Quinone Reductase Induction as a Biomarker for Cancer Chemoprevention

Abstract

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.

Sites of alkylation of human Keap1 by natural chemoprevention agents

“…10-Shogaol was isolated and provided by Dr. Yi Tao of the University of Illinois College of Pharmacy, and xanthohumol was isolated and proScheme 1. Structures of the natural product chemoprevention agents (A) isoliquiritigenin [22]; (B) xanthohumol [28]; and (C) 10-shogaol [29]. The CD values represent the concentration of each compound required to double the intracellular quinone reductase activity in Hepa 1c1c7 murine hepatoma cells [22] and indicate the relative activities of these compounds as chemopreventive reagents.…”

“…All three of these natural products contain electrophilic unsaturated ketones (Scheme 1). As an indication of their chemopreventive activity through the induction of ARE, the induction of the phase 2 enzyme quinone reductase in Hepa 1c1c7 murine hepatoma cells by xanthohumol, isoliquiritigenin, and 10-shogaol has been determined to be 1.7 Ϯ 0.7, 1.8 Ϯ 0.44, and 42.4 Ϯ 0.9 M, respectively [22,28,29]. In this investigation, the relative reactivities of each of these compounds toward specific cysteine residues of human Keap1 were determined using LC-MS/MS, and the most reactive amino acid residue was identified as C151 for all three compounds.…”

Structural modulation of reactivity/activity in design of improved benzothiophene selective estrogen receptor modulators: induction of chemopreventive mechanisms

“…NQO1Induction via ARE Activation Measurement of NQO1 activity in vitro and in vivo provides an efficient assay for discovery of chemopreventive agents (29), and NQO1 is a biomarker for cancer chemoprevention (42). NQO1, as other inducible phase II enzymes such as glutathione S-transferases and UDPglucuronyl transferase, provides cytoprotection by detoxification of small molecules; however, NQO1 also binds and regulates the stability of the tumor suppressor protein p53, inhibiting p53 degradation (43).…”

Effect of oral administration of green tea extract in various dosage schemes on oxidative stress status of mice in vivo

“…As NQO converts quinones to hydroquinones and reduces oxidative cycling, its increase is considered chemopreventive (24). Hence, elevation of NQO activity is probably benefi cial for green tea catechins consumers.…”