Inhibition of Cellular Replication

Dividing cells undergo a series of steps of well-defined cellular changes referred to as the cell cycle. Mitogenic growth signals are required for cells to move from the resting or quiescent state (G0) to the proliferative state, defined by a successive series of phases: initial gap (G1), DNA synthesis (S), second gap (G2), and mitosis (M). Each step is characterized by distinct cellular processes that are required for proper cell division. The formation of cyclin (a structural protein) with a cyclin-dependent kinase (CDK) into a complex regulates phase

TABLE 2.2

Mechanisms for Chemoprevention by Diet-Derived Agents with Possible Molecular Targets

Mechanism

Antimutagenesis

Inhibit carcinogen uptake Inhibit formation/activation of carcinogen

Deactivate/detoxify carcinogen Prevent carcinogen-DNA binding Increase level or fidelity of DNA repair

Inhibit oncogene activity

Inhibit polyamine metabolism Induce terminal differentiation

Restore immune response

Reduce inflammation

Inhibit eicosanoid production

Increase intercellular communication Induce apoptosis

Possible Molecular Targets

Bile acids Cytochrome P450s

PG synthase hydroperoxidase,

5-lipoxygenase Bile acids GSH/GST Cytochrome P450s

Poly(ADP-ribosyl)transferase

AP-1 PPARs

Farnesyl protein transferase

ODC induction TGF-P

T, NK lymphocytes Langerhans cells NF-kB

Cyclooxygenases and lipoxygenases Connexin 43

TGF-P

Ras farnesylation

Arachidonic acid Caspase

Representative Agents

Calcium

PEITC, tea, indole-3-carbinol, soy isoflavones Curcumin

Urosdiol

NAC, garlic/onion disulfides Tea

NAC, protease inhibitors (Bowman-Birk)

Soy isoflavones Tea

Soy isoflavones, retinoids, lycopene Retinoids Retinoids

Perillyl alcohol, limonene, DHEA Retinoids, curcumin, tea Retinoids, vitamin D, soy isoflavones Selenium, tea Vitamin E

Wogonin, EGCG, resveratrol, curcumin Tea, curcumin, resveratrol, EPA/DHA Carotenoids (lycopene), retinoids Retinoids, soy isoflavones, vitamin D Perillyl alcohol, limonene, DHEA Retinoic acid Retinoids

(continued)

Antiproliferation/Antiprogression

Modulate hormone/growth Estrogen receptor factor activity

Steroid 5a-reductase IGF-1

TABLE 2.2 (CONTINUED)

Mechanisms for Chemoprevention by Diet-Derived Agents with Possible Molecular Targets

Mechanism

Induce senescence

Inhibit angiogenesis

Correct DNA methylation imbalances Inhibit basement membrane degradation Inhibit DNA synthesis

Possible Molecular Targets

Telomerase

FGF receptor tyrosine kinase

Thrombomodulin

CpG island methylation

Type IV collagenase

Glucose 6-phosphate dehydrogenase

Representative Agents

Vitamin D, retinoids, EGCG, curcumin Soy isoflavones Retinoids Folic acid

Protease inhibitors

(Bowman-Birk), vitamin D DHEA

Abbreviations: PEITC, phenethyl isothiocyanage; PG, prostaglandin; GSH, glutathione; GST, glu-tathione-S-transferase; NAC, N-acetyl-L-cystein; IGF-1, insulin-like growth factor-1; AP-1, (transcription) activator protein-1; PPAR, peroxisome proliferator activated receptor; DHEA, dehydroepiandrosterone; EPA/DHA, eicosapentaenoic acid/ docosahexaenoic acid; ODC, ornithine decarboxylase; TGF-P, transforming growth factor-P; NK, natural killer; NF-kB, nuclear factor kappa B; RAS, ras oncogene product; FGF, fibroblast growth factor; CpG, cytosine-guanosine.

Source: Adapted from Kelloff GJ, Crowell JA, Steele VE et al. Progress in cancer chemoprevention: development of diet-derived chemopreventive agents. J Nutr 2000; 130:468S. With permission.

transitions. External stimuli (e.g., nutrients) and internal signals (e.g., DNA damage) regulate the formation of cyclin-CDK complexes via cyclin-dependent kinase inhibitors, which include the cip/waf family (p21, p27, p58). These regulated transitions are referred to as "checkpoints" and represent important targets for control.29

The most significant checkpoint occurs in late Gj, and when activated in response to DNA damage, entry into S-phase is delayed to allow time for DNA repair.23 If irreparable DNA damage is present, the pathway for programmed cell death, or apoptosis, is activated. Critical to the function of this restriction point is the interaction between the retinoblastoma (Rb) protein and the E2F family of transcription factors. When hypophosphorylated, Rb binds E2F to form a silencing complex inhibiting transcription of genes necessary for cell cycle entry. With mitogen stimulation, e.g., by growth factors, D-type cyclases are synthesized with their associated kinases. Rb is thus phosphorylated, releasing the E2F factors and allowing transcription of genes essential to DNA synthesis as well as other cyclins and CDKs that maintain the phosphorylated state of Rb, allowing mitogen-independent passage through the remainder of the S-phase. Additional checkpoints are present at the G2/M transition prior to mitosis and during metaphase of mitosis.23

Via Perillyl Alcohol

FIGURE 2.2 Dietary factors, smoking, physical activity, and obesity in relation to the carcinogenesis process, from the initiation and promotion stages to metastasis or apoptosis. (From Go VL, Wong DA, Butrum R. Diet, nutrition and cancer prevention: where are we going from here? J Nutr 2001; 131:3123S. With permission).

FIGURE 2.2 Dietary factors, smoking, physical activity, and obesity in relation to the carcinogenesis process, from the initiation and promotion stages to metastasis or apoptosis. (From Go VL, Wong DA, Butrum R. Diet, nutrition and cancer prevention: where are we going from here? J Nutr 2001; 131:3123S. With permission).

Growth signals are transmitted by transmembrane receptors that bind different classes of signaling molecules, including growth factors, extracellular matrix components, and cell adhesion molecules. In addition, nuclear receptors (e.g., estrogen and androgen receptors, peroxisome proliferating receptors, retinoic acid receptors, vitamin D receptor) activated by steroid hormones and other lipophilic substances (e.g., prostaglandins, retinoids, vitamin D) act as transcription factors to regulate genes, including those involved with cellular proliferation. Normal cells proliferate in response to an array of growth factor signals produced from cells in the immediate environment or circulating hormones. Local factors can include epidermal growth factor (EGF), fibroblast growth factor (FGF), tumor growth factor-a (TGF-a), and platelet derived growth factor (PDGF).23 Tumor cells characteristically show a decreased dependence on exogenous growth signals coming from the normal tissue environment by generating their own growth signals. In fact, many cancer cells acquire the ability to synthesize growth factors to which they are responsive, creating an autocrine-positive feedback loop. In addition, the components of the signal transduction pathways are perturbed. Changes include overexpression of growth factor receptors, which creates cells with an exaggerated response to growth signals, alteration in types of extracellular matrix receptors (integrins) expressed, and notably, modulation of the downstream cytoplasmic signaling pathways that define growth factor action resulting from ligand activation of growth factor receptors and integrins. Many growth factor receptors, when overexpressed, carry with them enhanced tyrosine kinase activities in their cytoplasmic domains. This overexpression may make cancer cells hyper-responsive to growth factor signals that under normal circumstances may not stimulate proliferation.26

Many of the proteins involved in growth regulation are proto-oncogenes; that is, they are oncogenic when mutated. For example, one central signaling pathway in proliferation is the mitogen-activated protein (MAP) kinase pathway. This pathway is overactive when the oncogenic form of ras proteins is mutated so that they are constitutively activated and disregulated from upstream regulators. Ras mutations are found in some 25% of human cancers.26

A comprehensive catalog of bioactive food components has been shown to inhibit cell proliferation in vitro at physiologically relevant doses, although there is specificity in the effects depending on dose, length of treatment, and cell type tested. A prominent example is genistein, an isoflavone and the major phytoestro-gen in soybeans and other legumes. Genistein and other phytoestrogens have a chemical structure reminiscent of 17P-estradiol, can bind the estrogen receptors (ERa and ERP), although with stronger affinity to ERP, and exhibit estrogenlike biological activity.9 Human breast and prostate cancer cell lines stimulated by EGF are inhibited by genistein independently of whether the cells express estrogen or androgen receptors. When all cell culture media are depleted of estrogens, genistein at concentrations <1 pmol/L acts as a growth stimulant to estrogen-dependent breast cancer cells; in the presence of 17P-estradiol (0.3 nmol/L, a physiological concentration) the effect of genistein is not additive. However, at concentrations >5 pmol/L, genistein causes a dose-dependent decrease in 17P-estradiol-induced cell proliferation.30

Genistein has been shown to inhibit cellular growth of a number of different cell types other than breast and prostate, including leukemia, lymphoma, neuroblastoma, gastric, lung, head, and neck squamous cancer cells; these lines vary in the presence of estrogen and androgen receptors and p53 status indicating effectiveness in cancer cells with varied molecular signatures. In a number of these cell types genistein induces a G2/M cell cycle arrest.31 This effect is borne out in a decrease in cyclin B, which is important for the formation of the cyclin B/CDK complex to allow progression through G2/M.31 The CDK inhibitor p21WAF1 was also upregulated in genistein-treated cells, which illustrates genistein's coordinated action in regulation of cell growth and the cell cycle.32,33

Genistein has also been postulated to have ER-independent action as well. Genistein was identified as a protein tyrosine kinase (PTK) inhibitor as it inhibited the EGF receptor PTK in vitro, and this function has been presumed to be a mechanism of genistein's antimitogenic action.30 However, proliferation in several cell lines stimulated by EGF is inhibited by genistein without inhibition of EGF-R tyrosine autophosphorylation or tyrosine phosphorylation of other substrates involved with signaling pathways, suggesting alterations tyrosine phosphorylation may be an indirect effect of genistein's actions.30 Alternatively, genistein may enhance production of TGF-P 1, which is normally a growth-inhibitory factor, as described below.34

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