1. Dietary cancer-chemopreventive compounds: from signaling and gene expression to pharmacological effects 
Chi Chen, Ah-Ng Tony Kong 
Trends in Pharmacological Sciences 
Volume 26, Issue 6, Pages (June 2005)
DOI: /j.tips
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2. Figure 1
Regulation of detoxifying enzymes by dietary chemopreventive compounds. Natural detoxifying enzyme inducers, such as curcumin, a phenolic compound, and sulforaphane, a sulfur-containing compound, regulate the expression of genes encoding detoxifying enzymes through the transcription factor NRF2 (nuclear factor E2-related factor 2). Under basal conditions, NRF2 protein is retained in the cytosol by Kelch-like ECH-associating protein 1 (KEAP1). KEAP1 also facilitates the proteasome-mediated degradation of NRF2 protein by facilitating as an adaptor for Cullin 3 (Cul3)-based E3 ligase. The function and localization of NRF2 is regulated by multiple upstream kinases that are activated by inducers of detoxifying enzymes. Modification of multiple cysteine residues in KEAP1 following treatment with these enzyme inducers leads to disassociation of NRF2 from KEAP1. Among three mitogen-activated protein kinase (MAPK) kinases, activated extracellular signal-regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) might promote translocation of NRF2 to the nucleus but p38 might inhibit NRF2 translocation in some cell types. Phosphorylation of Ser40 in NRF2 protein by protein kinase C (PKC) also leads to the release of NRF2 from KEAP1. Similarly, phosphatidylinositol 3-kinase (PI3K), and stress-related RNA-dependent protein kinase (PKR)-like endoplasmic reticulum kinase (PERK) derived from the endoplasmic reticulum (ER), might also elicit positive influences on NRF2 and subsequent induction of cellular defense enzymes. Once in the nucleus, NRF2 interacts with small Maf proteins, such as MafG and MafK, forming heterodimers, and binds to the antioxidant response element (ARE) sequence in the promoter regions of many genes encoding cytoprotective enzymes. Transcription of these genes is also enhanced by interactions between NRF2 and coactivators, such as cAMP response element binding protein (CREB)-binding protein (CBP) or p300. Finally, elevated levels of detoxifying enzymes [e.g. glutathione-S-transferase (GST), NAD(P)H:quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HO1) and multidrug resistance associated protein 1 (MRP1)] facilitate the detoxification and elimination of carcinogens and reactive intermediates, and protect the cells and the body against chemical carcinogenesis. Abbreviation: Ub, ubiquitin.
Trends in Pharmacological Sciences  , DOI: ( /j.tips )
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3. Figure 2
Induction of apoptosis and cell-cycle arrest by dietary chemopreventive compounds. Apoptosis and cell-cycle arrest are two important goals of dietary antiproliferative compounds against the promotion and progression of pre-neoplastic or neoplastic cells. Contrasting with death receptor-mediated cell death, chemopreventive compounds generally induce oxidative stress, which downregulates anti-apoptotic molecules such as Bcl-2 or Bcl-x and upregulates pro-apoptotic molecules such as Bax or Bak. The imbalance between anti-apoptotic and pro-apoptotic proteins elicits the release of cytochrome c (Cyt c) from the mitochondrial inner membrane; cytochrome c then forms an ‘apoptosome’ with apoptotic protease-activating factor 1 (APAF-1) and caspase-9, with the subsequent activation of caspases-3, -6 and -7. The activated caspases catalyze the dissolution of intracellular structure, which leads to apoptotic cell death. To enhance this mitochondria-mediated apoptosis, dietary cytotoxic compounds also activate pro-apoptotic c-Jun N-terminal kinase (JNK) and inhibit anti-apoptotic NF-κB signaling pathways. Furthermore, dietary chemopreventive compounds can also block growth factor-mediated anti-apoptotic signals through the direct inhibition of the binding of growth factors to the receptor, or inhibition of the downstream phosphatidylinositol 3-kinase (PI3K)–Akt pathway. At relatively lower concentrations, these same dietary chemopreventive compounds can achieve cell-cycle arrest by changing the balance between the cell-cycle regulators [cyclins, cyclin-dependent kinases (CDKs) and CDK inhibitors]. One potential mechanism is through the induction of the transcription factor activator protein 1 (AP-1) by dietary chemopreventive compounds, leading to the increased expression of p21, a CDK inhibitor, which subsequently arrests cells in G1–S or G2–M interphases.
Trends in Pharmacological Sciences  , DOI: ( /j.tips )
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