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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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Therefore, providing potent chemopreventive activities, phytochemicals like ursolic acid could in theory possibly serve as alternatives to chemically designed antineoplastic agents, as constituents of therapeutic drug combinations in advanced disease, or as adjuvant treatments.

ACKNOWLEDGEMENTS

This work was supported by a graduate scholarship grant from the DFG (GRK 757) to Sandra Ulrich and by the Else-Kröner Fresenius Foundation, Bad Homburg, Germany.

FIGURE LEGENDS

Fig 1. Cell counts and cell proliferation of colorectal cancer cell lines after incubation without (control) or with ursolic acid (UA). UA leads to a conspicuous time (24-72h) dependent decrease in cell counts (A) and to an inhibition of cell proliferation (B) of Caco-2-[30 µmol/L], HCT-116-[15 µmol/L] and HT29-cells [15 µmol/L]. After 72h of incubation, also a dose-dependent reduction of cell counts (C) as well as cell proliferation (D) could be observed in the tested cell lines (Caco-2 [10-30 µmol/L, HCT-116 and HT29 [5-15 µmol/L]. Means ± SE, n = 3; *p0.05, **p0.01, ***p0.001.

Fig 2. Expression of cell-cycle regulating proteins after ursolic acid treatment of Caco-2 cells.

Ursolic acid [10-30 µmol/L] leads to a dose-dependent protein increase of cell cycle inhibitor p21WAF1/Cip1 and Cyclin E after 24h of incubation. An up-regulation of p27Kip1 protein could be observed after 48h of incubation. For all proteins, a representative immunoblot of three independent experiments is shown. Means ± SE; n=3 Fig 3. (A) DNA-Fragmentation in colorectal cancer cells.

Ursolic acid leads to a significant dose-dependent induction of apoptosis in Caco-2-[10-30 µmol/L], HCT-116-[5-15 µmol] and HT29-cells [5-15 µmol/L] after 24h of incubation.

Means ± SE; **p0.01; ***0.001.

Fig. 4. Caspase-3-Activity in Caco-2 cells Treatment with ursolic acid in increasing concentrations [10-30 µmol/L] significantly activates pro-apoptotic caspase-3 after 24h. Means ± SE, n=3, ***p0,001.

Fig 5. Expression of apoptose-related proteins in Caco-2-cells.

(A) Western blot of BAX and Bcl-2 after incubation with ursolic acid [10-30 µmol/L] for 24h. For both proteins, a representative immunoblot of three independent experiments is shown. The graph presents the densitometric analysis of the BAX/Bcl-2 ratio after 24h. (B) TRAIL protein after incubation with ursolic acid [10-30 µmol/L] for 24h. A representative immunoblot of three independent experiments is shown. The graph presents the densitometric analysis of the TRAIL/β-actin ratio. Means ± SE; n=3; *p0.05. Means ± SE; n=3, # = not significant, **p0.01, ***p0.001 Fig. 6 Activity of spermine/spermidine acetyltransferase (SSAT) in Caco-2-wildtype cells in comparison to transfected Caco-2 empty vector- and Caco-2-dnPPARγ cells.

Ursolic acid [10-30 µmol/L] leads to a significant increase in SSAT-activity both in Caco-2wildtype- and Caco-2-empty vector-cells after 24h of incubation. But no effects could be observed, when PPARγ-mediated functions are suppressed. Means ± SE; n=4; Values not sharing a letter differ significantly. **p0.01.

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Review Molecular mechanisms of the chemopreventive effects of resveratrol and its analogs in carcinogenesis Sandra Ulrich, Freya Wolter and Jürgen M. Stein 1st Department of Medicine, ZAFES, JW Goethe University, Frankfurt, Germany Resveratrol (3,49,5-trihydroxy-trans-stilbene), a phytoalexin found in grape skins, peanuts, and red wine, has been reported to exhibit a wide range of biological and pharmacological properties. It has, been speculated that dietary resveratrol could be an explanation for the so-called French paradox’ as it may act as an antioxidant, promote nitric oxide production, inhibit platelet aggregation, and increase high-density lipoprotein cholesterol, and thereby serve as a cardioprotective agent. Recently, it has been demonstrated that resveratrol can function as a cancer chemopreventive agent, and there has been a great deal of experimental effort directed toward defining this effect. It has been shown that resveratrol and some of its analogs interfere with signal transduction pathways, modulate cell cycle-regulating proteins, and is a potent inducer of apoptosis in multiple carcinoma cell lines. This review summarizes the recent advances that have provided new insights into the molecular mechanisms underlying the promising properties of resveratrol.

Keywords: Apoptosis / Angiogenesis / Cancer / Cell cycle / Resveratrol / Signal transduction / Received: October 29, 2004; revised: January 10, 2005; accepted: January 26, 2005

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