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|Title:||Investigation into the mechanisms of colon tumour promotion by FP-12 and TNFα and its modulation by chemopreventive agents|
|Authors:||Holloway, Karen Alison.|
|Presented at:||University of Leicester|
|Abstract:||The mechanisms whereby two endogenous agents, Fecapentaene-12 (FP-12) and Tumour necrosis factor alpha (TNF) act as colon tumour promoters was investigated, in human colon epithelial cells (HCEC), a normal colon epithelial cell line. Cyclooxygenase-2 (COX-2), an inducible form of prostaglandin H synthase (PGHS), is induced selectively at the transcriptional level in human colon tumours compared to normal colon epithelium. Exposure to both FP-12 (1-40M) and TNF (0.1-10ng/ml), for 2 hours caused a dose dependent, 2 to 6- fold increase in COX-2 mRNA compared to unstimulated cells.;Since inactivation of COX-2 expression has been shown to inhibit colon carcinogenesis, the ability of the chemopreventive agents, sodium salicylate, curcumin, caffeic acid phenethyl ester (CAPE) and resveratrol to inhibit COX-2 mRNA expression was determined. Only curcumin pretreatment, prior to FP-12 or TNF caused a significant, dose dependent 20-90% inhibition of COX-2 mRNA expression.;The transcription factor nuclear factor kappa B (NF-B) has been shown to be an important regulator of COX-2 gene expression, and curcumin has been shown to inhibit NF-B to its consensus sequence in gel shift assays by 4 to 5- and 4-fold respectively (relative to unstimulated cells). This was reduced by 50 to 90% in cells pretreated with curcumin prior to TNF or FP-12.;Curcumin pretreatment, prior to FP-12 or TNF- appeared to increase cell death, compared to treatment with either agent alone, but no evidence for an apoptotic effect was observed.;Since COX-2 induction of colon tumour promoters may have a pivotal role in colon carcinogenesis, part of the chemopreventive activity of curcumin could be mediated in part through down-regulation of COX-2 gene expression via inhibition of NF-B activation.|
|Rights:||Copyright © the author. All rights reserved.|
|Appears in Collections:||Theses, MRC Toxicology Unit|
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