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Carcinogenesis Advance Access published online on August 5, 2008
Carcinogenesis, doi:10.1093/carcin/bgn180
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Guggulsterone Modulates MAPK and NF-kappaB Pathways and Inhibits Skin Tumorigenesis in Sencar Mice

Sami Sarfaraz1, Imtiaz A. Siddiqui, Deeba N Syed, Farrukh Afaq and Hasan Mukhtar*

Chemoprevention Program Paul P Carbone Comprehensive Cancer Center and Department of Dermatology, School of Medicine and Public Health, University of Wisconsin, Madison, WI

* Author for correspondence: Hasan Mukhtar, Ph.D., Helfaer Professor of Cancer Research, Director and Vice Chair of Research, Department of Dermatology, University of Wisconsin-Madison, 1300, University Avenue, Medical Sciences Center, B-25, Madison, WI- 53706. Phone: 608-263-3927, Fax: 608-263-5223 E-mail: 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 anti-tumor 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 µ mole/mouse) 30 min prior to TPA (3.2 n mole/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) ODC activity, (ii) ODC, COX-2 and iNOS protein expressions, (iii) phosphorylation of ERK1/2, JNKs and p38, (iv) activation of NF-{kappa}B/p65 and IKK{alpha}/β, and (v) phosphorylation and degradation of I{kappa}B{alpha}. We next assessed the effect of topically applied GUG on TPA-induced skin tumor promotion in 7, 12-dimethyl benz(a)anthracene (DMBA)-initiated mice. Compared to 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 antiskin 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.

1 Present Address: Medical Oncology Branch, National Cancer Institute, Building 37, Room 1136, 37 Convent Dr., Bethesda, MD.

Received March 25, 2008; revised July 29, 2008; accepted July 30, 2008.


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