Carcinogenesis Advance Access published online on January 16, 2004
Carcinogenesis, doi:10.1093/carcin/bgh034
© 2004 by Oxford University Press
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MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
1 Health and Bioscience Laboratories, Meiji Seika Kaisha Ltd., 5-3-1, Chiyoda Sakado 350-0289, Japan
* Corresponding author. E-mail: naomi_osakabe{at}meiji.co.jp.
Received 25 June 2003
; revised 26 October 2003
; accepted 13 November 2003
Perilla frutescens extract showed marked reduction on tumorigenesis in a murine, two-stage skin carcinogenesis model. In this model, cancer is initiated by application of 7, 12-dimethylbenz[a]anthracene (DMBA) and promoted by application of 12-tetradecanoylphorbol 13-acetate (TPA). Following tumor initiation with DMBA, topical application of a perilla-derived fraction(PF) at doses of 2 mg/mouse/application resulted in significant inhibition of tumorigenesis. The efficacy of each fraction was correlated with rosmarinic acid (RA) and luteolin concentration. Topical application of perilla extract (PE) that contained 68% RA or an equivalent amount of commercially available RA and luteolin showed nearly identical anti-inflammatory activity 5 hours after TPA treatment. Application of luteolin had less anti-inflammatory activity. Marked neutrophil infiltration was observed in TPA-challenged skin by histological examination using hematoxylin-eosin. This change was greatly reduced by pretreatment with PE or RA. Myeloperoxidase activity, a marker of neutrophil recruitment, was also increased in TPA-challenged skin and was significantly decreased in the PE and RA treated groups. ICAM-1 and VCAM-1 mRNA expression levels were reduced by pre-treatment with PE or RA. TPA-induced increases in synthesis of the chemokines KC and MIP-2 were significantly decreased by pre-treatment with PE or RA. Prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) levels were slightly increased 5 hours after TPA treatment. These levels were only numerically decreased in the PE and RA treated groups. However, induction of cyclooxygenase-2 (COX-2) mRNA expression was obviously reduced by pretreatment with PE or RA. Reactive oxygen radical production, detected as thiobarbituric acid reactive substance (TBARS) and lipid peroxide (LPO), by double treatment of TPA was reduced by pretreatment with PE or RA. Production of 8-hydroxy-2'deoxyguanosine (8OH-dG), which was detected immunohistochemically, was also induced by double treatment with TPA. This adduct was barely visible in PE or RA treated mice. Thus, we conclude that part of the anti-carcinogenic effects of Perilla flutescens extract is due to RA via two independent mechanisms: inhibition of the inflammatory response and scavenging of reactive oxygen radicals.
rosmarinic acid, two-stage skin tumor, adhesion molecule, chemokine, ROS
Rosmarinic acid inhibits epidermal inflammatory responses: anti-carcinogenic effect of Perilla frutescens extract in the murine two-stage skin model
2 First Department of Medicine, Kyoto Prefectural University of Medicine, Kamigyoku, Kyoto 602-8566 Japan
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