Modulation of signal transduction pathways by chemopreventive agents

Abstract

A disease such as cancer, where a number of alterations to normal cell function accumulate over time, presents several chernopreventive opportunities to inhibit, slow down or even reverse the process. Many of the crucial changes are induced by alterations to cell signalling pathways which regulate proliferation and apoptosis. As our knowledge of these complicated signalling networks improves, it is becoming clear that many molecules, both drugs and naturally occumng dietary constituents can interact beneficially with deregulated pathways. Molecules such as aspirin and other non-steroidal antiinflammatory drugs, as well as many dietary plant components, for example from green vegetables and tea, can inhibit signalling by affecting kinase activity and therefore phosphorylation of key molecules. Examples of pathways which can be modulated by these agents include activation of the transcription factor nuclear factor-* by tumour promoton or cytokines, signalling by growth factors through the epidermal growth factor receptor/mitogen activated protein kinase pathway and the stress activated (SAF'K)/p38 pathways. Evidence exists, at least from in virro experiments, that through targetting signalling pathways, some compounds may be able to restore rates of apoptosis and proliferation to normal levels, thus rendering them relatively non-toxic, an essential requirement for a good chemopreventive agent.c12 Diet and colorectal cancer prevention MRC Dunn Human Nutrition Unit. Hills Road, Cambridge CB2 2DH Colorectal cancer is the second most common cancer in the UK. The majority of cancers are sporadic and epidemiological estimates suggest that up to 80% of colorectal cancer is attributable to diet This means that it is potentially a preventable disease. Epidemiologically, cross sectional comparisons, case control studies and trends in food intakes show high rates of colorectal cancer in populations consuming diets high in meat and far, and low in starch, NSP (non starch polysaccharides. fibre) and vegetables. In general, prospective studies tend to support these findings although estimates of relative risk are not high. Existing prospective studies have however used crude indices of diet subject to substantial measurement error, and interactions with genetic polymorphisms in for example phase I and I1 enzymes have been studied only rarely. The association between meat consumption and colorectal cancer is usually attributed to the formation of heterocyclic amines in meat when it is cooked. In addition, in humans high meat diets increase the level of nitrosatable material entering the colon so that faecal N-nitrosocompounds (NOC) increase in a dose rcponsivc manner following endogenous synthesis in the colon. Some of the mutations and guanine adducts accumulated during colorcctal cancer progression are characteristic of alkylative damage which would be compatible with N O C exposure. To date, NSP, resistant starch and vegetables have not reduced faecal N O C levels. C13 Human metabolism of dietary chemopreventive compounds Gary...

Dietary agent indole‐3‐carbinol protects female rats against the hepatotoxicity of the antitumor drug ET‐743 (trabectidin) without compromising efficacy in a rat mammary carcinoma

“…Its ability to block tumor initiation has been rationalized in terms of upregulation of drug metabolizing enzymes, 27 whereas tumor suppression by I3C may be the consequence of modulation of pathways resulting in inhibition of cell proliferation or in compromised cell survival. 28,29 I3C has been shown to protect mice against hepatic damage induced by the hepatotoxicant carbon tetrachloride (CCl 4 ). 30 In this model, CCl 4 exerts its toxic effect via free radical species generated during reductive metabolism involving cytochrome P450.…”

Signaling Pathways Mediating Manganese-Induced Toxicity in Human Glioblastoma Cells (U87)

“…There are different groups of MAPK that are activated by different stimuli: among them ERK1 and ERK2 are activated by growth factor stimuli, whereas p38 kinases are activated by stress stimuli. Because treatment with low, physiological levels of Mn induces growth in astrocytes and astrocytoma cells [4,6] whereas treatment with higher, pathophysiological and toxicological levels of Mn induces stress in astrocytes [5], we have investigated the effects of Mn on both ERK1/2 and p38 proteins [7,8] in U87 astrocytoma cells.…”

Development of a Simple Method for Determination of Anti-cancer Component of Indole-3-carbinol in Cabbage and Broccoli

“…Epidemiological and clinical studies suggest that indole-3-carbinol is a potential agent in blocking tumour initiation, oestrogen metabolism, inhibition of cell proliferation and induction of apoptosis [3,4,5,6,7]. So far, many studies have shown indole-3-carbinol is a bioactive component that plays an important anti-cancer role against breast [8], liver [9], prostate [10], lung and colon cancers [11,12].…”