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.
Carcinogenesis (Impact Factor: 5.33). 09/2008; 29(10):2011-8. DOI: 10.1093/carcin/bgn180
Source: PubMed


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.

Download full-text


Available from: Imtiaz A Siddiqui
  • Source
    • "The values above the figures represent relative density in the term of fold change as compared to control after normalization with total protein or ␤-actin. and COX-2 expression or activity is important not only for treatment of chronic inflammation, but also for the prevention of cancer [13] [31] [32]. Therefore, suppression of iNOS and COX-2 induction during cancer progression is recognized as an important and commonly accepted approach to effectively inhibit tumor promotion. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Epidemiological studies suggested that plant-based dietary supplements can reduce the risk of liver cancer. Nexrutine (NX), an herbal extract from Phellodendronamurense, has been shown to have anti-inflammatory, anti-microbial and anti-tumor activities. In the present study, we have shown the anti-tumor potential of NX against Solt-Farber model with elimination of PH, rat liver tumor induced by diethylnitrosoamine (DEN) as carcinogen and 2-acetylaminofluorene (2-AAF) as co-carcinogen. The elucidation of mechanistic pathways was explored in human liver cancer cells. Dietary intake of NX significantly decreased the cell proliferation and inflammation, as well as increased apoptosis in the liver sections of DEN/2-AAF-treated rats. Moreover, NX (2.5-10 μg/ml) exposure significantly decreased the viability of liver cancer cells and modulated the levels of Bax and Bcl-2 proteins levels. NX treatment resulted in increased cytochrome-c release and cleavage of caspases 3 and 9. In addition, NX decreased the expression of CDK2, CDK4 and associated cyclins E1 and D1, while up-regulated the expression of p21, p27 and p53 expression. NX also enhanced phosphorylation of the mitogen-activated protein kinases (MAPKs) ERK1/2, p38 and JNK1/2. Collectively, these findings suggested that NX-mediated protection against DEN/2-AAF-induced liver tumorigenesis involves decrease in cell proliferation and enhancement in apoptotic cell death of liver cancer cells.
    Full-text · Article · Nov 2014 · Toxicology Reports
  • Source
    • "GS inhibits the activation of transcription factors NF-jB and STAT3 in cancer cells [6] [20] [21], decreases production of reactive oxygen species (ROS), suppresses inflammation and modulates anti-apoptotic and cell cycle-regulatory proteins [10] [12] [13] [17] [20] [22] [23]. Besides affecting NF-jB and STAT3 activation, GS binds and modulates the activity of several steroid receptors like FXR, estrogen receptor alpha (Era), progesterone receptor (PR), and pregnane X receptor (PXR) [24] [25]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Inadequate efficacy, high toxicity and drug resistance associated with existing chemotherapeutic agents mandate a need for novel therapeutic strategies for highly aggressive pancreatic cancer (PC). Guggulsterone (GS) exhibits potent anti-proliferative effects against various cancer cells and has emerged as an attractive candidate for use in complementary or preventive cancer therapies. However, the knowledge regarding the therapeutic potential of GS in PC is still limited and needs to be explored. We studied the effect of GS on PC cell growth, motility and invasion and elucidated the molecular mechanisms associated with its anti-tumor effects. Treatment of Capan1 and CD18/HPAF PC cells with GS resulted in dose- and time-dependent growth inhibition and decreased colony formation. Further, GS treatment induced apoptosis and cell cycle arrest as assessed by Annexin-V assay and FACS analysis. Increased apoptosis following GS treatment was accompanied with Bad dephosphorylation and its translocation to the mitochondria, increased Caspase-3 activation, decreased Cyclin D1, Bcl-2 and xIAP expression. Additionally, GS treatment decreased motility and invasion of PC cells by disrupting cytoskeletal organization, inhibiting activation of FAK and Src signaling and decreased MMP9 expression. More importantly, GS treatment decreased mucin MUC4 expression in Capan1 and CD18/HPAF cells through transcriptional regulation by inhibiting Jak/STAT pathway. In conclusion, our results support the utility of GS as a potential therapeutic agent for lethal PC.
    Full-text · Article · Aug 2013 · Cancer letters
  • Source
    • "It is reported that treatment with GL (3 μmol standardized to z-Gug, daily for 3 weeks) resulted in the enhancement of cetuximab activity in the xenograft model of head and neck cancer [20]. The Gugs-mediated suppression of cancer cell proliferation has also been reported in head and neck cancer cells [20], leukemia cells [11,22], lung cancer cells [22], human breast cancer cells [19], skin cancer cells [21], and colon cancer cells [23]. Gug treatment inhibited angiogenesis in vitro and in vivo to block prostate and colon cancer growth [14,23]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: z-Guggulsterone (z-Gug) and Gugulipid (GL) have been used to treat a variety of ailments. We now report their anti-cancer effect and mechanism against human breast cancer. Using the human estrogen receptor-positive (MCF-7) and triple-negative (MDA-MB-231) breast cancer cells as well as the normal human mammary epithelial cell line (HMEC), we evaluated the anti-breast-cancer efficacy and apoptosis inducing activity of GL. We determined the cellular and molecular mechanism of GL-inhibited breast cancer cell growth. GL significantly inhibited growth of MCF-7 and MDA-MB-231 cells with an IC50~2muM at pharmacologically relevant concentrations standardized to its major active constituent z-Gug. The GL-induced growth inhibition correlated with apoptosis induction as evidenced by an increase in cytoplasmic histone-associated DNA fragmentation and caspase 3 activity. The GL-induced apoptosis was associated with down-regulation of the beta-Catenin signaling pathway. The decreased expression of Wnt/beta-Catenin targeting genes, such as cyclin D1, C-myc and survivin, and the inhibition of the activity of the transcription factor (T-cell factor 4, TCF-4) were observed in GL-treated breast cancer cells. The GL treatment resulted in a significant reduction of beta-Catenin /TCF-4 complex in both of the cancer cells. The GL-induced apoptotic cell death was significantly enhanced by RNA Interference of beta-Catenin and TCF-4. On the other hand, the normal human mammary epithelial cell HMEC, compared with the human breast cancer cells, is significantly more resistant to growth inhibition and apoptosis induction by GL. The present study indicates that the beta-Catenin signaling pathway is the target for GL-induced growth inhibition and apoptosis in human breast cancer.
    Full-text · Article · Aug 2013 · BMC Complementary and Alternative Medicine
Show more