Ishikawa / Schuetz ABC Transporters and Cancer

1. Auflage 2015
ISBN: 978-0-12-801361-8
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, Band Volume 125, 282 Seiten

Reihe: Advances in Cancer Research

ABC Transporters and Cancer provides invaluable information on the exciting and fast-moving field of cancer research. Here, outstanding and original reviews are presented on a variety of topics. This volume covers ABC transporters and cancer, and is suitable for researchers and students alike. - Provides information on cancer research - Outstanding and original reviews - Suitable for researchers and students

Autoren/Hrsg.

Ishikawa, Toshihisa

Schuetz, John

Inhaltsverzeichnis

1;Front Cover;1
2;ABC Transporters and Cancer;4
3;Copyright;5
4;Dedication;6
5;Contents;8
6;Contributors;12
7;Preface;16
8;Chapter 1: Apical ABC Transporters and Cancer Chemotherapeutic Drug Disposition;20
8.1;1. Introduction to Apical ABC Transporters;21
8.2;2. Impact of Apical ABC Transporters on Intestinal Absorption of Oral Chemotherapeutic Drugs;24
8.2.1;2.1. Apical ABC transporters affecting the oral bioavailability of taxanes;27
8.2.1.1;2.1.1. ABCB1 and oral taxane availability;27
8.2.1.2;2.1.2. ABCC2 and oral taxane availability;28
8.2.1.3;2.1.3. ABCB1 inhibitors to improve taxane oral availability;29
8.2.1.4;2.1.4. Assessing CNS toxicity risks of using ABCB1 inhibitors to improve oral taxane availability;30
8.2.1.5;2.1.5. Possible effects of ABCB1 inhibitors on enhancing taxane antitumor efficacy;31
8.2.2;2.2. Apical ABC transporters in the oral bioavailability of rationally designed anticancer drugs;32
8.2.2.1;2.2.1. Tyrosine kinase inhibitors;32
8.2.2.2;2.2.2. PARP inhibitors;36
8.2.2.3;2.2.3. Chemical inhibition of transporters to increase oral availability of rationally designed anticancer drugs;37
8.2.2.4;2.2.4. Importance of the sensitivity and specificity of in vitro assays used to assess ABC transporter substrates;38
8.3;3. Impact of Apical ABC Transporters on Brain Disposition of Oral Chemotherapeutic Drugs;39
8.3.1;3.1. Does the BBB matter in drug delivery to brain tumors?;39
8.3.2;3.2. Apical efflux transporters in the BBB affecting brain accumulation of anticancer drugs;40
8.3.2.1;3.2.1. Drugs affected mostly by Abcb1a but also by Abcg2 in their brain accumulation;41
8.3.2.2;3.2.2. Drugs only affected by Abcb1a in their brain accumulation;43
8.3.2.3;3.2.3. Drugs affected mostly by Abcg2 but also by Abcb1a in their brain accumulation;44
8.3.2.4;3.2.4. Three different apical BBB ABC efflux transporters affect brain accumulation of some camptothecins;44
8.3.2.5;3.2.5. Models to explain the disproportionate effect of combined deficiency of Abcb1 and Abcg2 on brain accumulation of s...;45
8.3.2.6;3.2.6. Why are many rationally designed anticancer drugs still ABCB1 and/or ABCG2 substrates?;47
8.3.2.7;3.2.7. Limitations of knockout mouse models to study ABC transporter functions at the BBB;48
8.3.2.8;3.2.8. Tissue and cellular context may affect the in vivo impact of apical ABC efflux transporters;49
8.3.2.9;3.2.9. Use of chemical inhibitors to enhance brain accumulation of ABC transporter substrate drugs;49
8.4;4. Concluding Remarks;50
8.5;References;50
9;Chapter 2: Regulation of ABC Transporters Blood-Brain Barrier: The Good, the Bad, and the Ugly;62
9.1;1. Introduction;64
9.2;2. Blood-Brain Barriers;64
9.2.1;2.1. Assessing blood-brain barrier function;65
9.3;3. ABC Transporters at the Blood-Brain Barrier;67
9.4;4. The Bad and the Ugly: Mechanisms that Increase Transporter Expression and Reduce Drug Delivery to the CNS;69
9.4.1;4.1. Xenobiotic-activated transcription factors;70
9.4.2;4.2. Stress-activated transcription factors;72
9.4.3;4.3. Disease;76
9.5;5. The Good: Mechanisms that Reduce Transporter Activity/Expression and Have the Potential to Improve Drug Delivery to th...;77
9.5.1;5.1. P-glycoprotein;78
9.5.2;5.2. BCRP;82
9.6;6. Perspectives: Where the Field Is Headed;83
9.7;References;85
10;Chapter 3: Molecular Basis of the Polyspecificity of P-Glycoprotein (ABCB1): Recent Biochemical and Structural Studies;90
10.1;1. Introduction;91
10.2;2. Molecular Basis of Polyspecificity;92
10.2.1;2.1. Structural flexibility revealed by X-ray crystallography;92
10.2.2;2.2. Structural flexibility probed with disulfide cross-linking and biophysical methods;96
10.2.3;2.3. Substrate polyspecificity and ligand-based studies;98
10.2.4;2.4. P-glycoprotein portals;101
10.2.5;2.5. Drug-binding sites;101
10.2.6;2.6. The proposed R, H, and P sites;103
10.2.7;2.7. Primary and secondary sites;105
10.2.8;2.8. Pseudo-symmetric sites;107
10.3;3. Molecular Modeling Studies;108
10.4;4. Conclusions and Perspectives;109
10.5;Acknowledgments;110
10.6;References;110
11;Chapter 4: Lipid Regulation of the ABCB1 and ABCG2 Multidrug Transporters;116
11.1;1. Introduction-The Complex Interactions of Lipids and ABC Multidrug Transporters;117
11.2;2. Effects of Lipids on the Function of ABCB1 and ABCG2;122
11.2.1;2.1. Localization of ABCB1 and ABCG2 in specialized membrane domains;122
11.2.2;2.2. Substrate handling of ABCB1 and ABCG2 and the role of membrane lipids;123
11.2.3;2.3. Modulation of ABCB1 and ABCG2 function by lipids, lipid derivatives, and detergents;125
11.2.4;2.4. Role of lipids in MDR-ABC protein purification and reconstitution;128
11.2.5;2.5. MDR-ABC transporters may actively alter the membrane lipid environment;130
11.3;3. Effects of Lipids on the Expression of ABCB1 and ABCG2: Regulation by Nuclear Receptors;130
11.3.1;3.1. The NR superfamily of transcription factors and lipid-sensing NRs;131
11.3.2;3.2. Regulation of the expression of ABCB1 by NRs;133
11.3.3;3.3. Regulation of the expression of ABCG2 by NRs;134
11.3.4;3.4. Role of NRs in lipid metabolism and a potential indirect effect on ABCB1 and ABCG2 transporter function;135
11.4;4. Experimental Strategies to Define the Lipid-Interacting Regions of the ABCB1 and ABCG2 Proteins;135
11.4.1;4.1. Lipid sensing by the ABCB1 protein;136
11.4.1.1;4.1.1. Mutagenesis studies in ABCB1;136
11.4.1.2;4.1.2. Direct binding of lipids and MD simulations on ABCB1;138
11.4.2;4.2. Lipid sensing by the ABCG2 protein;140
11.4.2.1;4.2.1. Role of the R482 position;141
11.4.2.2;4.2.2. Role of the LxxL motif;141
11.4.2.3;4.2.3. Role of the CRAC motif;144
11.5;5. In Silico Modeling of the Lipid Interactions of ABCB1 and ABCG2;144
11.5.1;5.1. MD simulation;145
11.5.2;5.2. In silico docking;146
11.6;6. Conclusions;147
11.7;References;148
12;Chapter 5: ABC Transporters and Neuroblastoma;158
12.1;1. Introduction;159
12.2;2. Current Therapies for Neuroblastoma;160
12.3;3. MYCN;161
12.4;4. MYCN and ABC Transporters;164
12.4.1;4.1. ABCB1;167
12.4.2;4.2. ABCG2;168
12.4.3;4.3. ABCC1;168
12.4.4;4.4. ABCC3;170
12.4.5;4.5. ABCC4;171
12.5;5. Non-Drug Transport Roles of ABCC1, ABCC3, and ABCC4 in Cancer Biology;172
12.6;6. Development of Therapeutic ABCC1 and ABCC4 Inhibitors;175
12.7;7. Considerations for Targeting ABCC1 and ABCC4 in Cancer;179
12.8;8. Conclusions;180
12.9;References;180
13;Chapter 6: Leukemia and ABC Transporters;190
13.1;1. Hematopoiesis and Leukemia;191
13.1.1;1.1. Hematopoietic stem cells and ABC transporters;191
13.1.2;1.2. Leukemic stem cells;194
13.1.3;1.3. AML chemotherapy and ABC transporters;195
13.2;2. ABC Transporters That Export Regulatory Molecules;195
13.2.1;2.1. Cyclic nucleotides-c195
13.2.2;2.2. MRP4 and c196
13.2.3;2.3. Prostaglandins;197
13.2.4;2.4. Prostaglandin and HSCs;197
13.2.5;2.5. MRP4 and prostaglandins;199
13.2.6;2.6. Leukotrienes in hematopoietic cells;200
13.2.7;2.7. MRP1 and leukotrienes;201
13.2.8;2.8. Porphyrin and ABCG2;202
13.2.9;2.9. ABC transporters and AML;203
13.3;3. Kinases Impact Transporter Location and Function;205
13.3.1;3.1. Kinases and ABC transporters;205
13.3.2;3.2. Serine/threonine kinases Pim-1 and Akt affect ABCG2 location;206
13.3.3;3.3. Casein kinase 2 modulates MRP1 function;207
13.4;4. Future Perspective;208
13.5;Acknowledgments;209
13.6;References;209
14;Chapter 7: Critical Role of ABCG2 in ALA-Photodynamic Diagnosis and Therapy of Human Brain Tumor;216
14.1;1. Introduction;217
14.2;2. Biosynthesis and Transport of Porphyrins;218
14.3;3. Enforced Biosynthesis of Protoporphyrin IX in Cancer Cells by ALA Administration;218
14.4;4. PDD and Fluorescence-Guided Microsurgery;220
14.5;5. Oxidative Stress-Mediated Gene Expression in PDT;221
14.6;6. Role of ABCG2 in PDT;224
14.7;7. Mechanism of ABCG2 Inhibition by Gefitinib;225
14.8;8. The Effect of Gefitinib on ALA-PDT in Brain Tumor U87MG Cells In Vitro;226
14.9;9. The Effect of Gefitinib on ALA-PDT in Xenograft Model;228
14.10;10. Concluding Remarks;229
14.11;Acknowledgments;229
14.12;References;230
15;Chapter 8: Role of ABC Transporters in Fluoropyrimidine-Based Chemotherapy Response;236
15.1;1. Introduction: The Use of Fluoropyrimidines in Cancer Chemotherapy;237
15.1.1;1.1. Introduction;237
15.1.2;1.2. Pharmacokinetics of 5-FU;240
15.1.3;1.3. Pathways of fluoropyrimidine metabolism and mechanism of action;240
15.1.4;1.4. Limitations of fluoropyrimidine-based therapy: Toxicity and resistance;241
15.2;2. Overview of Transporters Involved in Cellular Uptake and Efflux of Fluoropyrimidines and Their Metabolites;242
15.2.1;2.1. Uptake transporters;242
15.2.2;2.2. Efflux transporters;243
15.2.3;2.3. Other transport mechanisms;243
15.3;3. Cell-Based Evidence for the Role of ABC Transporters in 5-FU Pathways;244
15.3.1;3.1. ABCB1;245
15.3.2;3.2. ABCB5;245
15.3.3;3.3. ABCC1;245
15.3.4;3.4. ABCC2;246
15.3.5;3.5. ABCC4;246
15.3.6;3.6. ABCC5;246
15.3.7;3.7. ABCC11;247
15.3.8;3.8. ABCG2;247
15.4;4. Association of ABC Transporter Expression with Resistance in Clinical Specimens;247
15.4.1;4.1. ABCB1;247
15.4.2;4.2. ABCB5;248
15.4.3;4.3. ABCC1;248
15.4.4;4.4. ABCG2;248
15.4.5;4.5. Combined analyses of ABC transporters;249
15.5;5. Genotype-Phenotype Correlations of ABC Transporters and Fluoropyrimidine-Based Therapy Response;249
15.6;Acknowledgments;255
15.7;References;255
16;Index;264
17;Color Plate ;271

Leseproben

Chapter one Apical ABC Transporters and Cancer Chemotherapeutic Drug Disposition
Selvi Durmus*; Jeroen J.M.A. Hendrikx†; Alfred H. Schinkel*,1    * Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
† Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
1 Corresponding author: email address: [e-mail] Abstract
ATP-binding cassette (ABC) transporters are transmembrane efflux transporters that mediate cellular extrusion of a broad range of substrates ranging from amino acids, lipids, and ions to xenobiotics including many anticancer drugs. ABCB1 (P-GP) and ABCG2 (BCRP) are the most extensively studied apical ABC drug efflux transporters. They are highly expressed in apical membranes of many pharmacokinetically relevant tissues such as epithelial cells of the small intestine and endothelial cells of the blood capillaries in brain and testis, and in the placental maternal–fetal barrier. In these tissues, they have a protective function as they efflux their substrates back to the intestinal lumen or blood and thus restrict the intestinal uptake and tissue disposition of many compounds. This presents a major challenge for the use of many (anticancer) drugs, as most currently used anticancer drugs are substrates of these transporters. Herein, we review the latest findings on the role of apical ABC transporters in the disposition of anticancer drugs. We discuss that many new, rationally designed anticancer drugs are substrates of these transporters and that their oral availability and/or brain disposition are affected by this interaction. We also summarize studies that investigate the improvement of oral availability and brain disposition of many cytotoxic (e.g., taxanes) and rationally designed (e.g., tyrosine kinase inhibitor) anticancer drugs, using chemical inhibitors of these transporters. These findings provide a better understanding of the importance of apical ABC transporters in chemotherapy and may therefore advance translation of promising preclinical insights and approaches to clinical studies. Keywords ABC transporters Chemotherapeutics Drug disposition Oral availability Brain disposition Abbreviations ABC ATP-binding cassette AUC area under the curve BBB blood–brain barrier CNS central nervous system EGFR epidermal growth factor receptor FGFR fibroblast growth factor receptor JAK Janus kinase MDR multidrug resistance mTOR mammalian target of rapamycin PDGFR platelet-derived growth factor receptor RET rearranged during transfection TKI tyrosine kinase inhibitor VEGFR vascular endothelial growth factor receptor WT wild type 1 Introduction to Apical ABC Transporters
ATP-binding cassette (ABC) transporters are active multispanning transmembrane protein pumps that, in higher organisms, are widely expressed in a broad range of membranes of tissues. Forming one of the largest protein families, these proteins are preserved across living organisms with different complexities, from bacteria to higher plants and animals, including humans, illustrating their essential functions (Glavinas, Krajcsi, Cserepes, & Sarkadi, 2004). ABC transporters utilize the energy generated by ATP hydrolysis to translocate a broad range of endogenous and exogenous substrates across membranes, often against a strong concentration gradient. In mammals, especially the well-studied rodents and man, typical substrates include amino acids, vitamins, lipids, sterols, bile salts, peptides, nucleotides, ions, toxins, and (anticancer) drugs (Borst & Elferink, 2002; Borst & Schinkel, 2013; Franke, Gardner, & Sparreboom, 2010; Hayashi & Sugiyama, 2013; Klaassen & Aleksunes, 2010; Lagas, Vlaming, & Schinkel, 2009; Pluchino, Hall, Goldsborough, Callaghan, & Gottesman, 2012; Tamaki, Ierano, Szakacs, Robey, & Bates, 2011; Vlaming, Lagas, & Schinkel, 2009). In this chapter, we focus on three members of the ABC superfamily: ABCB1 (P-GP, multidrug resistance (MDR)1, mouse ortholog; Abcb1a/1b), ABCC2 (MRP2, mouse ortholog; Abcc2), and ABCG2 (BCRP, mouse ortholog; Abcg2); these efflux transporters are potentially important in the pharmacokinetics of a wide range of substrate drugs, including chemotherapeutics (example drugs discussed in this chapter are given in Table 1). Table 1 Overlapping anticancer drug substrates of ABCB1, ABCG2, and ABCC2 Axitinib + + – Poller et al. (2011) Cediranib + + n.d. Wang, Agarwal, and Elmquist (2012) Crizotinib + – n.d. Tang et al. (2014) CYT387 + + n.d. Durmus et al. (2013) Dabrafenib + + n.d. Mittapalli, Vaidhyanathan, Dudek, and Elmquist (2013) Dasatinib + + – Lagas, van Waterschoot, et al. (2009) and Lagas, Vlaming, et al. (2009) Erlotinib + + – Marchetti et al. (2008) Everolimus + - n.d. Tang et al. (2014) Gefitinib + + n.d. Agarwal, Hartz, Elmquist, and Bauer (2011) Imatinib + + n.d. Oostendorp, Beijnen, and Schellens (2009) and Oostendorp, Buckle, Beijnen, van Tellingen, and Schellens (2009) N-desethyl sunitinib + + – Tang, Lagas, et al. (2012) and Tang, Lankheet, et al. (2012) Pazopanib + + n.d. Minocha, Khurana, Qin, Pal, and Mitra (2012b) Rucaparib + + n.d. Durmus et al. (2014) Sorafenib + + + Lagas, Fan, et al. (2010), Lagas, van Waterschoot, et al. (2010), and Shibayama et al. (2011) Sunitinib + + – Tang, Lagas, et al. (2012) and Tang, Lankheet, et al. (2012) Tandutinib + + n.d. Yang et al. (2010) Trametinib + + n.d. Vaidhyanathan, Mittapalli, Sarkaria, and Elmquist (2014) Vandetanib + + n.d. Minocha, Khurana, Qin, Pal, and Mitra (2012a) Veliparib + + n.d. Lin et al. (2014) Vemurafenib + + – Durmus, Sparidans, Wagenaar, Beijnen, and Schinkel (2012) Paclitaxel + – + Sparreboom et al. (1997), Lagas et al. (2006), and Zamek-Gliszczynski, Bedwell, Bao, and Higgins (2012) Docetaxel + – + Bardelmeijer et al. (2002), Huisman, Chhatta, van Tellingen, Beijnen, and Schinkel (2005), van Waterschoot et al. (2010), and Lagas et al. (2006) –, no noticeable effect; n.d., not determined. ABCB1, ABCC2, and ABCG2 are the most extensively studied apical ABC transporters in relation to chemotherapeutic drug disposition. They are localized at the apical membranes of intestinal and renal proximal tubule epithelial cells and at the bile canalicular membranes of the hepatocytes, where they efflux their substrates into intestinal lumen or feces, urine, and bile to protect the organism (Fig. 1; Borst & Schinkel, 2013; Klaassen & Aleksunes, 2010; Lagas, Vlaming, et al., 2009; Schinkel & Jonker, 2003; van Herwaarden & Schinkel, 2006; Vlaming et al., 2009). They are also expressed at the apical membranes of blood–brain, blood–testis, and blood–placenta barriers, where they extrude endogenous or exogenous substrates, including drugs, carcinogens, and toxins, into the main circulation in order to protect those tissue sanctuaries (Fig. 1). Interactions of many chemotherapeutics with these ABC efflux transporters are known to affect their intestinal uptake...