Guggulsterone modulates MAPK and NF-kappaB pathways and inhibits skin tumorigenesis in SENCAR mice

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Guggulsterone, a resin of the Commiphora mukul tree, has been used in ayurvedic medicine for centuries to treat a variety of ailments. Several studies have suggested that it may possess anticancer effects. In the present study, we show that guggulsterone possesses anti-tumor promoting effects in SENCAR mouse skin tumorigenesis model. Wefirst determined the effect of topical application of guggulsterone to mice against 12-O-tetradecanoylphorbol-13-acetate (TPA) induced epidermal ornithine decarboxylase (ODC) activity, cyclooxygenase-2 (COX-2) and ODC protein expression, edema and hyperplasia, the conventional markers and other novel markers of skin tumor promotion. We found that topical application of guggulsterone (0.5 mg/mouse) 30 min prior to TPA (3.2 nmole/mouse) application onto the skin of mice afforded significant inhibition, in a time-dependent manner, against TPA-mediated increase in skin edema and hyperplasia. Topical application of guggulsterone was also found to result in substantial inhibition (53%) against TPA-induced epidermal ODC activity and protein expressions of ODC and COX-2. Because of the role of mitogen activated protein kinases (MAPK) in inflammatory responses, cell proliferation, survival, and apostosis, we next assessed the effect of guggulsterone on TPA-mediated activation of MAPK pathway in mouse epidermis. Employing immunoblot analysis, we found that topical application of guggulsterone resulted in inhibition of TPA-induced phosphorylation of ERK1/2, JNKs and p38 in the epidermis. Since the nuclear factor kappa B (NFκB) has been implicated in cellular proliferation and tumor promotion, we next determined the effect of guggulsterone on TPA-mediated activation of NFκB pathway. Our data demonstrated that pre-application of guggulsterone to mouse skin significantly inhibited TPA-induced activation of NFκB, IKKα and degradation of IκBα. We next assessed the effect of skin application of guggulsterone on TPA-induced skin tumor promotion in DMBA initiated mice. Compared to non guggulsterone pretreated mice, animals pretreated with guggulsterone 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. In TPA-treated group, 100% of the mice developed tumors at 13 weeks on test, whereas at this time in guggulsterone-treated group, only 30% mice exhibited tumors. At the termination of the experiment at 20 weeks, 100% of the animals in TPA-treated group exhibited 10.6 ± 1.1 tumors/mouse, whereas at this time only 50% of the guggulsterone pretreated mice developed 3.3 ± 0.25 tumors/mouse. These results provide the evidence that guggulsterone possesses antiskin tumor-promoting effects in SENCAR mice and inhibits conventional as well as novel biomarkers of tumor promotion. Guggulsterone could be useful for delaying tumor growth in humans.