PPARδ status and mismatch repair mediated neoplasia in the mouse intestine

BACKGROUND: Therapeutic regulation of PPARδ activity using selective agonists has been proposed for various disorders. However, the consequences of altered peroxisome proliferator-activated receptor delta (PPARδ) activity in the context of intestinal tumourigenesis remain somewhat unclear. Contradictory evidence suggesting PPARδ either attenuates or potentiates intestinal neoplasia. To further investigate the PPARδ dependency of intestinal tumourigenesis, we have analysed the consequences of PPARδ deficiency upon intestinal neoplasia occurring in mice with impaired mismatch DNA repair. METHODS: Mice deficient for both PPARδ and the mismatch repair gene Mlh1 were produced and the incidence and severity of intestinal neoplasia recorded. RESULTS: No significant differences between the control genotypes and the double mutant genotypes were recorded indicating that deficiency of PPARδ does not modify impaired mismatch repair induced neoplasia. CONCLUSION: In contrast with the previously observed acceleration of intestinal neoplasia in the context of the Apc(Min/+ )mouse, PPARδ deficiency does not alter the phenotype of mismatch repair deficiency. This data supports the notion that PPARδ is not required for adenoma formation and indicate that any pro-tumourigenic effect of PPARδ inactivation may be highly context dependent

Growth-inhibitory effects of the chemopreventive agent indole-3-carbinol are increased in combination with the polyamine putrescine in the SW480 colon tumour cell line

BACKGROUND: Many tumours undergo disregulation of polyamine homeostasis and upregulation of ornithine decarboxylase (ODC) activity, which can promote carcinogenesis. In animal models of colon carcinogenesis, inhibition of ODC activity by difluoromethylornithine (DFMO) has been shown to reduce the number and size of colon adenomas and carcinomas. Indole-3-carbinol (I3C) has shown promising chemopreventive activity against a range of human tumour cell types, but little is known about the effect of this agent on colon cell lines. Here, we investigated whether inhibition of ODC by I3C could contribute to a chemopreventive effect in colon cell lines. METHODS: Cell cycle progression and induction of apoptosis were assessed by flow cytometry. Ornithine decarboxylase activity was determined by liberation of CO(2 )from (14)C-labelled substrate, and polyamine levels were measured by HPLC. RESULTS: I3C inhibited proliferation of the human colon tumour cell lines HT29 and SW480, and of the normal tissue-derived HCEC line, and at higher concentrations induced apoptosis in SW480 cells. The agent also caused a decrease in ODC activity in a dose-dependent manner. While administration of exogenous putrescine reversed the growth-inhibitory effect of DFMO, it did not reverse the growth-inhibition following an I3C treatment, and in the case of the SW480 cell line, the effect was actually enhanced. In this cell line, combination treatment caused a slight increase in the proportion of cells in the G(2)/M phase of the cell cycle, and increased the proportion of cells undergoing necrosis, but did not predispose cells to apoptosis. Indole-3-carbinol also caused an increase in intracellular spermine levels, which was not modulated by putrescine co-administration. CONCLUSION: While indole-3-carbinol decreased ornithine decarboxylase activity in the colon cell lines, it appears unlikely that this constitutes a major mechanism by which the agent exerts its antiproliferative effect, although accumulation of spermine may cause cytotoxicity and contribute to cell death. The precise mechanism by which putrescine enhances the growth inhibitory effect of the agent remains to be elucidated, but does result in cells undergoing necrosis, possibly following accumulation in the G(2)/M phase of the cell cycle

Resveratrol from Red Grapes - Pedestrian Polyphenol or Miraculous Anticancer Agent?

Resveratrol is a phytoalexin with cancer chemopreventive properties in preclinical models of carcinogenesis. The mechanisms via which resveratrol is thought to exert chemopreventive efficacy are inhibition of cyclooxygenase enzymes, inhibition of angiogenesis, modulation of drug metabolising enzymes, antioxidation and alterations of cell cycle components and apoptotic machinery. Pharmacokinetic evidence in rodents and humans suggests that the bioavailability of resveratrol is very low and that resveratrol conjugates are the major circulating agent-derived species. The recent realisation that resveratrol can mimic caloric restriction in several species has generated a lot of interest. Attempts to design analogues with the aim of optimising resveratrol pharmacology have furnished stilbenes with different aryl subtituents, e. g., methoxy instead of hydroxy. Some of these derivatives possess more potent pharmacological properties than the lead compound. More work is required to elucidate the role of metabolites in the pharmacological activity of resveratrol

Tea polyphenols as prostate cancer preventive agents

Prostate cancer is an ideal candidate for chemoprevention. Tea drinking is a possible explanation for the rarity of prostate cancer among Chinese men. Tea (Camellia sinensis) contains flavonoid polyphenols called catechins, believed to be responsible for this anti-carcinogenesis. In black tea these catechins are oxidised into theaflavins. Catechins and theaflavins both inhibit human prostate cancer cell proliferation in vitro. Catechins inhibit prostate cancer in the TRAMP mouse animal model of the disease. To determine if tea polyphenols warrant investigation in large trials, evidence is required from animal models and biomarkers of cancer prevention identified in small human studies. In the work presented here, prostate carcinogenesis was inhibited by orally administered tea polyphenols in the TRAMP mouse. Following 26 weeks of polyphenol administration median prostate masses were 0.54g, 0.28g and 1.01g for the theaflavin, catechin and control group respectively. This is the first in vivo evidence of prostate cancer chemoprevention by black tea theaflavins and adds to the previously published evidence for the same effect by green tea catechins. In the catechin group, this chemoprevention was associated with a significant reduction in the concentration of oxidative DNA adduct malondialdehydedeoxyguanosine (M1G) in prostate tissue. M1G, a marker of oxidative DNA damage, was therefore proposed as a putative biomarker of prostate cancer chemoprevention. A human trial was then performed involving 18 men randomised to receive four weeks of catechins, theaflavins or no polyphenol prior to transurethral resection of prostate. A significant reduction in M1G was detected in the DNA from prostate tissue of men who had received catechins. Tea polyphenols and particularly catechins may therefore represent prostate cancer prevention agents suitable for study in a larger human intervention trial however, this finding should be first be tested in further better designed biomarker studies using this result to inform decisions on study population size.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Modulation of response to cancer chemotherapeutic agents by diet constituents: is the available evidence sufficiently robust for rational advice for patients?

Background: Patients who are diagnosed with cancer want advice on how they may alter their diet or which diet supplements they should take to augment chemotherapy. Methods: We conducted a review of the literature mostly from the last 15 years on the interaction between dietary constituents and antineoplastic therapy in preclinical rodent models and in clinical trials. Results: Studies have explored the effect of predominantly antioxidant vitamins and folate on efficacy or toxicity mediated by cisplatin and anthracyclins. Cisplatin toxicity in rodents was ameliorated by vitamin E. The design of clinical studies of dietary agents in combination with cytotoxic agents has been very heterogeneous and results have been inconclusive. Conclusions: Whilst preclinical experiments hint at a potential benefit of certain dietary agents, the evidence emanating from clinical studies does not allow firm conclusions to be made. Future studies should explore physiological doses of dietary agent and include pharmacokinetic and pharmacodynamic measurements

Putative Cancer Chemopreventative Agents of Dietary Origin - How Safe Are They?

Putative Cancer Chemopreventative Agents of Dietary Origin - How Safe Are They