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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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I. ULRICH, S., LOITSCH, S., RAU O., VON KNETHEN, A., BRÜNE, B., SCHUBERTZSILAVECZ, M., STEIN, J. (2006) Peroxisome-Proliferator activated receptor γ as a molecular target of resveratrol-induced modulation of polyamine metabolism. Cancer Res 66(14): 7348-54.

II. ULRICH, S., HUWILER, A., LOITSCH, S., SCHMIDT, H., STEIN J. (2007) De novo ceramide biosynthesis is assaociated with resveratrol-induced inhibition of ornithine decarboxylase activity. Biochem Pharmacol 74(2):281-9.

III. ULRICH, S., JUNG, B., LOITSCH, S., KAMPAN, W., STEIN, J. (2007) Ursolic acid induces apoptosis through PPARγ mediated SSAT-activation in colon cancer cells. (submitted) IV. WOLTER, F., ULRICH, S., STEIN, J. (2004) Molecular mechanisms of the chemopreventive effetcs of resveratrol and its analogs in colorectal cancer: key role of polyamines. J Nutr 134(12): 3219-22. Review V. ULRICH, S., WOLTER, F., STEIN, J. (2005) Molecular mechanisms of the chemopreventive effects of resveratrol and its analogs in carcinogenesis.

Mol Nutr Food Res 49(5): 452-61. Review

XDANKSAGUNG

Bedanken möchte ich mich zuallererst bei Prof. Dr. Dr. Jürgen Stein für die Aufnahme in seine Arbeitsgruppe und die Überlassung des interessanten Themas. Danke auch für seine stete Diskussionsbereitschaft und den Freiraum für die Entwicklung eigener wissenschaftlicher Projekte und Ideen. Ich danke ihm auch für seine großzügige Unterstützung, an internationalen Kongressen teilnehmen und somit Teile dieser Arbeit präsentieren und disskutieren zu können.

Frau Prof. Katja Becker danke ich für die Betreuung meiner Arbeit im Fachbereich Ernährungswissenschaften der Justus Liebig Universität Giessen.

Herzlich bedanken möchte ich mich bei Dr. Stefan Loitsch für seine fachliche Unterstützung bei der Bearbeitung meiner Projekte. Zudem danke ich ihm für zahlreiche unterhaltsame Momente durch seinen unverwechselbaren Humor.

Tausend Dank an Carolin, die in den letzten vier Jahren immer an meiner Seite war und mit mir zusammen alle Höhen und Tiefen erlebt hat. Danke für die schöne Zeit und danke für das Wissen, dass es immerhin zwei von uns gibt.

Nadine möchte ich ganz herzlich für die gute und freundschaftliche Zusammenarbeit und Ihre Unterstützung bei allen praktischen und technischen Problemen danken.

Für eine gute Zusammenarbeit bei der Durchführung gemeinsamer Projekte danke ich zudem Bettina Jung, Dr. Waranya Kampan (It was a pleasure to work with you in joint projects), Dr. Oliver Rau, Dr. Andreas von Knethen, Prof. Dr.

Andrea Huwiler, Prof. Dr. Bernhard Brüne, Prof. Manfred Schubert-Zsilavecz, und Dr. Helmut Schmidt.

Thanks to Yogesh (and Sarika) for a nice time and the introduction to the Indian culture.

–  –  –

Danke auch an alle Mitglieder des Gastroenterologischen Routine-Labors, der Arbeitsgruppe und der Ernährungsambulanz.

Ein sehr herzlicher Dank gilt meinen Eltern, die mir mein Studium überhaupt erst ermöglicht haben. Danke auch für die uneingeschränkte Unterstützung während dieser Zeit.

Weiterhin danken möchte ich Jochen, meinen Freunden und meiner Familie, die alle auf ihre Weise zum Gelingen dieser Arbeit beigetragen haben.

Diese Arbeit wurde aus Mitteln der Else Kröner-Fresenius-Stiftung und dem Graduiertenkolleg G757 der Deutschen Forschungsgemeinschaft unterstützt.

–  –  –

INDEX SUMMARY

ZUSAMMENFASSUNG

DANKSAGUNG

LIST OF ABBREVIATIONS

FIGURE INDEX

TABLE INDEX

1 INTRODUCTION

1.1 COLORECTAL CANCER

1.2 CHEMOPREVENTION

1.2.1 Cell cycle regulation

1.2.2 Induction of apoptosis

1.3 PHYTOCHEMICALS

1.3.1 Resveratrol

1.3.2 Ursolic acid

1.4 POLYAMINES

1.4.1 Inhibition of polyamine biosynthesis

1.4.2 Induction of polyamine catabolism

1.5 AIMS

2 RESULTS

2.1 PPARΓ AS A MOLECULAR TARGET OF RESVERATROL-INDUCED MODULATION OF POLYAMINE

METABOLISM (MANUSCRIPT I)

2.2 DE NOVO CERAMIDE BIOSYNTHESIS IS ASSOCIATED WITH RESVERATROL-INDUCED INHIBITION OF

ORNITHINE DECARBOXYLASE ACTIVITY (MANUSCRIPT II)

2.3 URSOLIC ACID INDUCES APOPTOSIS THROUGH PPARΓ MEDIATED SSAT-ACTIVATION IN COLON

CANCER CELLS (MANUSCRIPT III)

3 DISCUSSION

3.1 RESVERATROL-INDUCED MODULATION OF POLYAMINE METABOLISM

3.1.1 Mitogen-activated protein kinases

3.1.2 Peroxisome-proliferator activated receptor γ

3.1.3 Sphingolipid metabolism

3.1.4 Summary and conclusion

3.2 MOLECULAR CHARACTERIZATION OF THE CHEMOPREVENTIVE ACTIVITIES OF PENTACYLIC

TRITERPENE URSOLIC ACID

3.2.1 Cell cycle regulation

3.2.2 Induction of apoptosis

3.2.3 Modulation of polyamine metabolism

3.2.4 Summary and conclusion

3.3 BIOAVAILABILITY OF PHYTOCHEMICALS

3.4 RED WINE CONSUMPTION AS A CHEMOPREVENTIVE STRATEGY?

3.5 THERAPEUTIC INDICATIONS FOR RESVERATROL IN COLORECTAL CANCERS – FUTURE PERSPECTIVES

REFERENCES

CURRICULUM VITAE

ORIGINALPUBLIKATIONEN

ÜBERSICHTSARBEITEN

–  –  –





KONGRESSBEITRÄGE/ABSTRACTS

EIDESSTATTLICHE ERKLÄRUNG

ABGRENZUNGSERKLÄRUNG

ANHANG

–  –  –

Rb retinoblastoma SAMDC S-adenosylmethionine decarboxylase SERM selective estrogen receptor modulator SIR2 silent information regulator 2 SIRT1 sirtuin 1 Skp2 S-phase kinase associated protein 2 Smac second mitochondria-derived activator of caspases SMase sphingomyelinase SPT serine palmitoyltransferase SSAT spemine/spermidine acetyltransferase TNF tumor necrosis factor TRAIL TNF-related apoptosis-inducing ligand

–  –  –

FIGURE INDEX

Figure 1: Adenoma-Carcinoma-Sequence

Figure 3: Phases of the cell cycle (adopted from MANUSCRIPT V)............ 6 Figure 4: Apoptotic pathways (adopted from MANUSCRIPT V).................. 8 Figure 5: Dietary agents and their major biological active compounds 9 Figure 6: Polyamine metabolism

Figure 7: Ceramide metabolism

Figure 8: Possible Mechanisms of Resveratrol action

TABLE INDEX Table 1 Causes of Death 1980-2003 (USA)

Table 2 Resveratrol in Preclinical animal models

–  –  –

1 INTRODUCTION

1.1 Colorectal Cancer Figure 1: Adenoma-Carcinoma-Sequence Colon cancer results from a series of pathologic changes that transform normal colonic epithelium into invasive carcinoma. Specific genetic events, shown by vertical arrows, accompany this multistep process [modified from Jänne [1]] Colorectal cancer (CRC) accounts for approximately 10–15% of all cancers and is the second leading cause of cancer-related death in Western countries with an estimated 71400 new cases and 28868 deaths in Germany in 2002 [2] and 153760 new cases and 52180 deaths in the United States in 2007 [3]. As with many other cancers, the development of colorectal cancer typically results from a complex interaction between genetic and environmental influences. 25% of patients with colorectal cancer have a family history of the disease, which suggests the involvement of a genetic factor. Such inherited colon cancers can be divided into two main types: the well-studied but rare familial adenomatous polyposis (FAP) syndrome, which accounts for approximately 1% of cases of colon cancer annually, and the increasingly well-characterized, more common hereditary nonpolyposis colorectal cancer (HNPCC), which accounts for 5% to 15% of cases [4-7]. The remaining 75% of colorectal tumors develop sporadically or are caused by environmental or lifestyle factors such as physical

INTRODUCTION

inactivity [8], obesity [9], smoking [10], alcohol consumption [11], a diet high in red meat [12], and inadequate intake of fruits and vegetables [13]. The World Cancer Research Fund estimates that 50% of colorectal tumors are avoidable through nutritional modifications [14;15].

The earliest model of pathogenesis of colorectal cancer - the adenomacarcinoma hypothesis [16], is now widely accepted. It proposes that the initial colorectal lesion arises as a benign adenomatous polyp that later undergoes further disorganisation of cellular and tissue phenotype. Some earlier stages in the process have also been proposed: hyperproliferation of the upper crypt cells leading to the formation of aberrant crypt foci and microadenomas [17].

Vogelstein and colleagues [18-20] have provided a molecular basis for the adenoma-carcinoma sequence by describing the complex multistep process in which cells accumulate alterations of multiple genes that control cell growth and differentiation, resulting in the neoplastic phenotype (Figure 1).

Mutations in at least four or five genes are required for formation of a malignant tumour [14]. The first events inactivate the APC (adenomatous polyposis of the colon) gene (also the cause of FAP) in both chromosomes. APC is a tumorsuppressor gene, and when mutation eliminates its function cells are immediately launched on the pathway toward malignancy. This is followed by mutation in the oncogene K-ras and further mutation of the tumor suppressor genes SMAD4 and p53 [21]. Other genetic events also play a role, for example modulation of DNA methylation in CpG sequences of the promoter regions of tumor-suppressor and DNA-repair genes leading to inactivation or DNA amplification as a mechanism of oncogene activation [22]. These genetic alterations are associated with the development of preneoplastic lesions (aberrant crypt foci, polyps, adenomas) which can develop into carcinomas [23].

Up to 10% of all sporadic cancer types feature an additional pattern which is characterised by development of deficient DNA repair; this leads to genetic instability and, therefore, to an increased rate of mutations, prevalently in the oncogene K-ras [24].

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Epidemiological data accumulated over the last 20 years show a significant decrease in the death rate within the US due to heart, cerebrovascular, and infectious diseases. However, cancer related mortality has slightly increased since 1980 [25;26]. Despite a better understanding of the disease and the advent of modern technology and rationally targeted drugs, the incidence and cure rate of cancer have not improved (Table 1). This failure to control cancer deaths from common epithelial malignancies provides the ultimate rationale for an approach based on prevention, before the complex series of genetic and epigenetic events that result in invasive and metastatic malignancy have occurred. It has been estimated that more than two-thirds of human cancers could be prevented through appropriate lifestyle modifications. Doll and Peto have reported that an average of 35% of human cancer mortality is attributable to diet [27], which has two rational explanations: (1) the presence of suspected carcinogens in the diet and (2) the absence in the diet of compounds possessing cancer preventing properties.

Cancer chemoprevention, as first defined in 1976 by Sporn, is the use of natural, synthetic, or biologic chemical agents to reverse, suppress, or prevent carcinogenic progression [28]. Chemoprevention has been successfully

–  –  –

Figure 2: Chemopreventive strategies achieved in numerous animal experiments over the past 25 years, and has been validated in several major clinical trials (for review see [29;30]) Based on these findings and following the indications of the National Cancer Institute (NCI), five classes of mainly chemically synthesized chemopreventive agents are considered of high priority: selective estrogen receptor modulators (SERMs), non-steroidal anti-inflammatory drugs (NSAIDs), calcium compounds, glucocorticoids and retinoids. In parallel, the NCI identified about 40 edible plants possessing potential chemopreventive compounds, globally known as phytochemicals [31]. These dietary agents are believed to block or reverse the premalignant stage (initiation, promotion and progression) of multistep carcinogenesis. In detail the cellular and molecular mechanisms affected by phytochemicals include carcinogen activation/detoxification by xenobiotic metabolizing enzymes; DNA repair, cell cycle progression, cell proliferation, differentiation and apoptosis, expression and functional activation of oncogenes or tumor-supressor genes, angiogenesis and metastasis and hormonal and growth-factor activity [32] (further chemopreventive strategies are reviewed in Figure 2).

INTRODUCTION

To meet the requirements an effective and acceptable chemopreventive agent

should have certain properties [33;34]:

• Little or no toxic effects in normal and healthy cells

• High efficacy against multiple sites

• Capability of oral consumption

• Known mechanism of action

• Low cost

• History of use by the human population

• Acceptance by human population

1.2.1 Cell cycle regulation



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