To everyone on the board interested in this new research chemical:
You may have seen the study indicating an increase in the size and quantity of intestinal adenomas in Apcmin mice (predisposed to intestinal polyposis).
Because GW-501516 works primarily and tangentially by up-regulating gene expression, I was curious to see if it had any effects on genes responsible for carcinogenesis.
Turns out it does. The COX-2 gene is primarily responsible for pain and inflammation in the body, but interestingly, increased mRNA expression of this gene alters the apoptotic mechanisms of certain cells. All cells have mechanisms to "self-destruct" when their DNA becomes damaged beyond repair, but by altering the Bcl-2 protein and p53 pathway, up-regulation of COX-2 reduces the apoptotic response.
COX-2 expression has already been shown to have a significant positive correlation with both carcinogenesis and tumorigenesis, and GW-501516 has also been proven to increase COX-2 expression.
Therefore, to anyone [who's rats are] taking this compound, you should ALWAYS co-supplement with a COX-2 inhibitor. There are various NSAIDs on the market which show an affinity for COX-2 inhibition (vs COX-1) such as Celecoxib (Celebrex), however these have also been linked in rare cases to renal failure, stroke, thrombosis, etc. Your best bet is Tribulus Terrestris, which is a natural extract, and has been shown to inhibit COX-2 expression by as much as 80%
Activation of nuclear hormone receptor peroxisome proliferator-activated receptor-delta accelerates intestinal adenoma growth.
Gupta RA, Wang D, Katkuri S, Wang H, Dey SK, DuBois RN.
Department of Medicine, The Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6838, USA.
We treated Apc(min) mice, which are predisposed to intestinal polyposis, with a selective synthetic agonist of peroxisome proliferator-activated receptor-delta (PPAR-delta). Exposure of Apc(min) mice to the PPAR-delta ligand GW501516 resulted in a significant increase in the number and size of intestinal polyps. The most prominent effect was on polyp size; mice treated with the PPAR-delta activator had a fivefold increase in the number of polyps larger than 2 mm. Our results implicate PPAR-delta in the regulation of intestinal adenoma growth.
PPARdelta activation induces COX-2 gene expression and cell proliferation in human hepatocellular carcinoma cells.
Glinghammar B, Skogsberg J, Hamsten A, Ehrenborg E.
King Gustaf V Research Institute, Karolinska Institutet, Karolinska Hospital, S-171 76 Stockholm, Sweden.
Cyclooxygenase-2 (COX-2) has been suggested to be associated with carcinogenesis. Recently, many studies have shown increased expression of COX-2 in a variety of human malignancies, including hepatocellular carcinoma (HCC). Therefore, it becomes important to know more about what determines COX-2 expression. In this work, we have studied the effect of PPARdelta activation on COX-2 expression using a selective agonist (GW501516) in human hepatocellular carcinoma (HepG2) cells. Activation of PPARdelta resulted in increased COX-2 mRNA and protein expression. The mechanism behind the induction seems to be increased activity of the proximal promoter of the COX-2 gene, spanning nucleotides -327 to +59. The increased COX-2 protein expression and promoter activity induced by the GW501516 was also confirmed in the monocytic cell line THP-1. Induced levels of COX-2 have previously been associated with resistance to apoptosis and increased cell proliferation in many cell types. In HepG2 cells, we observed a dose-dependent increase in cell number by GW501516 treatment for 72h. The levels of PCNA, used as an indicator of cell division were induced, and the cell survival promoting complex p65 (NF-kappaB) was phosphorylated under GW501516 treatment. We conclude that PPARdelta activation in HepG2 cells results in induced COX-2 expression and increased cellular proliferation. These results may suggest that PPARdelta plays an important role in the development of HCC by modulating expression of COX-2.
Evaluation of natural products on inhibition of inducible cyclooxygenase (COX-2) and nitric oxide synthase (iNOS) in cultured mouse macrophage cells.
Hong CH, Hur SK, Oh OJ, Kim SS, Nam KA, Lee SK.
Department of Pharmacy, College of Pharmacy, Ewha Womans University, 11-1 Daehyun-dong, Seodaemun-ku, 120-750, Seoul, South Korea.
The inhibitors of prostaglandin biosynthesis and nitric oxide production have been considered as potential anti-inflammatory and cancer chemopreventive agents. In this study, we evaluated approximately 170 methanol extracts of natural products including Korean herbal medicines for the inhibition of prostaglandin E(2) production (for COX-2 inhibitors) and nitric oxide formation (for iNOS inhibitors) in lipopolysaccharide (LPS)-induced mouse macrophages RAW264.7 cells. As a result, several extracts such as Aristolochia debilis, Cinnamomum cassia, Cinnamomum loureirii, Curcuma zedoaria, Eugenia caryophyllata, Pterocarpus santalius, Rehmania glutinosa and Tribulus terrestris showed potent inhibition of COX-2 activity (>80% inhibition at the test concentration of 10 micro g/ml). In addition, the extracts of A. debilis, Caesalpinia sappan, Curcuma longa, C. zedoaria, Daphne genkwa and Morus alba were also considered as potential inhibitors of iNOS activity (>70% inhibition at the test concentration of 10 micro g/ml). These active extracts mediating COX-2 and iNOS inhibitory activities are warranted for further elucidation of active principles for development of new cancer chemopreventive and/or anti-inflammatory agents.