Resistance to Targeted Anti-Cancer Therapeutics 4 Thomas Eff erth Editor Resistance to Targeted ABC Transporters in Cancer Resistance to Targeted Anti-Cancer Therapeutics Volume 4 Series Editor Benjamin Bonavida More information about this series at h ttp://www.springer.com/series/11727 Thomas Efferth Editor Resistance to Targeted ABC Transporters in Cancer Editor Thomas Efferth Department of Pharmaceutical Biology Johannes Gutenberg University Mainz, Germany ISSN 2196-5501 ISSN 2196-551X (electronic) ISBN 978-3-319-09800-5 ISBN 978-3-319-09801-2 (eBook) DOI 10.1007/978-3-319-09801-2 Springer Cham Heidelberg New York Dordrecht London Library of Congress Control Number: 2014951846 © Springer International Publishing Switzerland 2015 T his work is subject to copyright. 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Violations are liable to prosecution under the respective Copyright Law. T he use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com) Pref ace T he development of resistance is a major obstacle in cancer chemotherapy since decades. Drug resistance may develop during repeated treatment cycles after ini- tially successful therapy (acquired or secondary resistance). Alternatively, tumors may be resistant from the beginning (inherent or primary resistance). The failure of chemotherapy is a major reason for the fatal outcome of tumor diseases in many patients. Even worse, tumors frequently develop resistance not only to single drugs but also to many others at the same time. This phenomenon was termed m ultidrug resistance and decreases the success rates of therapy regimens with combinations of structurally and functionally different drugs. The pioneering research of Victor Ling, Michael M. Gottesman, and others led to the discovery of the drug effl ux transporter P -g lycoprotein and its encoding gene, M DR1. This membrane protein expels a large array of different drugs and xenobiotic compounds out of the tumor cell leading to sublethal intracellular drug concentration and ultimately survival of tumor cells. T he initial cross-resistance profi le of P-glycoprotein (P-gp) comprises a nthra- cyclines (d oxorubicin , d aunorubicin ), Vinca -a lkaloids (v incristine , v inblastine ), epipodophyllotoxins (e toposide , t eniposide ), t axanes ( paclitaxel , d ocetaxel ), and others. P-gp/M DR1 belongs to the family of ATP-binding cassette (ABC) transporters which are widely distributed in nature from bacteria to humans. The human genome consists of 48 ABC transporter genes, with P-gp/M DR1 as the best analyzed one. Other drug resistance mediating ABC transporters are the multidrug resistance- related proteins (MRPs), breast cancer resistance protein (BCRP), and others. These ABC transporters are also characterized by specifi c cross-resistance profi les, which partly differ from the one of P-gp. They can also confer resistance to c amptothecin derivatives (t opotecan , irinotecan ), Mitoxantrone , s terols , t yrosine kinase inhib- itors , compounds used in photodynamic therapy antimetabolites, and others. The uncommonly broad spectrum of anticancer agents that are transported by ABC transporters makes these proteins exquisite targets to search for compounds that inhibit their transport function. The idea is to block ABC transporter-mediated v vi Preface drug effl ux by specifi c inhibitors and thereby to overcome multidrug resistance. This concept was introduced by Takashi Tsuruo, who described that verapamil is able to inhibit P-gp’s transport function. Subsequently, a huge amount of com- pounds from many pharmacologically established drug classes (e.g., c alcium chan- nel blockers , c almodulin antagonists , c yclosporines , dipyridamole , and other hydrophobic , cationic compounds) were observed to inhibit P-gp and to reverse multidrug resistance. Interestingly, many natural compounds derived from plants or marine organisms were also found to block ABC transporters’ function. All these fascinating results from basic cancer research were complemented by investigations from clinical oncology. A plethora of analyses have shown that P-gp/M DR1 is of predictive value for success or failure of chemotherapy and of prognostic value for the survival time of cancer patients. Since certain r adiophar- maceuticals are also transported by ABC transporters, they can be used for radio- logical diagnosis of multidrug-resistant tumors. T he importance of ABC transporters for drug resistance in tumors and the thriv- ing development of research in this area can also be documented by the number of papers appearing every year during the past three decades (Fig. 1 ). ABC transport- ers have been a hot topic in cancer research for many years and still are. This moti- vated me to edit a book on this topic to keep scientists and physicians updated with the latest development in this exciting research area. I was fortunate to team up a panel of international experts with renowned expertise in the fi eld of ABC trans- porters in drug-resistant tumors. The book covers most currently relevant topics in Fig. 1 S urvey of the literature deposited in the PubMed database from 1980 to 2012 with the indicated keywords Preface vii the fi eld reaching from the clinical relevance of ABC transporters for resistance to novel and established anticancer drugs and prognosis of patients to compounds to modulate multidrug resistance, compounds used in photodynamic therapy, tyrosine kinase inhibitors, and others. Furthermore, the potential of radiopharmaceuticals for diagnosis of multidrug-resistant tumors will be discussed. Mainz, Germany Thomas Efferth Contents 1 Role of P-Glycoprotein for Resistance of Tumors to Anticancer Drugs: From Bench to Bedside ...................................... 1 Manfred Volm and Thomas Efferth 2 Clinical Relevance of Multidrug-Resistance-Proteins (MRPs) for Anticancer Drug Resistance and Prognosis .................................... 27 E.A. Roundhill, J.I. Fletcher, M. Haber, and M.D. Norris 3 Role of Breast Cancer Resistance Protein (BCRP, ABCG2) in Cancer Outcomes and Drug Resistance ........................................... 53 Karthika Natarajan, Maria R. Baer, and Douglas D. Ross 4 A New Strategy of ALA-Photodynamic Cancer Therapy: Inhibition of ABC Transporter ABCG2 ............................................... 89 Toshihisa Ishikawa, Yutaka Inoue, Yoji Ikegami, Takahiro Fujishiro, Tomohiro Osaki, Yoshinaga Kajimoto, Shin-Ichi Miyatake, and Toshihiko Kuroiwa 5 ATP Binding Cassette Transporters in Cancer Stem-Like Cells ........ 105 Paola Perego 6 Radiopharmaceuticals for the Imaging of ABC-Transporter-Mediated Multidrug Resistance in Cancer ....... 133 Sabina Dizdarevic and Adrien Michael Peters 7 Modulation of P-Glycoprotein-Mediated Multidrug Resistance by Synthetic and Phytochemical Small Molecules, Monoclonal Antibodies, and Therapeutic Nucleic Acids .................... 153 Thomas Efferth, Maen Zeino, and Manfred Volm 8 ABC Transporter Modulatory Drugs from Marine Sources: A New Approach to Overcome Drug Resistance in Cancer ................ 183 Atish Patel, De-Shen Wang, Hong-May Sim, Suresh V. Ambudkar, and Zhe-Sheng Chen ix