Drug Resistance in Cancer Cells (eBook)

Foreword 5
Contents 12
Contributors 14
1 Multidrug Resistance Mediated by MDR-ABC Transporters 17
Introduction 17
Mechanistic Aspects of ABC Transporters 18
MDR-ABC Transporters 19
Transported Substrates 20
Gene Regulation 22
Significance of MDR-ABC Transporters in Cancer 25
Association of MDR-ABC Transporters with Treatment Failure 26
Overcoming MDR with Inhibitors 26
Emerging Role of MDR-ABC Transporters in Resistance Against Targeted Agents 29
Conclusion 30
References 31
2 Metastasis and Drug Resistance 37
Introduction 37
The Pathogenesis of Metastasis 38
Multidrug Resistance 39
Reversal of Experimental MDR 40
Calcium Channel Blockers 40
Verapamil and Other Clinically Approved Agents 40
Verapamil Derivatives and Other Experimental Calcium Channel Blockers 42
Calmodulin Antagonists 42
Antibiotics and Analogs 43
Indole Alkaloids 43
Cyclosporins and Analogs 43
Hormones and Antihormones 44
Pharmaceutical Emulsifying Surfactants 44
Liposomal Encapsulation 45
Other Molecules 45
Clinical Reversal of MDR 46
Overview of Experimental MDR-Reversal 47
Metastasis and Drug Resistance 48
Tumor Angiogenesis 49
Antivascular Therapy of MDR Prostate Carcinoma 52
References 54
3 The Role of Autophagy and Apoptosis in the Drug Resistance of Cancer 69
Introduction 69
Role of Autophagy in the Drug Resistance of Cancer 70
Role of Autophagy in Cancer Treatment 70
Role of Autophagy in Tumorigenesis 72
Mechanism Regulating Autophagy and Apoptosis 73
PI3K-AKT-mTOR Signaling Pathway 74
BECN1 75
BCL2 and Adenovirus E1B 19kDa Interaction Protein 3 (BNIP3) 75
p53 Tumor Suppressor Pathway 76
ER Stress 76
Other Pathways 77
Targeting Autophagy in Drug Resistance of Cancer 77
Crosstalk Between Autophagy and Apoptosis 77
Combination Treatment for Drug Resistance 79
Conclusion 82
References 82
4 Mechanisms of Resistance to Targeted Tyrosine Kinase Inhibitors 88
Introduction 88
Discovery of Viral and Cellular Oncogenes 89
BCR-ABL Targeted Therapy 90
The Philadelphia Chromosome 90
BCR-ABL Signaling in CML 90
Imatinib 90
Imatinib Resistance in CML 91
Nonmutation-Dependent Mechanisms 93
Mutation of BCR-ABL 94
Second-Generation BCR-ABL Inhibitors Aimed at Overcoming Imatinib Resistance 94
Dasatinib 95
Dasatinib Resistance 95
Nilotinib 96
Overcoming T315I Resistance 96
EGFR-Targeted Therapy 97
EGFR and Cancer 97
Gefitinib and Erlotinib: EGFR-Targeted Therapies 98
Response to Gefitinib Treatment 98
Erlotinib 99
Gefitinib and Erlotinib Resistance 99
Secondary EGFR Mutations 99
Non-EGFR Mutation-Dependent Mechanisms 100
Overcoming T790M Resistance 100
Concluding Remarks 101
References 101
5 Targeting Transglutaminase-2 to Overcome Chemoresistance in Cancer Cells 109
Introduction 109
TG2-The Protein with a Split Personality 111
TG2, Drug Resistance, and Metastasis 112
TG2-Mediated Cell Signaling 115
TG2-Mediated NF-B Activation 117
TG2 Promotes Cell Survival and Chemoresistance 119
Therapeutic Significance of TG2 120
Conclusions 122
References 122
6 Extracellular Matrix-Mediated Drug Resistance 129
Introduction 130
ECM Proteins Promote Drug Resistance 131
Mechanisms of ECM-Mediated Drug Resistance 132
Altered Drug Penetration 133
Reduced DNA Damage 133
Effects on Cell Proliferation 134
Interaction with Cell-Surface Integrins 134
Integrin Signalling Pathways and Drug Resistance 136
The Role of FAK as a Mediator of Drug Resistance 137
The Role of ILK in Drug Resistance 138
The Role of PI3-K Signalling in Integrin-Mediated Drug Resistance 139
ECM-Mediated Drug Resistance in the Context of Metastatic Cancer 141
Conclusions and Future Directions 142
References 142
7 Oxidative Stress and Drug Resistance in Cancer 150
Introduction 151
Redox Alterations in Cancer 153
The Findings 153
Role of Oxidative Stress in Tumorigenesis 153
Mechanisms of the Intrinsic ROS Stress in Cancer Cells 154
Adaptive Response to Oxidative Stress 156
Activation of Redox-Sensitive Transcription Factors 157
NF-B 158
Nrf2 158
c-Jun 159
HIF-1 160
Alterations in Regulators of Redox Homeostasis 161
Alterations in the Function of Proteins Involving in Cell Survival 162
Mechanisms of Drug Resistance as the Consequence of Redox Adaptation 163
Enhanced Cell Survival 163
Increased Capacity to Maintain Redox Homeostasis 163
Moderate Increase of Oxidative Stress Inhibits Apoptotic Execution 165
Increased Repair and Tolerance of DNA Damage 167
Altered Drug Metabolism 167
Therapeutic Strategy to Overcome Drug Resistance 168
Targeting Transcription Factors that Regulate Survival Pathways 168
Targeting the Regulators of Redox Homeostasis 169
Targeting Redox-Sensitive Factors Involving Cell Survival and Apoptosis 173
Concluding Remarks 174
References 174
8 Nuclear Factor-B and Chemoresistance: How Intertwined Are They? 189
Introduction 189
What Is NF-B? 190
NF-B and Cancer 191
NF-B Regulates the Expression of Cell Proliferative Gene Products 193
NF-B Regulates the Expression of Anti-apoptotic Gene Products 193
NF-B Regulates the Expression of Invasive Gene Products 193
NF-B Regulates the Expression of Genes Involved in Angiogenesis 194
NF-B Regulates the Expression of Genes Involved in Tumor Cell Metastasis 194
Chemotherapeutic Agents Activate NF-B and Induce Drug Resistance 195
NF-B-Mediated Drug Resistance Mechanisms 196
Multidrug Resistance (MDR) Gene 197
COX-2 198
Survivin 198
Bcl-2/Bcl-xL 199
Inhibitor of Apoptosis Proteins 200
cFLIP 200
Cell Adhesion Molecules 201
PI3K/Akt 201
mTOR Pathway 202
Protein Tyrosine Kinases 203
5-LOX 203
EGFR 204
IL-6 204
HER-2 205
PKC/PKA 206
Cyclin D1 206
c-Myc 207
Integrin 207
TG-2 208
STAT3 209
NF-B Inhibitors and Chemosensitization 209
Conclusion 210
References 210
9 Drug Resistance and the Tumor Suppressor p53: The Paradox of Wild-Type Genotype in Chemorefractory Cancers 221
Introduction 221
Role of p53 in the Response of Sensitive Tumor Cells to Antitumor Agents 222
Concept of Drug Resistance Caused by p53 Mutation 224
Mutations in p53 Modulate Drug Response and Specificity 225
Gene Status of p53 and Clinical Drug Resistance 226
Relative Resistance Based on p53 Gene Status and the Role of the Antitumor Agent 227
Resistance Mechanisms in Tumor Cells Harboring Wild-Type p53 230
Downregulation of DNA Damage Recognition Proteins 230
Downregulation of Upstream Pathways 232
ATM/Chk2 and ATM/HIPK2 Pathways 232
ATR/Chk1 Pathway 233
Failure to Turn ''on'' the p53 Activation Switch 234
Downregulation of Promoter Response to p53 in Target Genes 235
Conclusion 236
References 237
10 Resistance to Differentiation Therapy 244
Introduction 244
Acute Promelocytic Leukemia and Differentiation Therapy 245
Retinoids and All-trans-Retinoic Acid 246
Pathogenesis of Acute Promyelocytic Leukemia 248
Molecular Basis of ATRA Therapy in APL 248
Resistance to Differentiation Therapy 250
Accelerated ATRA Metabolism 252
Increased Cellular RA-Binding Proteins (CRABPs) 253
Mutations at the Ligand-Binding Domain of RAR 255
Constitutive Degradation of PMLRAR 255
P-Glycoprotein Expression 256
Histone Deacetylase (HDAC) Activity 257
The Role of PML/RAR Isoforms in Resistance 257
Telemerase Activity 258
Tissue Transglutaminase Expression 258
Topoisomerase II Activity 259
Potential Treatment Strategies to Overcome ATRA Resistance in APL 259
Liposomal ATRA 259
Arsenic Trioxide (As 2 O 3 ) 261
Histone Deacetylase Inhibitors 262
Others 262
Conclusion 262
References 263
11 MicroRNAs and Drug Resistance 267
Introduction 267
Biogenesis 268
Cellular Function 270
MiRNA and Cancer 270
MiRNAs as Oncogenes and Tumor Suppressors 271
MiRNA and Drug Resistance 273
Conclusion 277
References 278
12 Molecular Signatures of Drug Resistance 281
Introduction 281
Microarrays in the Heterogeneity of Cancer 282
Observational vs. Experimental Studies in Drug Resistance 282
Microarray Analysis: Supervised, Unsupervised, Significance, and Prediction 284
Cancer Cell Lines and Signatures of Drug Resistance 286
Linking Cell Line Data with Human Observational Data 288
Animal Models and Signatures of Drug Resistance 291
Linking Mouse Models with Human Cancer Biology 292
Human Studies and Signatures of Drug Resistance 294
Future Directions in Molecular Signatures of Drug Resistance 295
Stem Cells 295
Microenvironment 296
Pathways or Modules vs. Individual Genes as Functional Units 297
Conclusions 297
References 298
13 Assessment of Drug Resistance in Anticancer Therapy by Nuclear Imaging 305
Introduction 305
Use of PET 305
Imaging with PET 306
Use of FDG to Identify Patients Resistant to Chemotherapy 306
Imaging Pharmacokinetic Resistance 308
Metabolic Resistance 309
Metabolism of 5-FU and Resistance 309
Imaging Physiological Causes of Resistance 310
Blood Flow 310
Angiogenesis 311
Hypoxia 313
Molecular Resistance 313
Hormone Receptor-Mediated Resistance 313
Apoptosis 314
p53 Tumour Suppressor 314
Imaging Signal Transduction Pathways 315
Imaging Proliferation 316
DNA Repair 316
Integrin Signalling 317
MDR 317
Conclusions 318
References 318
14 Overcoming Drug Resistance by Phytochemicals 324
Introduction 324
Cancer Drug Resistance 324
Phytochemicals 326
PhytochemicalChemotherapeutic Synergy 327
Epigallocatechin-3-gallate 327
Health Effects 327
Cancer Drug Resistance 329
Curcumin 330
Health Effects 330
Cancer Drug Resistance 331
Resveratrol 332
Health Effects 332
Cancer Drug Resistance 333
Other Phytochemicals 334
Quercetin 335
Genistein 335
Indole-3-carbinol 336
Phytochemicals from Medicinal Herbs 336
Botanical Extracts 336
Discussion 337
Antagonistic Effects 337
Combination Therapy 338
Multiple Molecular Targets 338
Safety 339
Consumer Use of Phytochemicals 339
Phytochemical Safety 339
Bioavailability 340
Bioefficacy 340
Hormesis 341
Conclusion and Perspective 341
References 343
Index 352