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«MODULATION OF POLYAMINE METABOLISM AS A CHEMOPREVENTIVE STRATEGY OF PHYTOCHEMICALS IN A CELL CULTURE MODEL OF COLORECTAL CANCERS Dissertation zur ...»

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gies for multiple cancers [3 – 9]. Chemoprevention is defined as the employment of drugs or natural compounds to prevent malignant tumors [10]. Several epidemiological, clinical, and experimental studies established nonsteroidal anti-inflammatory drugs (NSAIDs) as promising cancer chemopreventive agents [11]. Long-term use of aspirin and other NSAIDs has been shown to reduce the risk of cancer of the colon and other gastrointestinal organs as well as of cancer of the breast, prostate, lung, and skin [12]. But also a large number of natural compounds have been linked to a possible decreased incidence of developing cancers [13 – 15]. Among others there is a special focus on polyphenols present in dietary and medicinal plants exhibiting anti-carcinogenic activities [16].

The plant polyphenol resveratrol (3,49,5-trihydroxy-transstilbene; Fig. 1) has been classified as a phytoalexin, because it is synthesized in spermatophytes in response to certain types of stress, including injury, UV irradiation, or fungal attack [17, 18]. It was first described as a component in the root extracts of the weed Polygonum cuspidatum, Figure 1. Chemical structures of stilbene compounds cited in which has been known in traditional Asian medicine under this review. (I) 3,49,5-trihydroxystilbene (resveratrol); (II) transresveratrol-3-O-D-glucoside (piceid); (III) cis-3,49,5-trimethoxythe name Ko-jo-kon [19]. Resveratrol naturally occurs in stilbene; (IV) 3,39,49,5-tetramethoxystilbene (piceatannol); (V) grapes [20 – 22], wine [23], and peanuts [24 – 26]. An 3,5-dimethoxy-49-hydroxystilbene (pterostilbene); (VI) important factor for resveratrol concentrations in wine is 29,3,49,5-tetramethoxystilbene; (VII) 2,3,49,5-tetrahydroxystilthe fermentation time in contact with grape skins because bene. Substituents are hydroxyl (OH) and methoxy (OCH3) resveratrol is produced by the skin but not by the fruit flesh groups and O-b-D-glucose (OGlc).

[27]. This explains the low concentrations in white wine because the grape skins are not fermented in the production 2 Resveratrol and its analogs in carcinogenic process [23]. Resveratrol came to scientific attention as a possible explanation for the “French paradox” as it has ben- in vivo models eficial effects on the development of cardiovascular diseases [28]. It has been shown to inhibit platelet aggregation Oral administration of resveratrol inhibited tumor growth of T241 fibrosarcoma in mice [45]. Rats inoculated with and eicosanoid synthesis [29], to interfere with arachidonate metabolism [30], to exert strong inhibitory effects on Yoshida AH-130 hepatoma cells and treated with resverareactive oxygen species produced by human polymorpho- trol (intraperitoneal injection) had a decreased tumor cell nuclear leukocytes [31], to be an antioxidant more powerful number [46]. Lung cancer development in A/J mice than vitamin E in preventing low-density lipoprotein (LDL) induced by benzo[a]pyrene and 4-(methylnitrosamino)-1oxidation [32], and to exert vasorelaxing effects on (3-pyridyl)-1-butanone was not inhibited by oral adminisendothelium-intact aorta rings of rats [33]. Further studies tration of resveratrol [47, 48], whereas in Balb/c mice could show that resveratrol is an agonist for the estrogen resveratrol protects the lung from DNA damage and apopreceptor which may also be relevant to the reported cardio- tosis caused by benzo[a]pyrene [49]. Additionally adminisvascular benefits of drinking wine [34]. tration of resveratrol per os reduced the number of aberrant crypt foci in azoxymethane-induced tumorigenesis in the Additionally, we and others have examined that resveratrol rat colon and led to enhanced expression of the proapoptotic and its analogs (Fig. 1) exhibit multiple properties including protein Bax in these crypt foci [50]. In a 7,12-dimethylchemopreventive effects in several carcinogenesis models benz[a]anthracene (DMBA)-induced mammary carcinoboth in vivo and in vitro [35 – 41]. Several signal transduc- genesis model in Sprague Dawley rats dietary administration pathways have been examined to explain these effects. tion of resveratrol had indeed no effects on body weight One hypothesis is focusing on polyamine metabolism as a gain and tumor volume but produced reductions in the incipossible target of resveratrol activity [42]. Because many dence, multiplicity, and extended latency period of tumor reviews regarding the preventive effect of resveratrol on development [51]. The mean survival time of mice inocucardiovascular diseases have been published [43, 44], this lated with 32Dp210 leukemia cells and treated with up to review will summarize our work on the mechanisms and 80 mg resveratrol/kg body weight was not significantly activity of resveratrol and its derivatives in carcinogenesis. different from untreated controls, even though resveratrol

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after addition of resveratrol. This effect was demonstrated to be dependent on protein kinase A and phospholipase A2 activities and independent of the estrogen receptor [72].

3.2 Cell cycle Inhibition of cell cycle progression is a possible target for chemopreventive agents like resveratrol. The cell cycle is regulated by cyclins and cyclin-dependent kinases (Cdk), which are primarily regulated by their expression levels and by cell cycle-inhibiting proteins (p21Waf1/Cip1, p27Kip1, and members of the INK family of proteins) (Fig. 2). The effect of resveratrol on the cell cycle distribution of tumor cells seems to focus on the S-phase. A cell cycle arrest in the Sphase has been reported for different cell types [37, 73 – 81], except from HepG2 cells in which a G1 phase arrest could be observed [82]. An increased cyclin E and cyclin A expression was observed in HL-60 leukemia cells [83], Figure 2. Cell cycle and possible modulation by resveratrol.

U937 lymphoma cells [78], HCT-116, and Caco-2 colon The polyphenol resveratrol has been shown to inhibit the activcancer cells [37]. Ragione et al. [83] identified inactivation ity of cdc2 and cdk4. Additionally there is an accumulation of cyclins E and A, accompagnied by a decrease of D-type of Cdc2 by phosphorylation at tyrosine residue 15 as a poscyclins as well as an increase of p21 expression. Furthermore, sible pathway by which this S-phase arrest is mediated. A resveratrol promotes dephosphorylation and thus activation of concentration-dependent decrease of the p27Kip1 expression the tumor suppressor pRb. These activities contribute to the level was observed in LNCaP, U937, and Caco-2 cells [37, ability of resveratrol to inhibit cell progression at S-phase.

77, 78]. In bovine pulmonary artery endothelial cells [75], HL-60 cells [83], A431 cells [80], and U937 cells [78] resveratrol treatment led to an increased p21Waf1/Cip1 expres- Cell cycle regulation was also observed in a few in vivo sion, whereas the protein level of the cell cycle inhibitor studies. In H22-bearing mice, resveratrol inhibited the was unmodified in Caco-2 cells [37] and decreased in growth of transplantable liver cancer by decreasing the LNCaP cells [77] and neuroblastoma cells [55]. In the expression of cyclin B and cdc2 protein [88]. In another human prostate carcinoma cell line the antiproliferative study, resveratrol downregulated UVB-induced expression effect of resveratrol was associated with the inhibition of D- of Cdk2, 4, 6 and cyclin D1 and D2 in SKH-1 hairless type cyclins and Cdk 4 expression, and the induction of mouse skin, which was accompanied by an upregulated tumor suppressor p53 and Cdk inhibitor p21. Moreover, the UV-mediated increase in the expression of the Cdk inhibitor kinase activities of cyclin E and Cdk2 were inhibited by WAF1/p21 and the tumor supressor protein p53 [89]. In resveratrol without alteration of their protein levels [84]. addition to the regulation of cell cycle proteins, the negative The retinoblastoma protein (pRb) sequesters the transcrip- effect of resveratrol on proliferation has in part been attribtion factor E2F in the cytosol. Phosphorylation of pRb pre- uted to inhibition of ribonucleotide reductase and DNA vents binding of pRb to E2F which leads to the transloca- synthesis [90].

tion of E2F into the nucleus. Dephosphorylation and thus activation of the tumorsuppressor pRb was observed in Piceatannol is also a cell cycle inhibitor that acts preferably Caco-2 cells [37] and in A431 epidermoid carcinoma cells in the S-phase. It has been demonstrated to inhibit the after treatment with resveratrol. In A431 cells this effect growth of Caco-2 and HCT-116 colon cancer cell lines. Folwas accompanied by decreased protein levels of all E2F lowing piceatannol treatment, the number of Caco-2 cells family members (1 – 5) and their binding partners DP-1 and in the S-phase increased and reduced levels of Cdk4, Cyclin D1, Cyclin B1, and p27Kip1 were detected. At the same time DP-2 [85]. Resveratrol arrested the cell cycle of non-androgen responsive prostate cancer cell lines in the S-phase, but an increase in Cyclin E and Cyclin A expression could be did not modify the cell cycle distribution of the androgen- shown. Taken together, these effects were comparable to responsive cell line LNCaP [86]. Stivala et al. [87] demon- those observed after treatment with resveratrol [38]. The strated that the cell cycle effects of resveratrol are depend- methylated resveratrol analog cis-3,5,49-trimethoxystilbene (0.3 lM) induces accumulation of Caco-2 cells in the G2/Ment on certain structural determinants. The trans-configuration in combination with the hydroxy group in the 49-posi- phase with a diminished G0/G1-phase population. These tion is essential for the effects of resveratrol on the cell effects were caused by depolymerization of the microtubule cycle. network [91].

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