Carcinogenesis Advance Access originally published online on August 5, 2008
Carcinogenesis 2008 29(10):2011-2018; doi:10.1093/carcin/bgn180
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Guggulsterone modulates MAPK and NF-
B pathways and inhibits skin tumorigenesis in SENCAR mice
Chemoprevention Program Paul P Carbone Comprehensive Cancer Center and Department of Dermatology, School of Medicine and Public Health, University of Wisconsin, 1300 University Avenue, Medical Sciences Center, B-25, Madison, WI 53706, USA
1 Present address: Medical Oncology Branch, National Cancer Institute, Building 37, Room 1136, 37 Convent Drive, Bethesda, MD 20892, USA
* To whom correspondence should be addressed. Tel: +1 608 263 3927; Fax: +1 608 263 5223; Email: hmukhtar{at}wisc.edu
Guggulsterone (GUG), a resin of the Commiphora mukul tree, has been used in ayurvedic medicine for centuries to treat a variety of ailments. Recent studies have suggested that GUG may also possess anticancer effects. In the present study, we show that GUG possesses antitumor-promoting effects in SENCAR mouse skin tumorigenesis model. We first determined the effect of topical application of GUG to mice against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced conventional markers and other novel markers of skin tumor promotion. We found that topical application of GUG (1.6 µmol per mouse) 30 min prior to TPA (3.2 nmol per mouse) application onto the skin of mice afforded significant inhibition against TPA-mediated increase in skin edema and hyperplasia. Topical application of GUG was also found to result in substantial inhibition against TPA-induced epidermal (i) ornithine decarboxylase (ODC) activity; (ii) ODC, cyclooxygenase-2 and inducible nitric oxide synthase protein expressions; (iii) phosphorylation of extracellular signal-regulated kinase1/2, c-jun N-terminal kinases and p38; (iv) activation of NF-
B/p65 and IKK
/β and (v) phosphorylation and degradation of IB. We next assessed the effect of topically applied GUG on TPA-induced skin tumor promotion in 7,12-dimethyl benz[a]anthracene-initiated mice. Compared with non-GUG-pretreated mice, animals pretreated with GUG showed significantly reduced tumor incidence, lower tumor body burden and a significant delay in the latency period for tumor appearance from 5 to 11 weeks. These results provide the first evidence that GUG possesses anti-skin tumor-promoting effects in SENCAR mice and inhibits conventional as well as novel biomarkers of tumor promotion. In summary, GUG could be useful for delaying tumor growth in humans.
Abbreviations: COX-2, cyclooxygenase; DMBA, 7,12-dimethyl benz[a]anthracene; DMSO, dimethyl sulfoxide; EDTA, ethylenediaminetetraacetic acid; ERK, extracellular signal-regulated kinase; GUG, guggulsterone; iNOS, inducible nitric oxide synthase; JNK, c-jun N-terminal kinase; MAPK, mitogen-activated protein kinases; ODC, ornithine decarboxylase; TPA, 12-O-tetradecanoylphorbol-13-acetate
Received March 25, 2008; revised July 29, 2008; accepted July 30, 2008.