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Environmental Carcinogenesis Lab


Research

PPARg ligands on anti-cancer effects

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The peroxisome proliferator-activated receptor g (PPARg) is a ligand-activated transcription factor that belongs to the nuclear hormone receptor superfamily. PPARg forms a heterodimeric complex with the retinoid X receptor and then binds to the PPAR response element. This interaction can be responsible for the regulation of cellular events ranging from glucose and lipid homeostasis to cell differentiation and apoptosis. PPARg ligands include the natural prostaglandin 15-deoxy-Δ12,14-prostaglandin J2 (PGJ2), the synthetic anti-diabetic thiazolidinediones (TZDs), and oxidative metabolites of polysaturated fatty acids. These ligands activate PPARg and exhibit anti-tumorigenic effects in many types of tumor cells, including breast, lung, prostate, and pancreas. However, the most extensive investigations have focused on the colon, where PPARg is highly expressed both in well- and poorly-differentiated adenocarcinomas and in normal colonic mucosa. A large body of evidence demonstrates that the anti-tumorigenic activity of PPARg ligands such as troglitazone (TGZ) and PGJ2 is independent of PPARg activation in many cell types. Our laboratory has reported that TGZ, independent of PPARg, can induce the expression of early growth response transcription factor (EGR-1) and subsequently result in the increased expression of nonsteroidal anti-inflammatory drug (NSAID)-activated gene (NAG-1). However, TGZ was voluntarily withdrawn from the market in March 2000 because it caused severe idiosyncratic liver injury. A new class of TZDs was developed, and subsequent studies established one member, MCC-555 (also known as RWJ-241947), as an anti-diabetic drug in animal models of type II diabetes. Like other TZDs, MCC-555 binds to PPARg and increases transcriptional activities, but its binding affinity for PPARg is relatively weak. Interestingly, the anti-diabetic potency of MCC-555 is more effective than that in the other TZDs such as rosiglitazone. Moreover, cardiac and hematopoietic side effects were reduced compared to other TZDs, which may be associated with unique properties of MCC-555 for activation of PPARg; that is, MCC-555 acts as a full agonist, partial agonist, or antagonist depending on the cell type or DNA binding site. In addition to anti-diabetic activity, MCC-555 has potent anti-proliferative effects against colorectal cancer in vivo.

NSAIDs on anti-cancer effects

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Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of inflammatory disease and their anti‑inflammatory effects are believed to result from inhibition of prostaglandin H synthase (also known as cyclooxygenase, COX). Two isoforms of prostaglandin H synthase, COX‑1 and COX‑2 are known; COX‑1 is constitutively expressed in many tissues while mitogens, tumor promoters, and growth factors upregulate the expression of COX‑2. COX‑2 protein is also upregulated in human colorectal tumors and regulates tumor growth in animal models. NSAIDs reduce the number and size of polyps in animal models, and epidemiological studies reveal a 40-50% reduction in mortality from colorectal cancer. Chemopreventive effects of certain NSAIDs appear to be mediated through both COX-dependent and independent pathways. However, the target molecules that mediate chemopreventive effects are not elucidated. Identifying possible targets is important to understanding the mechanism of the chemopreventive actions. A number of molecular mechanisms responsible for the chemopreventive effects of NSAIDs have been proposed. One hypothesis is the obvious involvement of COX-2 inhibition but it is clear that prostaglandin-independent mechanisms are also involved. In either case, the mechanisms responsible for the chemopreventive activity are not clear. Changes in gene expression by COX inhibitors could provide an explanation for the activity. A number of studies with micro-array and PCR‑based subtractive hybridization have identified potential target genes including NAG-1, ATF3, EGR-1, and other tumor suppressor proteins.

Phytochemicals on anti-cancer effects

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Phytochemicals are found in dietary plant products, including fruits, vegetables, beverages, herbs and spices, and a number of these compounds have been found to inhibit tumorigenesis in experimental animals and/or exhibit potent biological properties.  In addition, epidemiological studies indicate that populations consuming foods rich in specific phytochemicals have lowered incidence of cancer, heart disease and osteoporosis. We have been studying several phytochemical compounds including resveratrol, genistein, and diallyl disulfide in the chemoprevention of human colon cancer. These compounds induce p53 tumor suppressor protein in colorectal cancer cells, thereby inducing several pro-apoptotic genes. Many other groups have also reported the anti-tumor effects of phytochemicals at the cell biological level, and the major phenomena induced by the phytochemicals included induction of apoptosis and cell cycle arrest. Potential mechanisms have also been suggested to include anti-oxidative activity, inhibition of enzymes related to tumor promotion such as cyclooxygenase and lipoxygenase, inhibition of activator protein-1, inhibition of angiogenesis, inhibition of vascular endothelial growth factor, and others. Thus, phytochemicals could influence many pathways but obvious mechanisms by which each phytochemical induces apoptosis or anti-tumorigenic effects remain to be elucidated.

 

 

Environmental Carcinogenesis Laboratory
The University of Tennessee Dept. of Pathobiology
2407 River Drive
Knoxville, TN 37996
Tel: 865-974-2310, 1884, 5875


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