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  • “Cytotoxicity and P-glycoprotein inhibition by

    cardiotonic steroids”

    Dissertation

    zur Erlangung des Grades

    “Doktor der Naturwissenschaften”

    im Promotionsfach Pharmazie

    am Fachbereich Chemie, Pharmazie und

    Geowissenschaften der Johannes Gutenberg-Universität in

    Mainz

    vorgelegt von Maen Zeino

    geboren am 88.03.1988 in Damaskus, Syrien

    Mainz, März 2015

  • Betreuer:

    Prof. Dr. Thomas Efferth

    Gutachter der Arbeit:

    Prof. Dr. Thomas Efferth

    Prof. Dr. Irene Krämer

    Prof. Dr. Gert Fricker

    Datum der mündlichen Prüfung:

    29.04.2015

    Prüfungskommission:

    Prof. Dr. Irene Krämer (Vorsitzende)

    Prof. Dr. Thomas Efferth

    Prof. Dr. Gert Fricker

    PD Dr. Rolf Postina

    Dr. Joachim Arend (Protokoll)

    D77 (Dissertation Universität Mainz)

  • Publications

    Original publications as lead author

     M. Zeino, M. Paulsen, M. Zehl, E. Urban, B. Kopp, T. Efferth, “Identification of New

    P-Glycoprotein Inhibitors Derived from Cardiotonic Steroids”, Biochemical

    Pharmacology, 93(1), 11-24, 2015.

     M. Zeino, M. E. Saeed, O. Kadioglu, and T. Efferth, "The ability of molecular docking

    to unravel the controversy and challenges related to P-glycoprotein-a well-known, yet

    poorly understood drug transporter," Invest New Drugs, Apr 22 2014

     M. Zeino, Q. Zhao, T. Eichhorn, J. Hermann, and R. Müller, "Molecular docking studies

    of myxobacterial disorazoles and tubulysins to tubulin," Journal of Bioscience and

    Medicine, vol. 3, pp. 31-43, 2013

    Original publications as co-author

     V. Kuete, L. P. Sandjo, J. A. Seukep, M. Zeino, A. T. Mbaveng, B. Ngadjui, et al.,

    "Cytotoxic Compounds from the Fruits of Uapaca togoensis towards Multifactorial

    Drug-Resistant Cancer Cells," Planta Med, vol. 81, pp. 32-8, Jan 2015.

     Saeed, M., Zeino, M., Kadioglu, O., Volm, M., & Efferth, T, “Overcoming of P-

    glycoprotein-mediated multidrug resistance of tumors in vivo by drug combinations,”

    Synergy, 1(1), 44-58, Sep 2014

     R. Hamm, M. Zeino, S. Frewert, and T. Efferth, "Up-regulation of cholesterol associated

    genes as novel resistance mechanism in glioblastoma cells in response to archazolid B,"

    Toxicol Appl Pharmacol, vol. 281, pp. 78-86, Sep 2014.

     V. Kuete, L. P. Sandjo, D. E. Djeussi, M. Zeino, G. M. Kwamou, B. Ngadjui, et al.,

    "Cytotoxic flavonoids and isoflavonoids from Erythrina sigmoidea towards multi-

    factorial drug resistant cancer cells," Invest New Drugs, vol. 32, pp. 1053-62, Dec 2014.

     R. Hamm, Y. R. Chen, E. J. Seo, M. Zeino, C. F. Wu, R. Müller, et al., "Induction of

    cholesterol biosynthesis by archazolid B in T24 bladder cancer cells," Biochem

    Pharmacol, vol. 91, pp. 18-30, Sep 2014.

     C. Noysang, A. Mahringer, M. Zeino, M. Saeed, O. Luanratana, G. Fricker, et al.,

    "Cytotoxicity and inhibition of P-glycoprotein by selected medicinal plants from

    Thailand," J Ethnopharmacol, vol. 155, pp. 633-41, Aug 2014.

     C. Reiter, A. Capcı Karagöz, T. Fröhlich, V. Klein, M. Zeino, K. Viertel, et al.,

    "Synthesis and study of cytotoxic activity of 1,2,4-trioxane- and egonol-derived hybrid

  • molecules against Plasmodium falciparum and multidrug-resistant human leukemia

    cells," Eur J Med Chem, vol. 75, pp. 403-12, Mar 2014.

     T. AlSalim, M. E. Saeed, J. S. Hadi, M. Zeino, R. Gany, O. Kadioglu, et al.,

    "Cytotoxicity of novel sulfanilamides towards sensitive and multidrug-resistant

    leukemia cells," Curr Med Chem, vol. 21, pp. 2715-25, 2014.

     A. Veerappan, T. Eichhorn, M. Zeino, T. Efferth, and D. Schneider, "Differential

    interactions of the broad spectrum drugs artemisinin, dihydroartemisinin and artesunate

    with serum albumin," Phytomedicine, vol. 20, pp. 969-74, Aug 2013.

     A. M. Saab, A. Guerrini, G. Sacchetti, S. Maietti, M. Zeino, J. Arend, et al.,

    "Phytochemical analysis and cytotoxicity towards multidrug-resistant leukemia cells of

    essential oils derived from Lebanese medicinal plants," Planta Med, vol. 78, pp. 1927-

    31, Dec 2012.

    Submitted manuscripts (in revision: meanwhile accepted)

     Zeino, M., Brenk, R., Gruber, L., Zehl, M., Urban, E., Kopp, B., & Efferth, T. (2015).

    Cytotoxicity of cardiotonic steroids in sensitive and multidrug-resistant leukemia cells

    and the link with Na+/K+-ATPase. The Journal of steroid biochemistry and molecular

    biology, 150, 97-111.

    Poster

     M. Zeino, M. Paulsen, M. Zehl, E. Urban, B. Kopp, T. Efferth, “Identification of New

    P-Glycoprotein Inhibitors Derived from Cardiotonic Steroids”, [Poster], 128th meeting

    of the Gesellschaft Deutscher Naturforscher und Ärzte (GDNÄ) “Vorbild Natur:

    Faszination Mensch und Technologie”, Mainz, 2014.

     M. Zeino, M. E. Saeed, O. Kadioglu, and T. Efferth, "The ability of molecular docking

    to unravel the controversy and challenges related to P-glycoprotein-a well-known, yet

    poorly understood drug transporter," [Poster], 128th meeting of the Gesellschaft

    Deutscher Naturforscher und Ärzte (GDNÄ) “Vorbild Natur: Faszination Mensch und

    Technologie”, Mainz, 2014.

  • Erklärung

    Hiermit erkläre ich an Eides statt, dass ich diese Arbeit selbständig verfasst und keine anderen

    als die angegebenen Quellen und Hilfsmittel verwendet habe.

    Mainz, 04.05.15 Keine Unterschift zwecks Datenschutz

    _______________________ _______________________

    Ort, Datum Maen Zeino

  • Acknowledgement I

    Acknowledgement

    My journey into exploring and applying the theoretical knowledge I have gained during my

    studies has begun, as I received an acceptance letter from him to a PhD position in his

    department while applying for a DAAD scholarship. Starting with that moment, my life was

    filled with eagerness, challenges and enthusiasm to have the chance to practice science in a

    leading country as Germany. Through the great scientific and internationally diverse

    atmosphere at his lab, I was able to develop at both the personal and professional level. For that,

    my deepest gratitude goes to Prof. Dr. Thomas Efferth with his great support and mentorship

    that made it possible to finalize this dissertation.

    I would like to also thank Prof. Dr. Irene Krämer, PD Dr. Rolf Postina and Prof. Dr. Gert Fricker

    for revising this scientific work and taking part in the examination process.

    Many thanks to Dr. Malte Paulsen, who helped me walk the first footsteps in the field of flow

    cytometry and was always there when help was needed. I also thank the kind staff at the IMB,

    specifically Ina Schäfer, Jens Hartwig and Katrin Kreisz for their technical and moral support,

    which made my time at the IMB most joyful.

    I would like to also take the chance to thank Prof. Dr. Birgitte Kopp, Dr. Martin Zehl and Prof.

    Dr. Ernst Urban for providing us with the substances and for their valuable advice whenever

    asked for.

    I am also grateful for the group of Prof. Dr. Ruth Brenk for the access to MOE software and

    their support in bioinformatics.

    A special word has to go to the outstanding team at the Department of Pharmaceutical Biology.

    Thanks to Christine Koeppel who showed me the various techniques in the cell culture lab with

    great patience and joy. It has been always a blast to work with you. Furthermore, your spiritual

    support along with that of Doris Rohr and Dr. Joachim Arend has always kept me going. Thank

    you all three for the fruitful and lovely conversations that always contributed to my personality.

    Many thanks to Mohammed Saeed and Ching-Fen Wu for their permanent encouragement and

    strong belief in me. I also thank Dr. Ean-Jeong Seo, Onat Kadioglu and Qiaoli Zhao for their

    readiness to help and support. Thanks to Ilona Zirbs, our secretary, for her help with university

    registration and office work. The last team member I would like to specially thank is Rebecca

    Hamm, first for critically reading and revising this thesis and second, because she has become

    a true companion of my journey with all its ups and downs. An authentic, sincere friendship

  • has developed over the years, for which I can only be most grateful. Whenever in need, she was

    always there with her words and deeds. Thank you for the limitless support, introducing me to

    the German culture and showing me how a true friendship is.

    Many thanks to the internship and diploma students Lisa Gruber, Johannes Kopp and Nada

    Aldabbag, whom I had the chance to supervise at some point, for the support and good times in

    the lab.

    Much gratitude is entitled to the German Academic Exchange Organization (DAAD) for the

    financial support throughout my PhD and to Birgit Klaes, my regional supervisor at DAAD for

    her careful and patient guidance.

    I have to mention my Syrian friends, who managed to maintain an everlasting friendship despite

    the seas separating us. Their E-mails and voices via skype always added happin