Lysosomes
Biology, Diseases, and Therapeutics
Herausgeber: Maxfield, Frederick R; Lu, Shuyan; Willard, James M
Lysosomes
Biology, Diseases, and Therapeutics
Herausgeber: Maxfield, Frederick R; Lu, Shuyan; Willard, James M
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Discussing recent findings, up-to-date research, and novel strategies, the book integrates perspectives from pharmacology, toxicology, and biochemistry to illustrate the potential of lysosomes in drug discovery and development. * Explores basic principles and properties of lysosomes that allow them to act as regulators of cell metabolism, therapeutic targets, and sites for activation of drug conjugates * Discusses the role of lysosomes in metabolism, drug targeting, apoptosis, cancer, aging, inflammation, autophagy, metabolism, toxicity, and membrane repair * Introduces new pathways in therapeutic development and new mechanisms in drug development…mehr
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- Drug Discovery Toxicology226,99 €
- Q Alan XuAnalytical Methods for Therapeutic Drug Monitoring and Toxicology211,99 €
- Souzan B YanniTranslational Admet for Drug Therapy157,99 €
- Oligonucleotide-Based Drugs and Therapeutics239,99 €
- Bile Acids108,99 €
- Study Director Nonclinical142,99 €
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- Produktdetails
- Verlag: John Wiley & Sons / Wiley
- Seitenzahl: 544
- Erscheinungstermin: 24. Juni 2016
- Englisch
- Abmessung: 236mm x 157mm x 36mm
- Gewicht: 930g
- ISBN-13: 9781118645154
- ISBN-10: 1118645154
- Artikelnr.: 42517488
- Verlag: John Wiley & Sons / Wiley
- Seitenzahl: 544
- Erscheinungstermin: 24. Juni 2016
- Englisch
- Abmessung: 236mm x 157mm x 36mm
- Gewicht: 930g
- ISBN-13: 9781118645154
- ISBN-10: 1118645154
- Artikelnr.: 42517488
2 References
4 2 Lysosome Biogenesis and Autophagy 7 Fulvio Reggiori and Judith Klumperman 2.1 Introduction
7 2.2 Pathways to the Lysosomes
10 2.2.1 Biosynthetic Transport Routes to the Lysosome
10 2.2.2 Endocytic Pathways to the Lysosome
10 2.2.3 Autophagy Pathways to the Lysosome
12 2.2.4 The ATG Proteins: The Key Regulators of Autophagy
14 2.3 Fusion and Fission between the Endolysosomal and Autophagy Pathways
16 2.3.1 Recycling Endosomes and Autophagosome Biogenesis
16 2.3.2 Autophagosome Fusion with Late Endosomes and Lysosomes
17 2.3.3 Autophagic Lysosomal Reformation
18 2.4 Diseases
19 2.4.1 Lysosome-Related Disorders (LSDs)
19 2.4.2 Lysosomes in Neurodegeneration and Its Links to Autophagy
20 2.4.3 Autophagy-Related Diseases
20 2.5 Concluding Remarks
22 Acknowledgments
23 References
23 3 Multivesicular Bodies: Roles in Intracellular and Intercellular Signaling 33 Emily R. Eden
Thomas Burgoyne
and Clare E. Futter 3.1 Introduction
33 3.2 Downregulation of Signaling by Sorting onto ILVs
35 3.3 Upregulation of Signaling by Sorting onto ILVs
38 3.4 Intercellular Signaling Dependent on Sorting onto ILVs
39 3.5 Conclusion
44 References
45 4 Lysosomes and Mitophagy 51 Dominik Haddad and Patrik Verstreken 4.1 Summary
51 4.2 Mitochondrial Significance
51 4.3 History of Mitophagy
52 4.4 Mechanisms of Mitophagy
53 4.4.1 Mitophagy in Yeast
54 4.4.2 Mitophagy in Mammals
55 4.5 Conclusion
57 Acknowledgments
57 References
58 5 Lysosome Exocytosis and Membrane Repair 63 Rajesh K. Singh and Abigail S. Haka 5.1 Introduction
63 5.2 Functions of Lysosome Exocytosis
63 5.2.1 Specialized Lysosome-Related Organelles
64 5.2.2 Lysosome Exocytosis for Membrane Repair
65 5.2.3 Lysosome Exocytosis as a Source of Membrane
66 5.2.4 Lysosome Exocytosis for Extracellular Degradation
66 5.2.5 Lysosome Exocytosis and Delivery of Proteins to the Cell Surface
68 5.3 Mechanisms of Lysosome Exocytosis
68 5.3.1 Maturation of Lysosomes and Lysosome-Related Organelles
69 5.3.2 Transport of Lysosomes to the Plasma Membrane
70 5.3.3 Tethering of Lysosomes to the Plasma Membrane
72 5.3.4 Lysosome Fusion with the Plasma Membrane
75 5.3.5 Calcium-Dependent Exocytosis
76 5.4 Conclusion
76 Acknowledgments
77 References
77 6 Role of Lysosomes in Lipid Metabolism 87 Frederick R. Maxfield 6.1 Introduction
87 6.2 Endocytic Uptake of Lipoproteins
88 6.3 Lipid Metabolism in Late Endosomes and Lysosomes
91 6.4 Autophagy and Lysosomal Lipid Turnover
94 6.5 Lysosomal Lipid Hydrolysis and Metabolic Regulation
95 6.6 Summary
96 References
96 7 TFEB
Master Regulator of Cellular Clearance 101 Graciana Diez-Roux and Andrea Ballabio 7.1 Lysosome
101 7.2 The Transcriptional Regulation of Lysosomal Function
102 7.3 TFEB Subcellular Regulation is Regulated by Its Phosphorylation
104 7.4 A Lysosome-to-Nucleus Signaling Mechanism
105 7.5 TFEB and Cellular Clearance in Human Disease
106 7.5.1 Lysosomal Storage Disorders
107 7.5.2 Neurodegenerative Disorders
109 7.5.3 Metabolic Syndrome
110 7.5.4 Cancer
Inborn Errors of Metabolism
Immunity
and Longevity
110 References
111 8 Lysosomal Membrane Permeabilization in Cell Death 115 Urska Repnik and Boris Turk 8.1 Introduction
115 8.2 Cell Death Modalities
116 8.3 Lysosomal Membrane Permeabilization (LMP) and Cell Death
117 8.3.1 Mechanisms of LMP
118 8.3.2 Upstream of LMP: Direct Insult Versus Molecular Signaling
121 8.3.3 Signaling Downstream of LMP
124 8.4 Conclusion
127 Acknowledgments
127 References
128 9 The Lysosome in Aging-Related Neurodegenerative Diseases 137 Ralph A. Nixon 9.1 Introduction
137 9.2 Lysosome Function in Aging Organisms
139 9.3 Lysosomes and Diseases of Late Age Onset
142 9.3.1 Cardiovascular Disease
142 9.4 Lysosomes in Aging-Related Neurodegenerative Diseases
144 9.4.1 Alzheimer's Disease (AD)
145 9.4.2 Parkinson's Disease and Related Disorders
150 9.4.3 Diffuse Lewy Body Disease (DLB)
155 9.4.4 Frontotemporal Lobar Degeneration (FTLD)
155 9.5 Conclusion
158 Acknowledgments
158 References
159 10 Lysosome and Cancer 181 Marja Jäättelä and Tuula Kallunki 10.1 Introduction
181 10.2 Lysosomal Function and Its Importance for Cancer Development and Progression
181 10.3 Cancer-Induced Changes in Lysosomal Function
182 10.3.1 Increased Activity of Lysosomal Enzymes
182 10.3.2 Altered Lysosome Membrane Permeability
184 10.3.3 Increased Lysosome Size
184 10.3.4 Altered Lysosome Trafficking - Increased Lysosomal Exocytosis
185 10.4 Cancer-Induced Changes in Lysosome Composition
185 10.4.1 Changes in Lysosomal Hydrolases
185 10.4.2 Changes in the Lysosomal Membrane Proteins
192 10.5 Molecular Changes Involving Lysosomal Integrity
193 10.5.1 Cancer-Associated Changes in Lysosomal Sphingolipid Metabolism
193 10.5.2 Targeting Lysosomal Membrane Integrity
195 10.6 Conclusion
196 References
197 11 The Genetics of Sphingolipid Hydrolases and Sphingolipid Storage Diseases 209 Edward H. Schuchman and Calogera M. Simonaro 11.1 Introduction and Overview
209 11.2 Acid Ceramidase Deficiency: Farber Disease
210 11.3 Acid Sphingomyelinase Deficiency: Types A and B Niemann-Pick Disease
213 11.4 Beta-Glucocerebrosidase Deficiency: Gaucher Disease
215 11.5 Galactocerebrosidase Deficiency: Krabbe Disease/Globoid Cell Leukodystrophy
218 11.6 Arylsulfatase a Deficiency: Metachromatic Leukodystrophy
219 11.7 Alpha-Galactosidase a Deficiency: Fabry Disease
221 11.8 Beta-Galactosidase Deficiency: GM1 Gangliosidosis
224 11.9 Hexosaminidase A and B Deficiency: GM2 Gangliosidoses
226 11.10 Sphingolipid Activator Proteins
229 References
231 12 Lysosome-Related Organelles: Modifications of the Lysosome Paradigm 239 Adriana R. Mantegazza and Michael S. Marks 12.1 Differences Between LROs and Secretory Granules
240 12.2 Physiological Functions of LROs
240 12.3 LRO Biogenesis
244 12.3.1 Chediak-Higashi Syndrome and Gray Platelet Syndrome
244 12.3.2 Hermansky-Pudlak Syndrome
246 12.3.3 Melanosome Biogenesis
247 12.3.4 HPS and Melanosome Maturation
248 12.3.5 HPS and the Biogenesis of Other LROs
250 12.3.6 HPS and Neurosecretory Granule Biogenesis
250 12.3.7 Weibel-Palade Body Biogenesis
251 12.4 LRO Motility
Docking
and Secretion
252 12.5 LROs and Immunity to Pathogens
253 12.5.1 Cytolytic Granules
253 12.5.2 Familial Hemophagocytic Lymphohistiocytosis and Cytolytic Granule Secretion
254 12.5.3 Azurophilic Granules
255 12.5.4 NADPH Oxidase-Containing LROs
255 12.5.5 IRF7-Signaling LROs and Type I Interferon Induction
256 12.5.6 MIICs: LROs or Conventional Late Endosome/Lysosomes?
256 12.5.7 Phagosomes and Autophagosomes as New Candidate LROs
258 12.6 Perspectives
260 Acknowledgments
260 References
260 13 Autophagy Inhibition as a Strategy for Cancer Therapy 279 Xiaohong Ma
Shengfu Piao
Quentin Mcafee
and Ravi K. Amaravadi 13.1 Stages and Steps of Autophagy
282 13.2 Induction of Autophagy
283 13.3 Studies in Mouse Models Unravel the Dual Roles of Autophagy in Tumor Biology
285 13.4 Clinical Studies on Autophagy's Dual Role in Tumorigenesis
286 13.5 Mouse Models Provide the Rationale for Autophagy Modulation in the Context of Cancer Therapy
288 13.6 Multiple Druggable Targets in the Autophagy Pathway
291 13.7 Overview of Preclinical Autophagy Inhibitors and Evidence Supporting Combination with Existing and New Anticancer Agents
292 13.8 Proximal Autophagy Inhibitors
293 13.9 Quinolines: From Antimalarials to Prototypical Distal Autophagy Inhibitors
293 13.10 Summary for the Clinical Trials for CQ/HCQ
295 13.11 Developing More Potent Anticancer Autophagy Inhibitors
298 13.12 Summary
Conclusion
and Future Directions
300 13.13 In Summary
302 References
302 14 Autophagy Enhancers
are we there Yet? 315 Shuyan Lu and Ralph A. Nixon 14.1 Introduction
315 14.2 Autophagy Impairment and Diseases
316 14.3 Autophagy Enhancer Screening
317 14.3.1 Methods for Monitoring Autophagy
317 14.3.2 Autophagy Enhancers Identified from Early Literature
326 14.3.3 mTOR Inhibitors
331 14.4 Other Agents that Boost Autophagy and Lysosomal Functions
335 14.4.1 HDAC Inhibition
336 14.4.2 pH Restoration
337 14.4.3 TRP Activator
337 14.4.4 TFEB Overexpression/Activation
338 14.4.5 Lysosomal Efficiency
338 14.4.6 MicroRNA
339 14.5 Concluding Remarks
340 References
341 15 Pharmacological Chaperones as Potential Therapeutics for Lysosomal Storage Disorders: Preclinical Research to Clinical Studies 357 Robert E. Boyd
Elfrida R. Benjamin
Su Xu
Richie Khanna
and Kenneth J. Valenzano 15.1 Introduction
357 15.2 Fabry Disease
359 15.3 Gaucher Disease
363 15.4 GM2 Gangliosidoses (Tay-Sachs/Sandhoff Diseases)
367 15.5 Pompe Disease
368 15.6 PC-ERT Combination Therapy
370 References
372 16 Endosomal Escape Pathways for Delivery of Biologics 383 Philip L. Leopold 16.1 Introduction
383 16.2 Endosome Characteristics
384 16.3 Delivery of Nature's Biologics: Lessons on Endosomal Escape from Pathogens
389 16.3.1 Viruses
390 16.3.2 Bacteria
Protozoa
and Fungi
392 16.3.3 Toxins
394 16.4 Endosomal Escape Using Engineered Systems
395 16.4.1 Peptides and Polymers
396 16.4.2 Lipids
398 16.4.3 Other Chemical and Physical Strategies
399 16.5 Conclusion
399 References
400 17 Lysosomes and Antibody-Drug Conjugates 409 Michelle Mack
Jennifer Kahler
Boris Shor
Michael Ritchie
Maureen Dougher
Matthew Sung
and Puja Sapra 17.1 Introduction
409 17.2 Receptor Internalization
410 17.3 Antibody-Drug Conjugates
413 17.4 Mechanisms of Resistance to ADCs
416 17.5 Summary
417 References
417 18 The Mechanisms and Therapeutic Consequences of Amine-Containing Drug Sequestration in Lysosomes 423 Nadia Hamid and Jeffrey P. Krise 18.1 Introduction
423 18.2 Lysosomal Trapping Overview
424 18.3 Techniques to Assess Lysosomal Trapping
427 18.4 Influence of Lysosomotropism on Drug Activity
429 18.5 Influence of Lysosomal Trapping on Pharmacokinetics
435 18.6 Pharmacokinetic Drug-Drug Interactions Involving Lysosomes
438 References
440 19 Lysosome Dysfunction: an Emerging Mechanism of Xenobiotic-Induced Toxicity 445 Shuyan Lu
Bart Jessen
Yvonne Will
and Greg Stevens 19.1 Introduction
445 19.2 Compounds that Impact Lysosomal Function
446 19.2.1 Lysosomotropic Compounds
446 19.2.2 Nonlysosomotropic Compounds
451 19.3 Cellular Consequences
452 19.3.1 Effect of Drugs on pH and Lysosomal Volume
452 19.3.2 Effects on Lysosomal Enzymes
453 19.3.3 Lysosomal Substrate Accumulation
454 19.3.4 Lysosomal Membrane Permeabilization (LMP) and Cell Death
454 19.3.5 Membrane Trafficking Changes
455 19.3.6 Other Cellular Impacts
458 19.4 Impaired Lysosomal Function as a Mechanism for Organ Toxicity
461 19.4.1 Liver Toxicity
462 19.4.2 Kidney Toxicity
464 19.4.3 Retinal
466 19.4.4 Peripheral Neuropathy
466 19.4.5 Muscle Toxicity
467 19.4.6 Tumorigenesis
468 19.4.7 General Considerations for Organ Toxicity
469 19.5 Concluding Remarks
471 References
472 20 Lysosomes and Phospholipidosis in Drug Development and Regulation 487 James M. Willard and Albert De Felice 20.1 Introduction
487 20.2 FDA Involvement
488 20.3 Autophagy and DIPL
489 20.4 Early Experience with Lethal DIPL
489 20.5 Clinical and Nonclinical Expressions of DIPL
490 20.5.1 Clinical
490 20.5.2 Nonclinical
491 20.6 Physical Chemistry
491 20.7 Quantitative Structure-Activity Relationship (QSAR)
492 20.8 Toxicogenomics
493 20.9 Fluorescence
Dye
and Immunohistochemical Methods for Screening
494 20.10 FDA Database and QSAR Modeling
494 20.11 Linking Phospholipidosis and Overt Toxicity
494 20.12 Phospholipidosis and QT Interval Prolongation
496 20.13 DIPL Mechanisms
500 20.14 Treatment
501 20.15 Discussion
501 20.16 Future Directions and Recommendations
505 References
506 INDEX 513
2 References
4 2 Lysosome Biogenesis and Autophagy 7 Fulvio Reggiori and Judith Klumperman 2.1 Introduction
7 2.2 Pathways to the Lysosomes
10 2.2.1 Biosynthetic Transport Routes to the Lysosome
10 2.2.2 Endocytic Pathways to the Lysosome
10 2.2.3 Autophagy Pathways to the Lysosome
12 2.2.4 The ATG Proteins: The Key Regulators of Autophagy
14 2.3 Fusion and Fission between the Endolysosomal and Autophagy Pathways
16 2.3.1 Recycling Endosomes and Autophagosome Biogenesis
16 2.3.2 Autophagosome Fusion with Late Endosomes and Lysosomes
17 2.3.3 Autophagic Lysosomal Reformation
18 2.4 Diseases
19 2.4.1 Lysosome-Related Disorders (LSDs)
19 2.4.2 Lysosomes in Neurodegeneration and Its Links to Autophagy
20 2.4.3 Autophagy-Related Diseases
20 2.5 Concluding Remarks
22 Acknowledgments
23 References
23 3 Multivesicular Bodies: Roles in Intracellular and Intercellular Signaling 33 Emily R. Eden
Thomas Burgoyne
and Clare E. Futter 3.1 Introduction
33 3.2 Downregulation of Signaling by Sorting onto ILVs
35 3.3 Upregulation of Signaling by Sorting onto ILVs
38 3.4 Intercellular Signaling Dependent on Sorting onto ILVs
39 3.5 Conclusion
44 References
45 4 Lysosomes and Mitophagy 51 Dominik Haddad and Patrik Verstreken 4.1 Summary
51 4.2 Mitochondrial Significance
51 4.3 History of Mitophagy
52 4.4 Mechanisms of Mitophagy
53 4.4.1 Mitophagy in Yeast
54 4.4.2 Mitophagy in Mammals
55 4.5 Conclusion
57 Acknowledgments
57 References
58 5 Lysosome Exocytosis and Membrane Repair 63 Rajesh K. Singh and Abigail S. Haka 5.1 Introduction
63 5.2 Functions of Lysosome Exocytosis
63 5.2.1 Specialized Lysosome-Related Organelles
64 5.2.2 Lysosome Exocytosis for Membrane Repair
65 5.2.3 Lysosome Exocytosis as a Source of Membrane
66 5.2.4 Lysosome Exocytosis for Extracellular Degradation
66 5.2.5 Lysosome Exocytosis and Delivery of Proteins to the Cell Surface
68 5.3 Mechanisms of Lysosome Exocytosis
68 5.3.1 Maturation of Lysosomes and Lysosome-Related Organelles
69 5.3.2 Transport of Lysosomes to the Plasma Membrane
70 5.3.3 Tethering of Lysosomes to the Plasma Membrane
72 5.3.4 Lysosome Fusion with the Plasma Membrane
75 5.3.5 Calcium-Dependent Exocytosis
76 5.4 Conclusion
76 Acknowledgments
77 References
77 6 Role of Lysosomes in Lipid Metabolism 87 Frederick R. Maxfield 6.1 Introduction
87 6.2 Endocytic Uptake of Lipoproteins
88 6.3 Lipid Metabolism in Late Endosomes and Lysosomes
91 6.4 Autophagy and Lysosomal Lipid Turnover
94 6.5 Lysosomal Lipid Hydrolysis and Metabolic Regulation
95 6.6 Summary
96 References
96 7 TFEB
Master Regulator of Cellular Clearance 101 Graciana Diez-Roux and Andrea Ballabio 7.1 Lysosome
101 7.2 The Transcriptional Regulation of Lysosomal Function
102 7.3 TFEB Subcellular Regulation is Regulated by Its Phosphorylation
104 7.4 A Lysosome-to-Nucleus Signaling Mechanism
105 7.5 TFEB and Cellular Clearance in Human Disease
106 7.5.1 Lysosomal Storage Disorders
107 7.5.2 Neurodegenerative Disorders
109 7.5.3 Metabolic Syndrome
110 7.5.4 Cancer
Inborn Errors of Metabolism
Immunity
and Longevity
110 References
111 8 Lysosomal Membrane Permeabilization in Cell Death 115 Urska Repnik and Boris Turk 8.1 Introduction
115 8.2 Cell Death Modalities
116 8.3 Lysosomal Membrane Permeabilization (LMP) and Cell Death
117 8.3.1 Mechanisms of LMP
118 8.3.2 Upstream of LMP: Direct Insult Versus Molecular Signaling
121 8.3.3 Signaling Downstream of LMP
124 8.4 Conclusion
127 Acknowledgments
127 References
128 9 The Lysosome in Aging-Related Neurodegenerative Diseases 137 Ralph A. Nixon 9.1 Introduction
137 9.2 Lysosome Function in Aging Organisms
139 9.3 Lysosomes and Diseases of Late Age Onset
142 9.3.1 Cardiovascular Disease
142 9.4 Lysosomes in Aging-Related Neurodegenerative Diseases
144 9.4.1 Alzheimer's Disease (AD)
145 9.4.2 Parkinson's Disease and Related Disorders
150 9.4.3 Diffuse Lewy Body Disease (DLB)
155 9.4.4 Frontotemporal Lobar Degeneration (FTLD)
155 9.5 Conclusion
158 Acknowledgments
158 References
159 10 Lysosome and Cancer 181 Marja Jäättelä and Tuula Kallunki 10.1 Introduction
181 10.2 Lysosomal Function and Its Importance for Cancer Development and Progression
181 10.3 Cancer-Induced Changes in Lysosomal Function
182 10.3.1 Increased Activity of Lysosomal Enzymes
182 10.3.2 Altered Lysosome Membrane Permeability
184 10.3.3 Increased Lysosome Size
184 10.3.4 Altered Lysosome Trafficking - Increased Lysosomal Exocytosis
185 10.4 Cancer-Induced Changes in Lysosome Composition
185 10.4.1 Changes in Lysosomal Hydrolases
185 10.4.2 Changes in the Lysosomal Membrane Proteins
192 10.5 Molecular Changes Involving Lysosomal Integrity
193 10.5.1 Cancer-Associated Changes in Lysosomal Sphingolipid Metabolism
193 10.5.2 Targeting Lysosomal Membrane Integrity
195 10.6 Conclusion
196 References
197 11 The Genetics of Sphingolipid Hydrolases and Sphingolipid Storage Diseases 209 Edward H. Schuchman and Calogera M. Simonaro 11.1 Introduction and Overview
209 11.2 Acid Ceramidase Deficiency: Farber Disease
210 11.3 Acid Sphingomyelinase Deficiency: Types A and B Niemann-Pick Disease
213 11.4 Beta-Glucocerebrosidase Deficiency: Gaucher Disease
215 11.5 Galactocerebrosidase Deficiency: Krabbe Disease/Globoid Cell Leukodystrophy
218 11.6 Arylsulfatase a Deficiency: Metachromatic Leukodystrophy
219 11.7 Alpha-Galactosidase a Deficiency: Fabry Disease
221 11.8 Beta-Galactosidase Deficiency: GM1 Gangliosidosis
224 11.9 Hexosaminidase A and B Deficiency: GM2 Gangliosidoses
226 11.10 Sphingolipid Activator Proteins
229 References
231 12 Lysosome-Related Organelles: Modifications of the Lysosome Paradigm 239 Adriana R. Mantegazza and Michael S. Marks 12.1 Differences Between LROs and Secretory Granules
240 12.2 Physiological Functions of LROs
240 12.3 LRO Biogenesis
244 12.3.1 Chediak-Higashi Syndrome and Gray Platelet Syndrome
244 12.3.2 Hermansky-Pudlak Syndrome
246 12.3.3 Melanosome Biogenesis
247 12.3.4 HPS and Melanosome Maturation
248 12.3.5 HPS and the Biogenesis of Other LROs
250 12.3.6 HPS and Neurosecretory Granule Biogenesis
250 12.3.7 Weibel-Palade Body Biogenesis
251 12.4 LRO Motility
Docking
and Secretion
252 12.5 LROs and Immunity to Pathogens
253 12.5.1 Cytolytic Granules
253 12.5.2 Familial Hemophagocytic Lymphohistiocytosis and Cytolytic Granule Secretion
254 12.5.3 Azurophilic Granules
255 12.5.4 NADPH Oxidase-Containing LROs
255 12.5.5 IRF7-Signaling LROs and Type I Interferon Induction
256 12.5.6 MIICs: LROs or Conventional Late Endosome/Lysosomes?
256 12.5.7 Phagosomes and Autophagosomes as New Candidate LROs
258 12.6 Perspectives
260 Acknowledgments
260 References
260 13 Autophagy Inhibition as a Strategy for Cancer Therapy 279 Xiaohong Ma
Shengfu Piao
Quentin Mcafee
and Ravi K. Amaravadi 13.1 Stages and Steps of Autophagy
282 13.2 Induction of Autophagy
283 13.3 Studies in Mouse Models Unravel the Dual Roles of Autophagy in Tumor Biology
285 13.4 Clinical Studies on Autophagy's Dual Role in Tumorigenesis
286 13.5 Mouse Models Provide the Rationale for Autophagy Modulation in the Context of Cancer Therapy
288 13.6 Multiple Druggable Targets in the Autophagy Pathway
291 13.7 Overview of Preclinical Autophagy Inhibitors and Evidence Supporting Combination with Existing and New Anticancer Agents
292 13.8 Proximal Autophagy Inhibitors
293 13.9 Quinolines: From Antimalarials to Prototypical Distal Autophagy Inhibitors
293 13.10 Summary for the Clinical Trials for CQ/HCQ
295 13.11 Developing More Potent Anticancer Autophagy Inhibitors
298 13.12 Summary
Conclusion
and Future Directions
300 13.13 In Summary
302 References
302 14 Autophagy Enhancers
are we there Yet? 315 Shuyan Lu and Ralph A. Nixon 14.1 Introduction
315 14.2 Autophagy Impairment and Diseases
316 14.3 Autophagy Enhancer Screening
317 14.3.1 Methods for Monitoring Autophagy
317 14.3.2 Autophagy Enhancers Identified from Early Literature
326 14.3.3 mTOR Inhibitors
331 14.4 Other Agents that Boost Autophagy and Lysosomal Functions
335 14.4.1 HDAC Inhibition
336 14.4.2 pH Restoration
337 14.4.3 TRP Activator
337 14.4.4 TFEB Overexpression/Activation
338 14.4.5 Lysosomal Efficiency
338 14.4.6 MicroRNA
339 14.5 Concluding Remarks
340 References
341 15 Pharmacological Chaperones as Potential Therapeutics for Lysosomal Storage Disorders: Preclinical Research to Clinical Studies 357 Robert E. Boyd
Elfrida R. Benjamin
Su Xu
Richie Khanna
and Kenneth J. Valenzano 15.1 Introduction
357 15.2 Fabry Disease
359 15.3 Gaucher Disease
363 15.4 GM2 Gangliosidoses (Tay-Sachs/Sandhoff Diseases)
367 15.5 Pompe Disease
368 15.6 PC-ERT Combination Therapy
370 References
372 16 Endosomal Escape Pathways for Delivery of Biologics 383 Philip L. Leopold 16.1 Introduction
383 16.2 Endosome Characteristics
384 16.3 Delivery of Nature's Biologics: Lessons on Endosomal Escape from Pathogens
389 16.3.1 Viruses
390 16.3.2 Bacteria
Protozoa
and Fungi
392 16.3.3 Toxins
394 16.4 Endosomal Escape Using Engineered Systems
395 16.4.1 Peptides and Polymers
396 16.4.2 Lipids
398 16.4.3 Other Chemical and Physical Strategies
399 16.5 Conclusion
399 References
400 17 Lysosomes and Antibody-Drug Conjugates 409 Michelle Mack
Jennifer Kahler
Boris Shor
Michael Ritchie
Maureen Dougher
Matthew Sung
and Puja Sapra 17.1 Introduction
409 17.2 Receptor Internalization
410 17.3 Antibody-Drug Conjugates
413 17.4 Mechanisms of Resistance to ADCs
416 17.5 Summary
417 References
417 18 The Mechanisms and Therapeutic Consequences of Amine-Containing Drug Sequestration in Lysosomes 423 Nadia Hamid and Jeffrey P. Krise 18.1 Introduction
423 18.2 Lysosomal Trapping Overview
424 18.3 Techniques to Assess Lysosomal Trapping
427 18.4 Influence of Lysosomotropism on Drug Activity
429 18.5 Influence of Lysosomal Trapping on Pharmacokinetics
435 18.6 Pharmacokinetic Drug-Drug Interactions Involving Lysosomes
438 References
440 19 Lysosome Dysfunction: an Emerging Mechanism of Xenobiotic-Induced Toxicity 445 Shuyan Lu
Bart Jessen
Yvonne Will
and Greg Stevens 19.1 Introduction
445 19.2 Compounds that Impact Lysosomal Function
446 19.2.1 Lysosomotropic Compounds
446 19.2.2 Nonlysosomotropic Compounds
451 19.3 Cellular Consequences
452 19.3.1 Effect of Drugs on pH and Lysosomal Volume
452 19.3.2 Effects on Lysosomal Enzymes
453 19.3.3 Lysosomal Substrate Accumulation
454 19.3.4 Lysosomal Membrane Permeabilization (LMP) and Cell Death
454 19.3.5 Membrane Trafficking Changes
455 19.3.6 Other Cellular Impacts
458 19.4 Impaired Lysosomal Function as a Mechanism for Organ Toxicity
461 19.4.1 Liver Toxicity
462 19.4.2 Kidney Toxicity
464 19.4.3 Retinal
466 19.4.4 Peripheral Neuropathy
466 19.4.5 Muscle Toxicity
467 19.4.6 Tumorigenesis
468 19.4.7 General Considerations for Organ Toxicity
469 19.5 Concluding Remarks
471 References
472 20 Lysosomes and Phospholipidosis in Drug Development and Regulation 487 James M. Willard and Albert De Felice 20.1 Introduction
487 20.2 FDA Involvement
488 20.3 Autophagy and DIPL
489 20.4 Early Experience with Lethal DIPL
489 20.5 Clinical and Nonclinical Expressions of DIPL
490 20.5.1 Clinical
490 20.5.2 Nonclinical
491 20.6 Physical Chemistry
491 20.7 Quantitative Structure-Activity Relationship (QSAR)
492 20.8 Toxicogenomics
493 20.9 Fluorescence
Dye
and Immunohistochemical Methods for Screening
494 20.10 FDA Database and QSAR Modeling
494 20.11 Linking Phospholipidosis and Overt Toxicity
494 20.12 Phospholipidosis and QT Interval Prolongation
496 20.13 DIPL Mechanisms
500 20.14 Treatment
501 20.15 Discussion
501 20.16 Future Directions and Recommendations
505 References
506 INDEX 513