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Carcinogenesis Advance Access published online on January 18, 2007
Carcinogenesis, doi:10.1093/carcin/bgm005
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Xanthorrhizol inhibits 12-O-tetradecanoylphorbol-13-acetate-induced acute inflammation and two-stage mouse skin carcinogenesis by blocking the expression of ornithine decarboxylase, cyclooxygenase-2, and inducible nitric oxide synthase through mitogen-activated protein kinases and/or the nuclear factor kB

Won Yoon Chung1,2,3, Jae Hee Park1, Mi Jeong Kim1,3, Heui Ok Kim1, Jae Kwan Hwang4, Sang Kook Lee5 and Kwang Kyun Park1,2,3,*

1 Department of Oral Biology
2 Oral Cancer Research Institute and Oral Science Research Institute
3 Brain Korea 21 Project, Yonsei University College of Dentistry, Seoul, 120-752, Korea
4 Department of Biotechnology, Yonsei University, Seoul 120-749, Korea
5 College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea

* Address correspondent to : Kwan Kyun Park, DDS, Ph.D.: Department of Oral Biology, Yonsei University College of Dentistry, Shinchon-Dong 134, Seodaemoon-Ku, Seoul 120-752, Korea, Phone: 82 2 2228-3056, Fax: 82 2 364 7113, E-mail: biochelab{at}yumc.yonsei.ac.kr

Xanthorrhizol is an active component isolated from Curcuma xanthorrhiza Roxb. (Zingiberaceae) that is traditionally used in Indonesia for medicinal purposes. In the present study, we found that the topical application of xanthorrhizol before 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment significantly inhibits TPA-induced mouse ear edema and TPA-induced tumor promotion in 7,12-dimethylbenz[a]anthracene (DMBA)-initiated ICR mouse skin. The topical application of xanthorrhizol following the induction of papillomas with TPA-induced hyperplasia and dysplasia also reduced tumor multiplicity and incidence in DMBA-initiated mouse skin. To further elucidate the molecular mechanisms underlying the antitumor-promoting activity of xanthorrhizol, its effect on the TPA-induced expression of ornithine decarboxylase (ODC), cyclooxygenase (COX)-2, and inducible nitric oxide synthase (iNOS) and the upstream signaling molecules controlling these proteins were explored in mouse skin. The pretreatment with xanthorrhizol inhibited the expression of ODC, iNOS, and COX-2 proteins and NF-{kappa}B activation in both mouse skin with TPA-induced acute inflammation and DMBA-initiated mouse skin promoted by TPA for 19 weeks. When mouse skin was treated after TPA-induced production of papillomas, xanthorrhizol remarkably suppressed the expression of ODC, iNOS, and COX-2 and inhibited the activation of NF-{kappa}B. Furthermore, Western blot analysis showed that xanthorrhizol suppressed the activation of ERK, p38, JNK, and Akt in mice after topical application for 6 weeks following the induction of papillomas. Taken together, the present study demonstrates that xanthorrhizol not only delays or inhibits tumor formation, but also reverses the carcinogenic process at premalignant stages by reducing the protein levels of ODC, iNOS, and COX-2 regulated by the NF-{kappa}B, MAPKs, and/or Akt.

Key Words: xanthorrhizol • TPA-induced inflammation • two-stage mouse skin carcinogenesis • cyclooxygenase-2 • ornithine decarboxylase


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