title: Guggulsterone modulates MAPK and NF-kappaB pathways and inhibits skin tumorigenesis in SENCAR mice.
abstract: 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 micromol 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 kinase 1/2, c-jun N-terminal kinases and p38; (iv) activation of NF-kappaB/p65 and IKK alpha/beta and (v) phosphorylation and degradation of I kappaB alpha. 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.
authors.affiliation: 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.
authors.forename: Sami
authors.initials: S
authors.lastname: Sarfaraz
authors.forename: Imtiaz A
authors.initials: IA
authors.lastname: Siddiqui
authors.forename: Deeba N
authors.initials: DN
authors.lastname: Syed
authors.forename: Farrukh
authors.initials: F
authors.lastname: Afaq
authors.forename: Hasan
authors.initials: H
authors.lastname: Mukhtar
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004487:Edema / Q000517:prevention & control; D005260:Female; D006965:Hyperplasia; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D018632:Mice, Inbred SENCAR; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D065108:Ornithine Decarboxylase Inhibitors; D010766:Phosphorylation; D011282:Pregnenediones / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects / Q000473:pathology; D012878:Skin Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D052246:Cyclooxygenase 2 Inhibitors; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D065108:Ornithine Decarboxylase Inhibitors; D011282:Pregnenediones; D000072000:NF-KappaB Inhibitor alpha; D015127:9,10-Dimethyl-1,2-benzanthracene; C023617:pregna-4,17-diene-3,16-dione; D052247:Nitric Oxide Synthase Type II; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; D013755:Tetradecanoylphorbol Acetate