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Chemoprevention of 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster cheek pouch carcinogenesis by a 5-lipoxygenase inhibitor, garcinol.

Abstract
Our previous studies have shown that aberrant arachidonic acid metabolism, especially the 5-lipoxygenase (5-Lox) pathway, is involved in oral carcinogenesis and can be targeted for cancer prevention. To develop potent topical agents for oral cancer chemoprevention, 5 known 5-Lox inhibitors from dietary and synthetic sources (Zileuton, ABT-761, licofelone, curcumin, and garcinol) were evaluated in silico for their potential efficacy. Garcinol, a polyisoprenylated benzophenone from the fruit rind of Garcinia spp., was found to be a promising agent based on the calculation of a theoretical activity index. Computer modeling showed that garcinol well fit the active site of 5-Lox, and potentially inhibited enzyme activity through interactions between the phenolic hydroxyl groups and the non-heme catalytic iron. In a short-term study on 7,12-dimethylbenz[a]anthracene (DMBA)-treated hamster cheek pouch, topical garcinol suppressed leukotriene B4 (LTB4) biosynthesis and inhibited inflammation and cell proliferation in the oral epithelium. In a long-term carcinogenesis study, topical garcinol significantly reduced the size of visible tumors, the number of cancer lesions, cell proliferation, and LTB4 biosynthesis. These results demonstrated that topical application of a 5-Lox inhibitor, garcinol, had chemopreventive effect on DMBA-induced hamster cheek pouch carcinogenesis.
AuthorsXin Chen, Xinyan Zhang, Ye Lu, Joong-Youn Shim, Shengmin Sang, Zheng Sun, Xiaoxin Chen
JournalNutrition and cancer (Nutr Cancer) Vol. 64 Issue 8 Pg. 1211-1218 ( 2012) ISSN: 1532-7914 [Electronic] United States
PMID23137051 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Anticarcinogenic Agents
  • Carcinogens
  • Lipoxygenase Inhibitors
  • Plant Extracts
  • Terpenes
  • Leukotriene B4
  • 9,10-Dimethyl-1,2-benzanthracene
  • garcinol
Topics
  • 9,10-Dimethyl-1,2-benzanthracene
  • Animals
  • Anticarcinogenic Agents (administration & dosage)
  • Carcinogens
  • Cell Proliferation (drug effects)
  • Cheek
  • Cricetinae
  • Leukotriene B4 (antagonists & inhibitors, biosynthesis)
  • Lipoxygenase Inhibitors (administration & dosage)
  • Male
  • Mesocricetus
  • Mouth Neoplasms (chemically induced, pathology, prevention & control)
  • Plant Extracts
  • Terpenes (administration & dosage)

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