Uniform TitleInvolvement of the 5-lipoxygenase pathway in oro-esophageal carcinogenesis and chemopreventive effects of ziIeuton and green tea catechins
NameSood, Sandeep (author), Yang, Chung S. (chair), Chen, Xiaoxin (internal member), Ho, Chi Tang (internal member), Reuhl, Kenneth (outside member), Rutgers University, Graduate School-New Brunswick,
DescriptionOral and esophageal squamous cell carcinomas (SCC) are common neoplasms worldwide, especially in developing countries. Aberrant arachidonic acid (AA) metabolism, involving both the cyclooxygenase (Cox) and lipoxygenase (Lox) pathways has been suggested to play an important role in the development of inflammation and associated carcinogenesis.
The primary aim of this study was to evaluate the role of 5-Lox in oro-esophageal carcinogenesis. Zileuton, a 5-Lox inhibitor, was evaluated for its effect, in short- and long-term studies on oral carcinogenesis using the 7,12-dimethylbenz[a]anthracene (DMBA) induced hamster cheek pouch model. In the short-term study, zileuton significantly inhibited aberrant AA metabolism and cell hyperproliferation and in the long-term experiment it suppressed the incidence of visible tumors as well as the SCC. Zileuton and green tea catechins, alone and in combination, were also evaluated in 4-nitroquinoline-1-oxide (4-NQO)-induced oro-esophageal carcinogenesis in mice. In the first experiment, 4-NQO was administered to A/J mice (wild-type and p53A135V mutant) in drinking water for 8 weeks, followed by zileuton (1000 ppm in diet) or polyphenon E (PPE, 0.6% in drink) for another 16 weeks. Zileuton significantly reduced the overall incidence of SCC in tongue, esophagus and forestomach in wild-type A/J mice. PPE only significantly reduced carcinogenesis in the tongue of p53A135V mutant mice. Both agents suppressed cell proliferation and induced apoptosis, while only zileuton significantly reduced the mast cells density in cancer tissues of tongue and esophagus. In the second experiment, 4-NQO was administered to C57BL/6J mice in drinking water for 12 weeks, followed by zileuton (500, 1000 and 2000 ppm in diet) and epigallocatechin-3-gallate (EGCG, 0.16% and 0.32% in drink) alone or in combination (500 ppm zileuton and 0.16% EGCG) for another 16 weeks. Both agents were able to significantly inhibit tongue cancer. Zileuton and EGCG inhibited overall carcinogenesis, though only the effect of the former was dose-dependent. An additive effect was observed in the combination group in inhibiting the tongue and overall cancer incidence. In summary, we report here that 5-Lox is involved in the pathogenesis of oro-esophageal carcinogenesis and its inhibitors, zileuton and green tea catechins, elicit chemopreventive activity in animal models.
Note[bibliography] Includes bibliographical references (p. 65-78).
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.