Reactive oxygen species (ROS) and related oxidative stress are linked with various diseases including cardiovascular disease, cancer, chronic lung diseases, and diabetes mellitus. Interventions favoring the scavenging of ROS to attenuate the oxidative stress may prevent oxidant stress associated diseases. Recent studies suggest that various fruits and vegetables contain high concentrations of antioxidants. Quercitrin is a glycosylated form of flavonoid compounds, widely distributed in nature, and is ubiquitous in plants, fruits, seeds, and vegetables. Our preliminary studies show that this compound displayed a stronger antioxidant activity than that of ascorbic acid over the same concentration range. It blocked TPA-induced neoplastic transformation in JB6 P+ cells. Pretreatment of JB6 cells with quercitrin down-regulated activation of AP-1, NF- :B induced by UVB or TPA. In the skin of AP-1-luciferase transgenic mice, topical treatment of mouse with quercitrin markedly blocked the TPA-induced AP-1 activation. Further studies indicated that these inhibitory actions appear to be mediated through the inhibition of MAPKs phosphorylation, including ERKs, p38 kinase, and JNKs. In addition, quercitrin stimulated the activation of NF-E2-related factor (Nrf2) and GST ARE- luciferase activity. Comet assays showed that quercitrin could block DNA damage induced by UVB. These preliminary studies indicate that quercitrin may function as a potential chemopreventive and chemotherapeutic agent. The overall hypothesis of this application is that quercitrin functions as an antioxidant and protects UV- induced carcinogenesis. The goal of this proposal is to test this hypothesis.
Aim 1 will investigate the antioxidant properties of quercitrin in both non-cellular and cellular. We will study whether quercitrin scavenges free radicals or inhibits their generation and determine reaction rate constants of the reactions between quercitrin and oxygen radicals. Moreover, we will detect the UV-induced free radical generation from UV- irradiated skin of living animal using in vivo electron spin resonance (ESR) spin trapping and identify the radicals generated.
Aim 2 will investigate the inhibitory effects of quercitrin against the UV-induced oxidative damage to lipid, protein, and DNA, and UV-induced tumorigenesis and cell proliferation in SKH-1 hairless mice. This study represents first detection of free radicals generated by UV-irradiated skin of living animals and may potentially open a new avenue to evaluate the properties of antioxidant against free radicals generated in living animals. Another significance of the study is the identification of qucertrin as a preventive agent against UV-induced skin cancers.

Public Health Relevance

Reactive oxygen species (ROS) and related oxidative stress are linked with various diseases including cardiovascular disease, cancer, chronic lung diseases, and diabetes mellitus. Interventions favoring the scavenging of ROS to attenuate the oxidative stress may prevent oxidative stress associated diseases. This proposal will test the hypothesis that quercitrin, a compound found in blackberries and other foods, functions as an antioxidant and protects UV-induced carcinogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21ES019249-02
Application #
8227982
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Humble, Michael C
Project Start
2011-02-15
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2012
Total Cost
$185,625
Indirect Cost
$60,625
Name
University of Kentucky
Department
Pharmacology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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Gao, Ning; Cheng, Senping; Budhraja, Amit et al. (2012) 3,3'-Diindolylmethane exhibits antileukemic activity in vitro and in vivo through a Akt-dependent process. PLoS One 7:e31783
Gao, Ning; Cheng, Senping; Budhraja, Amit et al. (2012) Ursolic acid induces apoptosis in human leukaemia cells and exhibits anti-leukaemic activity in nude mice through the PKB pathway. Br J Pharmacol 165:1813-26