Apoptotis: Pharmacological Implications and Therapeutic Opportunities (eBook)

Front Cover 1
Apoptosis: Pharmacological Implications and Therapeutic Opportunities 4
Copyright Page 5
Contents 8
Contributors 20
Foreword 24
Part 1: Biology of Cell Death 28
Chapter 1. Apoptosis: An Overview of the Process and Its Relevance in Disease 28
I. Introduction 28
ll. Morphology of Apoptosis 30
lll. Genetics and Biochemistry of Apoptosis 33
IV. Apoptosis as a Therapeutic Target 50
V. Conclusion 54
References 55
Chapter 2. Genetics of Apoptosis 62
I. Introduction 62
II. Programmed Cell Death Pathway in C. elegans 63
III. Apoptosis in Drosophila melanogaster 70
VI. Apoptosis in Mammals 72
V. Viral Genes Involved in Host Cell Apoptosis 74
VI. Programmed Cell Death in Unicellular Organisms 76
VII. Conclusion 78
References 79
Chapter 3. Methods Utilized in the Study of Apoptosis 84
I. Introduction 84
ll. Detection of PCD Based on Morphology 85
lll. Detection of DNA Fragmentation 88
IV. Terminal Deoxyribonucleotidyl Transferase-Mediated dUTP Nick end Labeling (TUNEL) 93
V. Flow Cytometry 95
VI. Annexin V Staining 99
VII. Alterations in Plasma Membrane Permeability 100
VIII. Enzyme Assays 101
IX. Use of Inhibitors to Study Apoptotic Processes 103
Chapter 4. In Vitro Systems for the Study of Apoptosis 116
I. Introduction of Cell-Free Systems for Apoptosis Studies 116
ll. Examples of Cell-Free Systems 118
lll. Criteria for Relevant Systems 122
IV. Biochemical Dissection of in Vitro Systems 124
V. Future Directions 130
References 131
Chapter 5. The Fas Pathway in Apoptosis 134
I. Introduction 134
ll. Fas 135
lll. Fas Ligand 136
IV. Regulatory Roles of Fas and FasL 137
V. Signaling from the Fas Receptor 141
VI. Fas/FasL-Associated Disease States 146
VII. Modulating Fas and/or FasL for Therapeutic Purposes 150
VIII. Conclusion 153
References 154
Chapter 6. Ceramide: A Novel Lipid Mediator of Apoptosis 160
I. Introduction 160
ll. The Sphingomyelin Cycle 161
lll. Apoptosis 164
IV. Conclusions and Prospects for the Future 175
References 178
Chapter 7. Control of Apoptosis by Proteases 182
I. Introduction 182
ll. The ICE/CED-3 Family of Proteases 183
lll. Other Proteases Implicated in Apoptosis 194
IV. Proteases as Therapeutic Targets in Apoptosis 197
References 199
Part 2: Apoptosis under Physiologic Conditions 206
Chapter 8. Death and Dying in the Immune System 206
I. Death 206
ll. Dying 219
lll. Summary 233
References 235
Chapter 9. Control of Apoptosis by Cytokines 246
I. Introduction 246
ll. Cytokines and Survival 247
lll. Hematopoietic Growth Factors/Cytokines and Antiapoptotic Signals 250
IV. Unresolved Issues Concerning Apoptotic Signals 263
V. Novel Therapeutic Strategies Targeting Apoptosis: Tipping the Balance 264
References 266
Chapter 10. Glucocorticoid-Induced Apoptosis 274
I. Introduction 274
ll. The Decision to Die: Role of the Glucocorticoid Receptor and Glucocorticoid-Regulated Gens 276
Ill. The Decision to Die: Cell Cycle Arrest and Mtabolic Changs 279
IV. The Decision to Die: Regulation by Cytokines and T Cell Receptor 280
V. Execution Phase: Role of Proteases 281
VI. Execution and Degradation: Role of Calcium 282
VII. Execution and Degradation: Role of Oxygen Radicals 285
VIII. Execution Phase: Bcl-2 and p53 286
IX. Engulfment 287
X. Degradation: Morphological Changes 287
XI. Degradation: Endonuclease Activation and DNA Fragmentation 288
XII. Defects in the Cell Death Pathway Associated with Glucocorticoid Resitance 290
XIII. New Research Questions and Therapeutic Possibilities 292
References 293
Part 3: Apoptosis in Pathologic States 298
Chapter 11. Apoptosis in AIDS 298
I. Introduction 298
ll. Animal Models and Human Studies of HIV-Induced CD4 T Cell Apoptosis 301
Ill. Mechanisms of CD4 T Cell Apoptosis Following HIV Infection 303
IV. Putting It All Together 314
References 316
Chapter 12. Virus-Induced Apoptosis 322
I. Introduction 322
ll. Inhibition of Virus-Induced Apoptosis 324
lll. Induction of Programmed Cell Death by Viruses 342
IV. Role of Apoptosis in Viral Pathogenesis 348
References 353
Chapter 13. Apoptosis in Neurodegenerative Diseases 364
I. Introduction 364
ll. Pathological Features of Neurodegenerative Diseases and Desorders 366
lll. Mechanisms for Cytotoxicity in Alzheimer’s Disease 371
IV. Closing Remarks 385
References 386
Chapter 14. Apoptosis in the Mammalian Kidney: Incidence, Effectors, and Molecular Control in Normal Development and Disease States 396
I. Introduction 396
ll. Apoptosis in Normal and Abnormal Renal Development 397
lll. Apoptosis and the Adult Kidney: Detection and Occurrence 400
IV. Apoptosis in Tubulointerstitial and Glomerular Diseases of the Kidney 401
V. Apoptosis in the Genesis and Resolution of Renal Neoplasms 429
VI. Molecular and Genetic Factors Involved in the Regulation of Renal Cell Apoptosis 404
VII. Summary 405
References 406
Chapter 15. Apoptosis in the Heart 410
I. Introduction 410
ll. Two Types of Cell Death–Necrosis and Apoptosis 411
lll. Cardiomyocyte Death in Development 415
IV. Cardiomyocyte Death in Ischemia and Reperfusion 416
V. Modification of Cardiomyocyte Death 429
VI. Perspective 431
References 432
Chapter 16. Apoptosis and the Gastrointestinal System 436
l. Introduction 436
ll. Liver 437
lll. Pancreas 443
IV. Small and Large Intestine 446
V. Esophagus, Stomach, and Duodenum 450
VI. A Vision for Apoptosis as a Therapeutic Target in GI Diseases 451
Part 4: Apoptosis in the pathogenesis and Treatment of Cancer 456
Chapter 17. Role of p53 in Apoptosis 456
I. Introduction 456
ll. The p53 Tumor Suppressor Gene 457
lll. p53-Mediated GI Arrest 458
IV. p53 and Cell Survival 464
V. Implications for Tumor Progression and Therapy 475
VI. Conclusion 479
References 479
Chapter 18. Chemotherapy-Induced Apoptosis 488
I. Introduction 488
ll. Induction of Apoptosis by Chemotherapeutic Agents 489
lll. Mechanisms of Induction of Apoptosis by Chemotherapeutic Drugs 495
IV. Issues for the Future 511
References 518
Chapter 19. Bcl-2 Family Proteins: Strategies for Overcoming Chemoresistance in Cancer 528
I. Introduction 528
ll. Bcl-2 Family Proteins as Determinants of Chemosensitivity 529
lll. Dysregulation of Bcl-2 Family Protein Production in Human Cance: Prognostic Implications 531
IV. Interactions among Bcl-2 Family Proteins 533
V. Potential Functions of Bcl-2 Family Proteins 537
VI. Bcl-2 Family Proteins as Pore Formers and Adaptor Proteins 541
VII. Posttranslational Modifications of Bcl-2 545
VIII. Are Tumor Cells More Dependent on Bcl-2 Than Normal Cells? 546
IX. Strategies for Inhibiting Bcl-2 Function in Cancers 548
References 549
Chapter 20. Role of Bcr-Abl Kinase in Resistance to Apoptosis 560
I. Introduction 560
ll. Chronic Myelogenous Leukemia 561
lll. Apoptosis: Role of Cellular and Viral Genes 562
IV. Abl Family of Tyrosine Kinases 564
V. Activated Forms of Abl and Suppression of Apoptosis 568
VI. Signaling Mechanism by which Bcr-Abl/v-Abl 571
VII. Novel Therapeutic Strategies Based on Interfering with the Exprsion or Activity of Bcr-Abl 574
VIII. Mechanism of Resistance to Apoptosis 575
References 576
Chapter 21. Apoptosis in Hormone-Responsive Malignancies 560
I. Introduction 560
ll. Breast Cancer 581
lll. Prostate Cancer 592
IV. Conclusions 605
References 606
Index 612
Contents of Previous Volumes 626