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E J Patten

Publications and source records attributed to E J Patten.

4 recordsLinked to original sources
PubMed1999

Effects of sulindac, sulindac metabolites, and aspirin on the activity of detoxification enzymes in HT-29 human colon adenocarcinoma cells.

Non-steroidal anti-inflammatory drugs (NSAIDs) have been found to reduce cancer rates in various segments of the gastro-intestinal tract in both animals and humans. In this study we examined the effect of sulindac, sulindac sulfide, sulindac sulfone and aspirin on QR and GST activity. We found that sulindac itself increased QR activity as much as 2-fold over controls but had no effect on GST activity. Sulindac sulfone, a metabolite of sulindac which lacks the ability to inhibit prostaglandin (PG) synthesis, increased QR and GST to 1.5-fold over controls in both cases. Aspirin increased QR and GST to 1.5-fold and 3.5-fold over controls respectively. These data indicate that NSAIDs increase phase II enzyme detoxification enzyme activity. Consequently, this effect may contribute to the protective effect of NSAIDs against colon cancer and may be an anticarcinogenic effect of these drugs that is distinct from their ability to inhibit PG synthesis.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

Temporal effects of the detoxification enzyme inducer, benzyl isothiocyanate: activation of c-Jun N-terminal kinase prior to the transcription factors AP-1 and NFkappaB.

Benzyl isothiocyanate (BIT), a microconstituent found in cruciferous vegetables, is known to be a potent inducer of the detoxification enzyme, NAD(P)H: quinone reductase (QR). QR catalyzes a two-electron transfer to a wide variety of redox-cycling species, including quinones, transforming them into dihydrodiols, thereby preventing the mutation of DNA and reducing cancer risk. The upstream signaling mechanisms that lead to the induction of QR remain unclear. The 5' promoter region of the human QR gene contains the cis-acting AP-1 and NFkappaB transcription factor binding sites. When HT29 human colon cells were exposed to 25microM benzyl isothiocyanate, AP-1 binding increased, beginning at 3 hours and increasing until 16 hours. NFkappaB binding also increased, reaching a maximum at around 6 hours. We also found that c-Jun N-terminal kinase (JNK), which phosphorylates c-Jun, a component of AP-1, was activated 9-fold over controls, beginning at 60 minutes. The temporal sequence of these events supports the idea that JNK is involved in the induction of QR and that this is an initial event preceding an increase in transcription factor binding and subsequent QR activity.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1999

Dietary compounds that induce cancer preventive phase 2 enzymes activate apoptosis at comparable doses in HT29 colon carcinoma cells.

Dietary agents that induce glutathione S-transferases and related detoxification systems (Phase 2 enzyme inducers) are thought to prevent cancer by enhancing elimination of chemical carcinogens. The present study shows that compounds of this group (benzyl isothiocyanate, allyl sulfide, dimethyl fumarate, butylated hydroxyanisole) activated apoptosis in human colon carcinoma (HT29) cells in culture over the same concentration ranges that elicited increases in enzyme activity (5-25, 25-100, 10-100, 15-60 micromol/L, respectively). Pretreatment of cells with sodium butyrate, an agent that induces HT29 cell differentiation, resulted in parallel increases in Phase 2 enzyme activities and induction of apoptosis in response to the inducers. Cell death characteristics included apoptotic morphological changes, appearance of cells at sub-G1 phase on flow cytometry, caspase activation, DNA fragmentation and TUNEL-positive staining. The results suggest that dietary Phase 2 inducers may protect against cancer by a mechanism distinct from and in addition to that associated with enhanced elimination of carcinogens. If this occurs in vivo, diets high in such compounds could eliminate precancerous cells by apoptosis at time points well after initial exposure to chemical mutagens and carcinogens.

Apoptosis↗