Resistance to Targeted ABC Transporters in Cancer

307 Pages·2015·7.32 MB·English

by  Thomas Efferth (eds.)

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
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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