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
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
Front Cover 1
ABC Transporters and Cancer 4
Copyright 5
Dedication 6
Contents 8
Contributors 12
Preface 16
Chapter 1: Apical ABC Transporters and Cancer Chemotherapeutic Drug Disposition 20
1. Introduction to Apical ABC Transporters 21
2. Impact of Apical ABC Transporters on Intestinal Absorption of Oral Chemotherapeutic Drugs 24
2.1. Apical ABC transporters affecting the oral bioavailability of taxanes 27
2.1.1. ABCB1 and oral taxane availability 27
2.1.2. ABCC2 and oral taxane availability 28
2.1.3. ABCB1 inhibitors to improve taxane oral availability 29
2.1.4. Assessing CNS toxicity risks of using ABCB1 inhibitors to improve oral taxane availability 30
2.1.5. Possible effects of ABCB1 inhibitors on enhancing taxane antitumor efficacy 31
2.2. Apical ABC transporters in the oral bioavailability of rationally designed anticancer drugs 32
2.2.1. Tyrosine kinase inhibitors 32
2.2.2. PARP inhibitors 36
2.2.3. Chemical inhibition of transporters to increase oral availability of rationally designed anticancer drugs 37
2.2.4. Importance of the sensitivity and specificity of in vitro assays used to assess ABC transporter substrates 38
3. Impact of Apical ABC Transporters on Brain Disposition of Oral Chemotherapeutic Drugs 39
3.1. Does the BBB matter in drug delivery to brain tumors? 39
3.2. Apical efflux transporters in the BBB affecting brain accumulation of anticancer drugs 40
3.2.1. Drugs affected mostly by Abcb1a but also by Abcg2 in their brain accumulation 41
3.2.2. Drugs only affected by Abcb1a in their brain accumulation 43
3.2.3. Drugs affected mostly by Abcg2 but also by Abcb1a in their brain accumulation 44
3.2.4. Three different apical BBB ABC efflux transporters affect brain accumulation of some camptothecins 44
3.2.5. Models to explain the disproportionate effect of combined deficiency of Abcb1 and Abcg2 on brain accumulation of s... 45
3.2.6. Why are many rationally designed anticancer drugs still ABCB1 and/or ABCG2 substrates? 47
3.2.7. Limitations of knockout mouse models to study ABC transporter functions at the BBB 48
3.2.8. Tissue and cellular context may affect the in vivo impact of apical ABC efflux transporters 49
3.2.9. Use of chemical inhibitors to enhance brain accumulation of ABC transporter substrate drugs 49
4. Concluding Remarks 50
References 50
Chapter 2: Regulation of ABC Transporters Blood-Brain Barrier: The Good, the Bad, and the Ugly 62
1. Introduction 64
2. Blood-Brain Barriers 64
2.1. Assessing blood-brain barrier function 65
3. ABC Transporters at the Blood-Brain Barrier 67
4. The Bad and the Ugly: Mechanisms that Increase Transporter Expression and Reduce Drug Delivery to the CNS 69
4.1. Xenobiotic-activated transcription factors 70
4.2. Stress-activated transcription factors 72
4.3. Disease 76
5. The Good: Mechanisms that Reduce Transporter Activity/Expression and Have the Potential to Improve Drug Delivery to th... 77
5.1. P-glycoprotein 78
5.2. BCRP 82
6. Perspectives: Where the Field Is Headed 83
References 85
Chapter 3: Molecular Basis of the Polyspecificity of P-Glycoprotein (ABCB1): Recent Biochemical and Structural Studies 90
1. Introduction 91
2. Molecular Basis of Polyspecificity 92
2.1. Structural flexibility revealed by X-ray crystallography 92
2.2. Structural flexibility probed with disulfide cross-linking and biophysical methods 96
2.3. Substrate polyspecificity and ligand-based studies 98
2.4. P-glycoprotein portals 101
2.5. Drug-binding sites 101
2.6. The proposed R, H, and P sites 103
2.7. Primary and secondary sites 105
2.8. Pseudo-symmetric sites 107
3. Molecular Modeling Studies 108
4. Conclusions and Perspectives 109
Acknowledgments 110
References 110
Chapter 4: Lipid Regulation of the ABCB1 and ABCG2 Multidrug Transporters 116
1. Introduction-The Complex Interactions of Lipids and ABC Multidrug Transporters 117
2. Effects of Lipids on the Function of ABCB1 and ABCG2 122
2.1. Localization of ABCB1 and ABCG2 in specialized membrane domains 122
2.2. Substrate handling of ABCB1 and ABCG2 and the role of membrane lipids 123
2.3. Modulation of ABCB1 and ABCG2 function by lipids, lipid derivatives, and detergents 125
2.4. Role of lipids in MDR-ABC protein purification and reconstitution 128
2.5. MDR-ABC transporters may actively alter the membrane lipid environment 130
3. Effects of Lipids on the Expression of ABCB1 and ABCG2: Regulation by Nuclear Receptors 130
3.1. The NR superfamily of transcription factors and lipid-sensing NRs 131
3.2. Regulation of the expression of ABCB1 by NRs 133
3.3. Regulation of the expression of ABCG2 by NRs 134
3.4. Role of NRs in lipid metabolism and a potential indirect effect on ABCB1 and ABCG2 transporter function 135
4. Experimental Strategies to Define the Lipid-Interacting Regions of the ABCB1 and ABCG2 Proteins 135
4.1. Lipid sensing by the ABCB1 protein 136
4.1.1. Mutagenesis studies in ABCB1 136
4.1.2. Direct binding of lipids and MD simulations on ABCB1 138
4.2. Lipid sensing by the ABCG2 protein 140
4.2.1. Role of the R482 position 141
4.2.2. Role of the LxxL motif 141
4.2.3. Role of the CRAC motif 144
5. In Silico Modeling of the Lipid Interactions of ABCB1 and ABCG2 144
5.1. MD simulation 145
5.2. In silico docking 146
6. Conclusions 147
References 148
Chapter 5: ABC Transporters and Neuroblastoma 158
1. Introduction 159
2. Current Therapies for Neuroblastoma 160
3. MYCN 161
4. MYCN and ABC Transporters 164
4.1. ABCB1 167
4.2. ABCG2 168
4.3. ABCC1 168
4.4. ABCC3 170
4.5. ABCC4 171
5. Non-Drug Transport Roles of ABCC1, ABCC3, and ABCC4 in Cancer Biology 172
6. Development of Therapeutic ABCC1 and ABCC4 Inhibitors 175
7. Considerations for Targeting ABCC1 and ABCC4 in Cancer 179
8. Conclusions 180
References 180
Chapter 6: Leukemia and ABC Transporters 190
1. Hematopoiesis and Leukemia 191
1.1. Hematopoietic stem cells and ABC transporters 191
1.2. Leukemic stem cells 194
1.3. AML chemotherapy and ABC transporters 195
2. ABC Transporters That Export Regulatory Molecules 195
2.1. Cyclic nucleotides-cAMP 195
2.2. MRP4 and cAMP 196
2.3. Prostaglandins 197
2.4. Prostaglandin and HSCs 197
2.5. MRP4 and prostaglandins 199
2.6. Leukotrienes in hematopoietic cells 200
2.7. MRP1 and leukotrienes 201
2.8. Porphyrin and ABCG2 202
2.9. ABC transporters and AML 203
3. Kinases Impact Transporter Location and Function 205
3.1. Kinases and ABC transporters 205
3.2. Serine/threonine kinases Pim-1 and Akt affect ABCG2 location 206
3.3. Casein kinase 2 modulates MRP1 function 207
4. Future Perspective 208
Acknowledgments 209
References 209
Chapter 7: Critical Role of ABCG2 in ALA-Photodynamic Diagnosis and Therapy of Human Brain Tumor 216
1. Introduction 217
2. Biosynthesis and Transport of Porphyrins 218
3. Enforced Biosynthesis of Protoporphyrin IX in Cancer Cells by ALA Administration 218
4. PDD and Fluorescence-Guided Microsurgery 220
5. Oxidative Stress-Mediated Gene Expression in PDT 221
6. Role of ABCG2 in PDT 224
7. Mechanism of ABCG2 Inhibition by Gefitinib 225
8. The Effect of Gefitinib on ALA-PDT in Brain Tumor U87MG Cells In Vitro 226
9. The Effect of Gefitinib on ALA-PDT in Xenograft Model 228
10. Concluding Remarks 229
Acknowledgments 229
References 230
Chapter 8: Role of ABC Transporters in Fluoropyrimidine-Based Chemotherapy Response 236
1. Introduction: The Use of Fluoropyrimidines in Cancer Chemotherapy 237
1.1. Introduction 237
1.2. Pharmacokinetics of 5-FU 240
1.3. Pathways of fluoropyrimidine metabolism and mechanism of action 240
1.4. Limitations of fluoropyrimidine-based therapy: Toxicity and resistance 241
2. Overview of Transporters Involved in Cellular Uptake and Efflux of Fluoropyrimidines and Their Metabolites 242
2.1. Uptake transporters 242
2.2. Efflux transporters 243
2.3. Other transport mechanisms 243
3. Cell-Based Evidence for the Role of ABC Transporters in 5-FU Pathways 244
3.1. ABCB1 245
3.2. ABCB5 245
3.3. ABCC1 245
3.4. ABCC2 246
3.5. ABCC4 246
3.6. ABCC5 246
3.7. ABCC11 247
3.8. ABCG2 247
4. Association of ABC Transporter Expression with Resistance in Clinical Specimens 247
4.1. ABCB1 247
4.2. ABCB5 248
4.3. ABCC1 248
4.4. ABCG2 248
4.5. Combined analyses of ABC transporters 249
5. Genotype-Phenotype Correlations of ABC Transporters and Fluoropyrimidine-Based Therapy Response 249
Acknowledgments 255
References 255
Index 264
Color Plate 271
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: a.schinkel@nki.nl
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...
Erscheint lt. Verlag | 27.1.2015 |
---|---|
Sprache | englisch |
Themenwelt | Medizin / Pharmazie ► Medizinische Fachgebiete ► Onkologie |
Studium ► 2. Studienabschnitt (Klinik) ► Humangenetik | |
Naturwissenschaften ► Biologie ► Genetik / Molekularbiologie | |
Naturwissenschaften ► Biologie ► Zellbiologie | |
Technik | |
ISBN-10 | 0-12-801361-3 / 0128013613 |
ISBN-13 | 978-0-12-801361-8 / 9780128013618 |
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