Mechanisms of cell cycle arrest and apoptosis induction by sulforaphane and compinatorial effects of sulforaphane and 3,3'-Diindolylmethane on cancer cell growth inhibition [Elektronische Ressource] / von Gerlinde Pappa

Gerlinde Gruber

Sujets

• Gesundheit

Informations

• Publié par: friedrich-schiller-universitat_jena
• Publié le: 01 janvier 2007
• Nombre de lectures: 36
• Langue: Deutsch
• Poids de l'ouvrage: 2 Mo

Extrait

MECHANISMS OF CELL CYCLE ARREST AND APOPTOSIS
INDUCTION BY SULFORAPHANE
AND
COMBINATORIAL EFFECTS OF SULFORAPHANE AND
3,3’-DIINDOLYLMETHANE ON CANCER CELL GROWTH
INHIBITION




DISSERTATION



zur Erlangung des akademischen Grades
doctor rerum naturalium (Dr. rer. nat.)


vorgelegt dem Rat der Biologisch-Pharmazeutischen Fakultät
der Friedrich-Schiller-Universität Jena

von
Diplom-Ernährungswissenschaftlerin
Gerlinde Pappa
geboren am 19.08.1978 in Hamburg




















































Meiner Familie und Alexander


















MECHANISMS OF CELL CYCLE ARREST AND APOPTOSIS
INDUCTION BY SULFORAPHANE
AND
COMBINATORIAL EFFECTS OF SULFORAPHANE AND
3,3’-DIINDOLYLMETHANE ON CANCER CELL GROWTH
INHIBITION




DISSERTATION



zur Erlangung des akademischen Grades
doctor rerum naturalium (Dr. rer. nat.)


vorgelegt dem Rat der Biologisch-Pharmazeutischen Fakultät
der Friedrich-Schiller-Universität Jena

von
Diplom-Ernährungswissenschaftlerin
Gerlinde Pappa
geboren am 19.08.1978 in Hamburg


Gutachter:


1. Prof. Dr. Beatrice L. Pool-Zobel
Lehrstuhl für Ernährungstoxikologie
Institut für Ernährungswissenschaften
Friedrich-Schiller-Universität Jena
Dornburger Str. 24
07743 Jena

2. Prof. Dr. Frank-D. Böhmer
Arbeitsgruppe Molekulare Zellbiologie
Klinikum der Friedrich-Schiller-Universität Jena
Drackendorfer Str. 1
07747 Jena

3. Prof. Dr. Sabine E. Kulling
Lehrstuhl für Lebensmittelchemie
Institut für Ernährungswissenschaft
Universität Potsdam
Arthur-Scheunert-Allee 114-116
14558 Nuthetal




Der experimentelle Teil dieser Arbeit wurde am Deutschen Krebsforschungszentrum
Heidelberg, Abteilung Toxikologie und Krebsrisikofaktoren, Prof. Dr. Helmut Bartsch, in
der Arbeitsgruppe Chemoprävention, Dr. Clarissa Gerhäuser, angefertigt.

Diese Arbeit wurde als kumulative Dissertation eingereicht. Gemäß der Anlage zum
§8(3) der Promotionsordnung der Biologisch-Pharmazeutischen Fakultät der Universität
Jena hat der Dekan dem Antrag auf Vorlage einer kumulativen Dissertation zugestimmt.


Tag der mündlichen Prüfung: 22.10.2007

Tag der öffentlichen Verteidigung: 19.11.2007




























Der Langsamste,
der sein Ziel nicht aus den Augen verliert,
ist immer noch schneller,
als jener, der ohne Ziel umher irrt.

- Gotthold Ephraim Lessing - Table of contents I

TABLE OF CONTENTS

I. INTRODUCTION ........................................................................................ 1
1. The Formation and the Prevention of Cancer .................................................... 1
1.1 Cancer in general ............................................................................................. 1
1.2 Cancer Prevention............................................................................................ 1
1.3 Chemoprevention............................................................................................. 3
1.4 The role of nutrition in cancer formation and development............................ 3
2. Brassica Vegetables and Cancer Prevention....................................................... 5
2.1 Brassicaceae and Glucosinolates .................................................................... 5
2.2 Uptake and Metabolism of Glucosinolates...................................................... 7
2.3 Epidemiology................................................................................................... 8
2.4 Sulforaphane and 3,3’-Diindolylmethane: two promising cancer
chemopreventive compounds from brassica vegetables................................ 10
2.4.1 Sulforaphane .......................................................................................................10
2.4.2 3,3’-Diindolylmethane – a condensation product of Indole-3-Carbinol...............12
3. Anti-proliferative Mechanisms for Cancer Prevention and Treatment......... 13
3.1 Arrest of the Cell Cycle ................................................................................. 14
3.1.1 Cell Cycle Regulation .........................................................................................14
3.1.2 Cell Cycle Checkpoints .......................................................................................14
3.1.2.1 The DNA damage- or G Checkpoint...............................................................14 2
3.1.2.2 The Spindle- or Metaphase Checkpoint ...........................................................15
3.2 Apoptosis - Programmed Cell Death............................................................. 16
3.2.1 Apoptosis in general............................................................................................16
3.2.2 The Mitochondrial Pathway ................................................................................17
3.2.3 The Death Receptor Pathway ..............................................................................19
3.3 Inhibition of Nuclear factor-κB ..................................................................... 19
4. Aim of the Study .................................................................................................. 20
II. MANUSCRIPTS - OVERVIEW ............................................................... 23
III. MANUSCRIPTS .................................................................................... 26 Table of contents II

1. Pappa G., Golks A., Pforr C., Strathmann J., Bartsch H., Gerhauser C.,
Sulforaphane-induced mitotic cell cycle arrest is followed by mitochondria-mediated
apoptosis induction. Manuscript in preparation for Molecular Cancer Therapeutics... 26
2. Pappa G., Bartsch H., Gerhauser C. (2007), Biphasic modulation of cell
proliferation by sulforaphane at physiologically relevant exposure times in a human
colon cancer cell line. Accepted for publication in Molecular Nutrition & Food
Research. ....................................................................................................................... 64
3. Pappa G., Strathmann J., Löwinger M., Bartsch H., Gerhauser C. (2007),
Quantitative combination effects between sulforaphane and 3,3’-diindolylmethane on
proliferation of human colon cancer cells in vitro. Accepted for publication in
Carcinogenesis (doi:10.1093/carcin/bgm044). ............................................................. 88
IV. DISCUSSION ...................................................................................... 119
V. SUMMARY ......................................................................................... 128
VI. ZUSAMMENFASSUNG ........................................................................ 130
VII. REFERENCES ................................................................................. 132















List of Abbreviations III

LIST OF ABBREVIATIONS

40-16 human colon carcinoma cell line, random clone derived from
HCT116
AhR aryl hydrocarbon receptor
ARE antioxidant response element
AOM azoxymethane
BCA bicinchoninic acid
BSA bovine serum albumin
BSO L-buthionine-S,R-sulfoximine
Cdk cyclin-dependent kinase
c-FLIP cellular FLICE-inhibitory protein
Cox-2 cyclooxygenase-2
CYP450 cytochrome P450 (Phase I-enzymes)
DIM 3,3’-diindoylmethane
DISC death-inducing signaling complex
DMBA 7,12-Dimethyl-benz[a]anthracene
DMSO dimethyl sulfoxide
DNA deoxyribonucleic acid
DTNB 5,5-dithiobis(2-nitrobenzoic) acid
EGCG epigallocatechin gallate
ELISA enzyme-linked immunoabsorbant assay
FCS