxification pathway. Following evaluation of approximately 3000 plant and marine organism extracts, the number characterized as "active" was established in the range of 12% of the total, and over 60 active compounds have been isolated as quinone reductase inducers. One of them, isoliquiritigenin (1), isolated from tonka bean, was shown to be a monofunctional inducer by having similar quinone reductase inducing ability in wild-type Hepa 1c1c7 cells and two mutant cell lines. To further investigate the mechanism of induction, HepG2 human hepatoma cells stably transfected with ARE-luciferase plasmid were used. Isoliquiritigenin (1) significantly induced the luciferase activity in a dose-dependent manner. On the basis of these results, a full-term cancer chemoprevention study was conducted with 7,12-dimethylbenz[a]anthracene (DMBA)-treated female Sprague-Dawley rats. Dietary administration of 1 increased tumor latency. Based on these promising preliminary results, additional mechanistic studies are underway, as well as full-term carcinogenesis studies with chronic administration schedules.
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
Muriel
M
Cuendet
Carol P
CP
Oteham
Richard C
RC
Moon
John M
JM
Pezzuto
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D015415:Biomarkers; D002599:Chalcone / Q000031:analogs & derivatives* / Q000494:pharmacology; D047188:Chalcones; D004195:Disease Models, Animal; D004790:Enzyme Induction; D015394:Molecular Structure; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis / Q000378:metabolism; D010946:Plants, Medicinal / Q000737:chemistry*; D051381:Rats
D016588:Anticarcinogenic Agents; D015415:Biomarkers; D047188:Chalcones; D002599:Chalcone; C040920:isoliquiritigenin; D016660:NAD(P)H Dehydrogenase (Quinone)