BIOACTIVITIES OF HOP-DERIVED PRENYLFLAVONOIDS IN RELATION TO PROSTATE CANCER Apr. Lies Delmulle

FACULTEIT FARMACEUTISCHE WETENSCHAPPEN
Vakgroep Geneesmiddelenleer | Laboratorium voor Farmacognosie en Fytochemie
Thesis submitted to the Faculty of Pharmaceutical Sciences in order to obtain the degree of Doctor in Pharmaceutical Sciences
promotor: Prof. Dr. D. De Keukeleire
Academic year 2006-2007
BIOACTIVITIES OF HOP-DERIVED
PRENYLFLAVONOIDS IN RELATION TO
PROSTATE CANCER
Apr. Lies Delmulle
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ACKNOWLEDGEMENTS
This Ph.D. project would never have been succeeded without the help, the support,
and the patience of a number of persons and, to some of them, I would like to express my
sincere gratitude.
First and foremost, I would like to thank the promoter of my Ph.D. project, Prof. Dr.
Denis De Keukeleire, for offering me unique research opportunities, for conveying his
knowledge on hop and hop-derived prenylflavonoids, and, above all, for his confidence to let
me work in a serene environment and in full scientific freedom.
This Ph.D. work would not have been succesful without the essential contribution of
Prof. Dr. Em. F. Comhaire, who hosted me for more than a year in his laboratory at the Ghent
University Hospital, Faculty of Medicine and Heath Sciences, Department of Endocrinology.
The expertise present in this laboratory undoubtly improved my scientific skills and I would
very much like to thank in this respect the colleagues, who assisted me personally during this
period and shared their scientific knowledge: Willem, Frank, Sabrina and Katelijne.
During the execution of the experimental work, I was offered the opportunity to
discover the exciting world of cell cultures thanks to Prof. Dr. V. Castronovo, who kindly
invited me to work for almost a year in his Metastasis Research Laboratory at the University
of Liège. I would like to thank particularly Akeila and Naïma, who assisted me on a daily
basis and shared their broad experience on the in vitro bio-assays using cancer cell lines and
on cancer research in general. Also, I am grateful to all members of the laboratory: Stephan,
Marie-Hélène, Frédéric (I am sorry to hear that you are no longer with us and herewith I
would like to express my sincere condolences to the family), David, Cédric, Michaël, Sabine,
Pascale who made my stay in Liège unforgettable! I would also like to thank the other
members of the department for the pleasant atmosphere.
I would like to express my special gratitude to Prof. Dr. P. Vandenabeele from Ghent
University, Faculty of Sciences, Flanders Interuniversity Institute for Biotechnology,
Department for Molecular Biomedical Research, Molecular Signalling, and Cell Death Unit,
who allowed me to work in his laboratory for several months to conduct studies on the
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mechanisms of cell death. Dr. Tom Vanden Berghe assisted me during this research and
shared all his expertise on apoptosis and necrosis. I acknowledge his help greatly and I add
many thanks to the colleagues, who made that period very pleasant!
I am also very grateful to Prof. Dr. M. Bracke from Ghent University, Faculty of
Medicine and Health Sciences, Department of Radiotherapy and Nuclear Medicine, for the
scientific conversations and the help during the preparation of my IWT defences.
Thanks are due to Prof. Dr. J. Sumpter from Brunel University, UK, who kindly
provided a yeast assay to assess estrogenic activity and to Dr. Wim Vanden Berghe from
Ghent University, Faculty of Sciences, Department of Molecular Biology, Laboratory for
Eucaryotic Gene Expression and Signal Transduction, who kindly delivered the program
Clonewin to develop oligonucleotide primers.
Undoubtly, the close contacts with the colleagues of the Laboratory of Pharmacognosy
and Phytochemistry at the Faculty of Pharmaceutical Sciences, Ghent University, were
conducive to my scientific education and therefore I recognize the invaluable help of Dr. Arne
Heyerick, Julie, Frederik, Kevin, Ulrik, Bram, Lieve, and Barbara. In particular, I would like
to thank Ina for the nice moments we shared together.
I express my gratitude to IWT-Vlaanderen (Institute for the Promotion of Innovation
by Science and Technology in Flanders, Brussels) for granting a pre-doctoral fellowship.
Last but not least, people in my personal environment must be recognized for their
continuous support throughout my research and afterwards for their encouragements to finish
the writing of my thesis. Mum and dad, thank you very much for everything! Nele, Alex,
Stain&Stan, Yvon&Elvis&Canis, Ingrid&Fripoen, and especially Muriel, I would not have
succeeded without you!! And of course I’m grateful to my phantastic loyal dog, Denka, for
the warm huggs and long relaxing walks!
Orroir, September 2007.
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CONTENTS
ABBREVIATIONS VII
PURPOSE 1
1 HOP (HUMULUS LUPULUS L.) 4
1.1 Botanical overview 4
1.1.1 Taxonomy and ethymology 4
1.1.2 Botanical description 5
1.1.3 Plant origin 7
1.2 Use of hops 7
1.2.1 Traditional use 7
1.2.2 Modern use 8
1.3 Hop chemistry 10
1.3.1 Presence of hop-derived prenylflavonoids 10
1.3.2 Biosynthesis of hop-derived prenylflavonoids 12
1.3.3 Biological activities of hop-derived prenylflavonoids 12
1.3.3.1 In vitro estrogenic activity 12
1.3.3.2 In vivo estrogenic activity 15
1.3.3.3 Effect on bone resorption and uterus growth 16
1.3.3.4 Anticancer activity 17
1.3.3.5 Effect on lipid metabolism 21
1.3.3.6 Antimicrobial effects 22
1.3.3.7 Conclusions 22
1.3.4 Metabolization of hop-derived prenylflavonoids 23
1.4 Hops legislation 24
1.5 Side effects and toxicity 25
1.6 Contra-indications and drug-botanical interactions 25
2 BENIGN PROSTATE HYPERTROPHY AND PROSTATE CANCER 26
2.1 Benign prostatic hypertrophy 28
2.1.1 Incidence and prevalence 28
2.1.2 Risk factors 29
2.1.3 Causes 29
2.1.4 Signs and symptoms 29
2.1.5 Diagnosis 30
2.1.6 Current treatment methods 30
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