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

Quality of life and psychological impact in patients with noncardiac chest pain

BACKGROUND: Chest pain is common and data regarding noncardiac chest pain (NCCP) in Asia are lacking. AIM: To determine the differences in clinical presentations, psychologic impact, and quality of life between patients with NCCP and cardiac chest pain (CCP), and to identify any factors that impacted on these patients. METHODS: Consecutive patients undergoing coronary angiography for the evaluation of chest pain were recruited in Hong Kong and Wuhan, China. One hundred and forty patients with abnormal and 141 patients with normal angiography were included in the study. The validated gastroesophageal reflux disease questionnaire, the Hospital Anxiety-Depression Scale, and the 12-item Short Form Health Survey (SF-12) were used for assessment. RESULTS: NCCP patients reported similar days-off work and impairment of their social life compared with those with CCP. No difference was found in the anxiety and depression scores between the 2 groups. NCCP patients with reflux symptoms had higher anxiety score (7.19 vs. 5.74, P=0.044), reported more interruption of their social life (26% vs. 5%, P<0.0001), and had taken more sick leaves (17% vs. 5%, P=0.018) compared with those without gastroesophageal reflux disease. CONCLUSIONS: The quality of life and psychologic impact of patients with NCCP were as significant as those with CCP. NCCP patients with reflux symptoms were more anxious and were impaired in their productivity and social life. © 2009 Lippincott Williams & Wilkins, Inc.link_to_subscribed_fulltex

Predicting the physiological relevance of in vitro cancer preventive activities of phytochemicals.

There is growing interest in the ability of phytochemicals to prevent chronic diseases such as cancer and heart disease. However, some of these agents have poor bioavailability and many of the in depth studies into their mechanisms of action have been carried out in vitro, using doses which are unachievable in humans. In order to optimize the design of chemopreventive treatment, it is important to determine which of the many reported mechanisms of action are clinically relevant. In this review we consider the physiologically achievable doses for a few of the best studied agents (indole-3-carbinol, diindolylmethane, curcumin, epigallocatechin-3-gallate and resveratrol) and summarize the data derived from studies using these low concentrations in cell culture. We then cite examples of in vitro effects which have been observed in vivo. Finally the ability of agent combinations to act synergistically or antagonistically is considered. We conclude that each of the compounds shows an encouraging range of activities in vitro at concentrations which are likely to be physiologically relevant. There are also many examples of in vivo studies which validate in vitro observations. An important consideration is that combinations of agents can result in significant activity at concentrations where any single agent is inactive. Thus for each of the compounds reviewed here, in vitro studies have provided useful insights into their mechanisms of action in humans. But data are lacking on the full range of activities at low doses in vitro and the benefits or otherwise of combinations in vivo