Apoptosis and Cancer Therapy: From Cutting-edge Science to Novel Therapeutic Concepts

APOPTOSIS AND CANCER THERAPY: FROM CUTTING-EDGE SCIENCE TO NOVEL THERAPEUTIC CONCEPTS......Page 1
Half-title......Page 2
Title Page......Page 4
Copyright Page......Page 5
Contents Volume I......Page 6
Preface......Page 20
Contributors......Page 22
Contents Volume II......Page 32
Part I: Death Receptor......Page 43
1.1 Introduction......Page 45
1.1.2 The Intrinsic Pathway – Mitochondrial Involvement in Apoptosis......Page 46
1.1.3 The Extrinsic Pathway – The Role of Death Receptors and their Ligands......Page 47
1.1.4 The CD95 System......Page 49
1.1.5 The Two-pathways Model for CD95 Signaling......Page 50
1.1.6 The Death Ligand – CD95L......Page 52
1.2.1 Resistance Mechanisms – Expression of Antiapoptotic Proteins......Page 55
1.3.1 Resistance Mechanisms – Mutations and Reduced Expression of CD95/CD95L......Page 56
1.3.2 Resistance Mechanisms – Induction of CD95/CD95L Signaling......Page 58
1.3.3 The CD95/CD95LSystem and Cancer Therapy......Page 59
2.1 Introduction......Page 73
2.2.2 The TRAIL-Receptors......Page 75
2.2.3 TRAIL-induced Signaling......Page 78
2.3.1 Expression of TRAIL and its Receptors......Page 87
2.3.2 Efficacy and Safety of Soluble Recombinant TRAIL......Page 91
2.3.3 Agonistic TRAIL-R1- and TRAIL-R2-specific Monoclonal Antibodies......Page 94
2.3.4 TRAIL Gene Therapy......Page 96
2.3.5 Tumor-specific TRAIL Sensitization by Combinatorial Therapy......Page 97
2.4 The Physiological Role of the TRAIL System......Page 103
2.4.1 TRAIL and T cells......Page 104
2.4.2 TRAIL and Immune Surveillance of Cancer......Page 105
2.4.3 TRAIL and Viral Infections......Page 108
2.4.4 Role of TRAIL in Immunopathologies, Autoimmune Diseases and Negative Selection......Page 111
2.4.5 TRAIL in Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)......Page 113
2.5 Concluding Remarks......Page 116
3.1.1 The Tumor Necrosis Factor (TNF)–TNF Receptor (TNF-R) System......Page 135
3.1.2 TNF-R1 and TNF-R2 Belong to Different Subgroups of the TNF Receptor Family......Page 137
3.2.1 TNF-R1Triggers NF-κB Activation and Apoptosis Induction......Page 138
3.2.2 TNF-R1 Induces Apoptosis by a Fas-associated Death Domain (FADD)- and Caspase-8-dependent Pathway......Page 141
3.3.1 Apoptotic TNF Receptor Crosstalk......Page 146
3.3.2 TNF-R2-induced Apoptosis......Page 148
3.4.1 TNF-induced NF-κB Signaling Interferes with Prolonged JNK Activation......Page 149
3.4.3 Targets of Proapoptotic JNK Signaling......Page 150
3.5 TNF-induced Necrosis......Page 151
3.6 TNF in Tumor Therapy......Page 154
4.1 Introduction......Page 162
4.2 Structure of c-FLIPs......Page 163
4.3.1 c-FLIP L – a caspase-8/-10 Inhibitor or Activator?......Page 165
4.3.2 c-FLIP L immune and Nonimmune Functions......Page 166
4.4 Regulation of c-FLIP Expression......Page 171
4.5 c-FLIP and Human Diseases......Page 172
4.6 c-FLIP and Cancer......Page 182
4.7 Conclusions......Page 184
5.1 Dependence Receptors: Apoptosis when Unbound......Page 199
5.1.1 p75^NTR: The First Dependence Receptor Described......Page 201
5.1.2 The Putative Tumor Suppressor and Axon Guidance-related Receptor DCC......Page 202
5.1.4 Neogenin: A DCC Homolog Joins the Family......Page 204
5.1.6 Integrins as Dependence Receptors......Page 205
5.1.8 AR: A Nuclear Dependence Receptor......Page 206
5.2 Dependence Receptors: To Get Caspase Amplification......Page 207
5.3 Dependence Receptors: Patterning during Neural Development......Page 212
5.4 Dependence Receptors: Conditional Tumor Suppressors......Page 214
5.5 Concluding Remarks......Page 221
Part II: Mitochondria......Page 225
Xavier Saelens, Nele Festjens, Lieselotte Vande Walle and Peter Vandenabeele......Page 227
6.1 Introduction......Page 228
6.2 Bcl-2 Family Proteins and Mitochondrial Membrane Permeabilization......Page 229
6.3 Mutations in the Intrinsic Apoptotic Pathway Contributing to Cancer......Page 231
6.4 Cytochrome c......Page 232
6.5 Cytochrome c Release: A Point of No Return?......Page 237
6.6.1 Smac/DIABLO......Page 239
6.6.2 HtrA2/OMI......Page 243
6.6.3 ARTS......Page 246
6.6.4 AIF......Page 247
6.6.5 EndoG......Page 250
6.7 Other Mitochondrial Factors Released During Apoptosis......Page 251
6.8 Conclusions and Perspectives......Page 252
7.1 Introduction......Page 264
7.2 Structure and Properties of Omi/HtrA2......Page 266
7.3 Cell Death Regulation by Omi/HtrA2......Page 267
7.4 Omi/HtrA2 Mutant Mice......Page 269
7.5 Omi/HtrA2 and Cancer Therapy......Page 270
7.6 Conclusions......Page 271
8.1 Introduction......Page 275
8.2 AIF Expression, Structure and Localization......Page 276
8.2.1 Isoforms......Page 278
8.2.2 Nonmammalian Orthologs and Mammalian Homologs......Page 279
8.3.1 Cell-free Systems......Page 280
8.3.3 Downregulation of AIF......Page 281
8.4.1 How is AIF Released?......Page 283
8.4.2 Are Caspases Required?......Page 285
8.4.3 When is AIF Released?......Page 286
8.4.4 Hsp70......Page 287
8.5.1 EndoG......Page 288
8.6.1 Radical Scavenger and/or Maintenance Factor in the Respiratory Chain......Page 289
8.6.3 AIF is a Bifunctional Protein......Page 290
8.7.2 AIF in Acute Cell Loss......Page 291
8.8 Concluding Remarks......Page 292
Part III: Effector Systems......Page 299
9.1 Introduction......Page 301
9.2 Caspases: Ubiquitous Mediators of Apoptotic Cell Death…And More......Page 302
9.3 Caspase Structure and Classification......Page 304
9.4 Catalytic Properties of Caspases......Page 305
9.5.1 Biochemical Mechanisms of Executioner Caspase Activation......Page 307
9.5.2 Biochemical Mechanisms of Initiator Caspase Activation......Page 308
9.6.1 The Mitochondrial Apoptosome Pathway......Page 309
9.6.5 The Inflammasome......Page 311
9.7.1 Amplification of Apoptosis by Activation of the Apoptosome Cascade: Role of Bid......Page 312
9.7.2 Nuclear Changes during Apoptosis......Page 313
9.7.5 Cell Rounding and Blebbing......Page 314
9.8.1 Caspases and Apoptosis: Initiator Caspase-9......Page 315
9.8.3 Caspases and Apoptosis: Initiator Caspase-8......Page 316
9.8.4 Primacy or Redundancy of Caspase-3 in Apoptotic Execution?......Page 317
9.8.5 Physiological Roles of the Inflammatory Caspases......Page 318
9.9 Deregulation of Caspases in Cancer......Page 319
9.10 Harnessing Caspase Activation in Anticancer Therapy......Page 320
Kelvin Cain......Page 324
10.1 Introduction......Page 325
10.2 Cytochrome c: The Intracellular Signal for Apoptosome Formation......Page 327
10.3 Domains of Apaf-1: The Building Block of the Apoptosome......Page 330
10.4 Activation of Apaf-1 and Apoptosome Formation Requires Adenine Nucleotides and Cytochrome c......Page 332
10.5 Assembly and Composition of the Apoptosome......Page 334
10.6 The Apoptosome Processes and Activates Caspase-9 and the Effector Caspases......Page 336
10.7 Physiological Mechanisms that Regulate the Apoptosome......Page 338
10.8 Apaf-1 and Apoptosome Function are Essential for Embryonic Development......Page 340
10.9 The Role of the Apoptosome in Cancer Therapy......Page 341
10.10 Apoptosome and Caspase-independent Cell Death......Page 344
10.11 The Effect of Small Molecules on Apoptosome Formation and Function......Page 345
10.12 Is the Apoptosome a Good Target for Cancer Therapy?......Page 346
Part IV: Bcl-2 Family......Page 357
11.1 Introduction......Page 359
11.2 Tools of the Trade: The Cell Death Machinery......Page 362
11.3.1 Prosurvival Bcl-2 Family Members......Page 364
11.3.2 Multi-BH Domain Proapoptotic Bcl-2 Family Members are Essential for Apoptosis......Page 367
11.3.3 BH3-only Proteins are Sensors of Cellular Stress Essential for Apoptosis Initiation......Page 369
11.3.4 The Balance between Pro- and Antiapoptotic Bcl-2 Family Members Determines Cell Fate......Page 372
11.3.5 Bcl-2 Family Members Function Downstream of Tumor Suppressor Pathways......Page 373
11.4.1 Role of prosurvival Bcl-2 Family Members in Tumorigenesis......Page 374
11.4.3 Contribution of Loss of BH3-only Proteins to Tumorigenesis......Page 376
11.5 Bcl-2 Family Members Regulate Apoptotic Responses to Anticancer Agents......Page 377
11.6.2 RNA-mediated Gene Silencing – The Small Interfering RNA (siRNA) approach......Page 379
11.6.3 Translating Structural Knowledge to Rational Drug Design – Small-molecule Inhibitors and BH3 Mimetics......Page 380
11.7 Conclusions and Future Directions......Page 381
12.1 The Intrinsic Pathway of Apoptosis......Page 388
12.2 Mechanism of Mitochondrial Killing......Page 389
12.3 The Bcl-2 Family......Page 390
12.4 Multidomain Proapoptotic Proteins Bax and Bak......Page 391
12.4.1 Possible Redundancy of Bax/Bak-like Molecules......Page 392
12.4.2 Role of Bax in Mitochondrial Fission and Fusion......Page 393
12.5 Release of Mitochondrial Cytochrome c by Bcl-2 Family Proteins......Page 394
12.6.1 Multiplicity of BH3-only proteins......Page 395
12.7 A BH3-only Protein, Bid, That Can Interact with Both Pro- and Antiapoptotic Proteins......Page 396
12.8 Functional Interactions between BH3-only Proteins and Multidomain Bcl-2 Proteins......Page 398
12.9 Regulation of Bid......Page 399
12.10 The Physiological Role of Bid......Page 400
12.12 Mechanisms by which Bid Causes Cytochrome c Release......Page 402
12.13 Are Mitochondria Actually Required for Apoptosis?......Page 404
12.14 Bid, Bax and Bak – Localization and Function at other Intracellular Organelles......Page 405
12.15 Splice Variants of Bax, Bak and Bid......Page 406
12.16 Bax, Bak and Bid in Cancer......Page 407
12.17 Therapeutic Opportunities......Page 408
13.1 Introduction......Page 421
13.1.1 Regulation of p53 Function......Page 422
13.1.2 Cell Fate Decisions by p53......Page 423
13.2 p53 and Cell Death Signaling......Page 424
13.2.2 p53 Induces Cell Death Mainly via Activation of the Bcl-2-regulated Cell Death Pathway......Page 425
13.3.1 Puma and Noxa: Two Brothers in Arms......Page 427
13.3.2 Molecular Mechanisms of Puma-induced Apoptosis......Page 430
13.3.3 Noxa/APR......Page 431
13.4 Lessons from Animal Models – When the Cat is Away…......Page 432
13.4.1 Does p53-mediated Tumor Suppression Depend on Puma or Noxa?......Page 434
13.4.2 Is Loss of Puma or Noxa Selected for during Tumorigenesis in Humans?......Page 436
Part V: IAPs......Page 445
14.1 Introduction......Page 447
14.2.1 Apoptotic Pathways......Page 448
14.2.2 The IAP gene family......Page 449
14.2.3 The Mechanism of IAP Action......Page 451
14.3.1 Translational Regulation of IAPs......Page 454
14.3.2 Regulation by IAP-interacting Proteins......Page 456
14.3.3 IAP RING-mediated Ubiquitylation......Page 460
14.4 The Role of IAPs in Cancer......Page 461
14.4.1 Targeting IAPs in Cancer – Proof of Principle Studies......Page 462
14.5 Concluding Remarks......Page 463
15.1 Introduction – Apoptotic Pathways......Page 469
15.2 Survivin Structure–Function......Page 470
15.3 Role of Survivin in Cell Division......Page 471
15.4 Role of Survivin in Apoptosis Inhibition......Page 473
15.5 Translational Targeting of the Survivin Pathway in Cancer......Page 475
15.6 Concluding Remarks......Page 477
Part VI: Survival Pathways......Page 485
16.1 Family Members......Page 487
16.2 Regulation by the IκB Kinase (IKK) Complex......Page 488
16.3 NF-κB and Regulation of Apoptosis......Page 489
16.4 Survival Mechanisms......Page 491
16.5 NF-κB in Tumorigenesis......Page 494
16.6 Lessons from In Vivo Studies using Genetic and Pharmacologic Tumor Models......Page 495
16.7 NF-κB as a Target for Tumor Therapy......Page 498
17.1 Introduction......Page 504
17.1.1 A Brief History......Page 505
17.2 PKB: A Member of the “AGC” Kinase Subfamily......Page 506
17.3 DNA-dependent Protein Kinase (DNA-PK) is a PKB Kinase......Page 508
17.4 Mammalian Target of Rapamycin (mTOR) – Another PKB Kinase......Page 509
17.5.3 TCL1......Page 511
17.6.1 Cell Death Machinery......Page 512
17.6.2 Transcription Factor Control......Page 513
17.7.1 Cell Cycle Inhibitors p21^Waf1/Cip1 and p27^Kip1......Page 515
17.7.2 MDM2......Page 516
17.8.1 Hexokinase......Page 517
17.8.2 GSK-3......Page 518
17.8.3 PKB, GSK-3 and the Wnt Pathway......Page 519
17.9 PKB Inhibits Transforming Growth Factor (TGF)-β Signaling......Page 521
17.10.1 Huntingtin......Page 522
17.11 Conclusions......Page 523
18.1 Introduction......Page 532
18.2.1 Ras-dependent Protection against Apoptosis......Page 534
18.2.2 Survival Control by Raf Kinases......Page 536
18.3 Conclusions......Page 548
Part VII: Oncogenes/Tumor Suppressor Genes......Page 557
19.1 Introduction......Page 559
19.2 Proapoptotic p53 Signaling I: Transcriptional Activities......Page 561
19.3 Proapoptotic p53 Signaling II: Nontranscriptional Activities......Page 564
19.4 Integration of Transcriptional and Nontranscriptional Proapoptotic p53 Activities......Page 566
19.5 Added Complexity: Antiapoptotic p53 Signaling......Page 570
19.6 Integration of Anti- and Proapoptotic p53 Activities......Page 571
19.7 Mutant p53 Signaling......Page 572
19.8 Concluding Remarks......Page 573
20.1 Introduction......Page 578
20.2.1 Role of Post-translational Modifications......Page 580
20.2.2 Changes in Subcellular Localization......Page 581
20.2.3 p73 Protein Interactors and Regulators......Page 582
20.3 Proapoptotic Mechanisms Elicited by p73......Page 584
20.4.1 Disruption of the Balance between TAp73 and DNp73 Isoforms as a Determinant of Cancer Development......Page 585
20.4.2 Does the Internal Ribosome Entry Site (IRES)-dependent Translation of the p73 mRNA Lead to the Generation of a Transactivation-deficient p73 Protein?......Page 587
21.1 Introduction......Page 593
21.2 RB: A Tissue-specific Tumor-suppressor Gene......Page 595
21.3 The RB Gene Product......Page 596
21.5 Regulation of RB by Phosphorylation......Page 598
21.6.1 RB and Terminal Differentiation......Page 599
21.6.3 RB and Apoptosis......Page 600
21.7 RB-negative Cancer Cells are Hypersensitive to Chemotherapeutics......Page 601
21.9 Two Models for the Antiapoptotic Function of RB......Page 602
21.10 Apoptotic Defects Accompany RB Loss in Tumor Development......Page 603
21.12 Upregulation of RB in Sporadic Human Cancer Cells......Page 604
21.13 Summary and Future Prospects......Page 605
Part VIII: Modulators......Page 611
22.1 Introduction......Page 613
22.2 Major Forms of Cell Death......Page 614
22.3 The Regulation of Intracellular Ca 2+ Compartmentalization......Page 615
22.4 The ER, Ca 2+ and Apoptosis......Page 616
22.4.1 ER Stress......Page 617
22.5 Mitochondria, Ca 2+ and Apoptosis......Page 619
22.5.1 Mechanisms of Mitochondrial Permeabilization during Apoptosis......Page 620
22.6 Ca 2+-activated Effector Mechanisms......Page 622
22.6.3 Endonucleases......Page 623
22.6.6 Proteases......Page 624
22.7 Crosstalk between Caspases and Calpains in Regulation of Cell Death......Page 625
22.8 Caspases, Calpain and Intracellular Ion Homeostasis......Page 626
22.9 Effects of Bcl-2 Family Proteins on ER Ca 2+ Storage......Page 627
22.10 Ca 2+ and the Phagocytosis of Apoptotic Cells......Page 628
22.11 Calcium and Apoptosis in Cancer Cells......Page 629
22.12 Conclusions......Page 630
Part IX: Lysosomes and Nonapoptotic Pathways......Page 639
23.1 Introduction......Page 641
23.3 Trafficking To and From the Lysosomes......Page 642
23.3.1 The Endocytic Route......Page 643
23.3.2 The Biosynthetic Route......Page 644
23.3.3 Autophagic Route......Page 645
23.4 Lysosomal Involvement in PCD......Page 646
23.4.1 LMP and its Consequences......Page 647
23.4.2 LMP as a Trigger of the Mitochondrial Apoptosis Pathway......Page 648
23.4.4 Caspase-dependent and -independent Signaling to LMP......Page 650
23.5 Altered Lysosomal Function in Cancer Cells......Page 653
23.5.2 Immortalization and Transformation Sensitize Cells to the Lysosomal Death Pathway......Page 654
23.5.3 Hsp70 – The Guardian of Cancer Cell Lysosomes?......Page 656
23.5.4 Lysosomes as Targets for Future Cancer Therapy......Page 657
Part X: Phagocytosis/Clearance......Page 665
24.1 Introduction......Page 667
24.2.1 “Eat me” Signals, Bridging Proteins and Phagocyte Receptors......Page 668
24.2.2 “Don’t Eat Me” Signals......Page 673
24.2.3 “Find Me” Signals......Page 674
24.3 The Engulfment Machinery of C. elegans......Page 675
24.4 Postphagocytic Responses......Page 678
24.5 Apoptotic Cell Removal and Autoimmunity......Page 679
24.7 Conclusions......Page 681
25.1 Overview......Page 689
25.2 Mechanisms and Consequences of Macrophage-mediated Clearance of Apoptotic Cells in Tumors......Page 690
25.2.1 Evidence for Apoptotic Cell Clearance by Macrophages in the Tumor Microenvironment......Page 691
25.2.2 Interactions between Macrophages and Apoptotic Cells......Page 692
25.2.3 Macrophage Responses to Apoptotic Cells......Page 697
25.3.2 Interplay between Tumor Cells and TAMs......Page 700
25.4 Hypothesis: Apoptosis as a Primary Oncogenic Event?......Page 702
Part XI: Model Systems......Page 711
26.1 Introduction......Page 713
26.2 No All-in-one Models Anymore......Page 714
26.3 Mouse Models are Model Systems in Mice......Page 715
26.4 Genetic Engineering of the Model Mouse......Page 717
26.5 Milestone Cancer Models Based on Genetically Engineered Mice......Page 719
26.6 Mouse Models to Dissect the Pathways to Cancer......Page 722
26.7 Mouse Models to Exploit Treatment Sensitivity of Cancer......Page 723
26.8 Modeling Temporal and Spatial Complexities......Page 728
26.9 Imaging in Mouse Models......Page 730
26.10 Mouse Models as Complex Reporter Systems......Page 732
26.11 Mouse Models for Genetic Screenings......Page 733
26.12 Mice and Men … and Worms, Flies, Fish and Yeast......Page 734
26.13 Mice and the Web......Page 735
References......Page 736
Part XII: Molecular Diagnosis......Page 745
27.1 Introduction to Molecular Imaging and its Role in Cancer......Page 747
27.2 Imaging Modalities and Molecular Imaging Probes for the Study of Cancer......Page 750
27.2.1 Optical Imaging: Bioluminescence Imaging......Page 752
27.2.2 Optical Imaging: Fluorescent Imaging......Page 753
27.2.4 Nuclear Imaging (SPECT and PET)......Page 754
27.2.5 Multimodality Imaging......Page 755
27.3.1 Imaging p53......Page 756
27.3.3 Metastasis Angiogenesis and Tumor Invasion......Page 758
27.3.4 Apoptosis and Therapy Responsiveness......Page 760
27.4 Concluding Comments......Page 762
28.1 Introduction......Page 770
28.2.1 Ideal, Diffusion-independent Hybridization Kinetics......Page 773
28.2.2 Limitation of Microspot Reaction by Mass Flux to the Spot......Page 774
28.2.3 Mass Transport Limited Reaction Mechanisms......Page 775
28.2.4 The Importance of Mixing......Page 777
28.3.1 PCR Fragment Arrays......Page 778
28.3.2 Oligonucleotide Arrays......Page 779
28.3.3 Alternative DNA Microarray Platforms......Page 781
28.3.4 Antibody Microarray Formats......Page 782
28.5 Sample Collection Guidelines......Page 783
28.6 Data Analysis......Page 784
28.7 Screening, Prognosis and Diagnosis......Page 786
Part XIII: Cellular Stress, DNA Damage and Repair......Page 797
29.1 Pathways of Apoptosis......Page 799
29.2 Stress Signaling by the BH3-only Proteins......Page 804
29.3 Signaling by SAPKs......Page 808
29.4 Countering Apoptotic Responses......Page 810
29.5 Adapting to Stressful Situations......Page 811
29.6 Conclusion......Page 813
30.1 Introduction......Page 819
30.2 HIF......Page 823
30.3 BNip3 and BNip3-like (BNip3L)......Page 825
30.4 The p53 Tumor Suppressor Gene......Page 826
30.5 Unfolded Protein Response (UPR)......Page 831
31.1 Introduction......Page 841
31.2 Evidence that DNA Damage Triggers Apoptosis: Response of DNA Repair-defective Cells......Page 842
31.3 MGMT- and MMR-deficient (Tolerant) Cells: Evidence for Apoptosis Triggered by the Specific Lesion O6MeG......Page 843
31.4 Apoptosis in BER Mutants......Page 845
31.5 Apoptosis in NER Mutants......Page 847
31.6 Apoptosis Triggered by DNA Incorporated Gancyclovir (GCV)......Page 848
31.7 Are DNA DSBs the Ultimate Trigger of Apoptosis?......Page 849
31.8 Role of DRs in DNA Damage-triggered Apoptosis......Page 850
31.9 The Ataxia Telangiectasia Mutated Protein ATM and its related Protein ATR in Chk/p53 Signaling......Page 851
31.10 A Dual Role for p53 in Apoptosis......Page 854
31.11 Role of Caspase-2 in DNA Damage-induced Apoptosis......Page 855
31.12 Immediate Early cellular Responses: Fos/AP-1......Page 856
31.14 Conclusions......Page 857
32.1 Introduction......Page 864
32.2 Repair of Base Damage......Page 865
32.3 NER......Page 867
32.4 MMR......Page 870
32.5.1 Homology-directed Pathways......Page 873
32.5.2 NHEJ......Page 875
32.5.3 Surveillance of DSB Repair......Page 877
32.6 Novel Mechanisms......Page 882
32.6.2 Translesion Synthesis (TLS)......Page 883
32.7 Clinical Relevance......Page 884
Part XIV: Molecular Targets and Therapeutics......Page 889
33.1 Introduction......Page 891
33.2 Apoptosis Pathways......Page 892
33.4.1 The Death Receptor Pathway as a Target for Cancer Therapy......Page 893
33.4.3 IAPs as Targets for Cancer Therapy......Page 896
33.5 Conclusions......Page 898
34.1 Introduction......Page 904
34.2 Caspases: Catalysts of Death and Innate Immune Responses......Page 906
34.3 Biochemistry of Caspases......Page 907
34.4 Pharmacological Approaches of Caspase Inhibition......Page 911
34.5 Therapeutic Approaches Leading to Caspase Activation......Page 918
34.6 IAP-based Therapeutics......Page 920
34.7 Conclusions......Page 925
35.1 Introduction......Page 933
35.2 Novel Therapeutic Strategies for Tumors Carrying Wild-type p53......Page 935
35.3.1 Structural Studies of p53 and Classification of p53 Mutants......Page 939
35.3.3 Antibodies and Peptides that Modulate Mutant p53 Structure and Function......Page 941
35.3.4 Mutant p53 Reactivation by Low-molecular-weight Compounds......Page 943
35.3.5 Chemical Chaperones and Geldanamycin (GA)......Page 944
35.3.6 p53 Gene Therapy......Page 945
35.4 Combination Therapy Targeting the p53 Pathway......Page 946
35.4.2 Mutant p53 Reactivation and Cytostatic Drugs......Page 947
34.4.5 Synergies with PRIMA-1......Page 948
35.5 Conclusions......Page 949
36.1 Introduction......Page 955
36.2 Structural and functional features of IAP family members......Page 956
36.3 Evidence for a Role in Cancer......Page 959
36.4 Pharmaceutical Approaches to Target IAPs......Page 960
36.4.1 Small-molecule BIR3 Antagonists......Page 962
36.4.2 Targeting the BIR domain of ML-IAP......Page 965
36.4.4 Small-molecule BIR2 Antagonists......Page 966
37.1.1 The Heat Shock Protein 90 (Hsp90) Family: An Evolutionary Conserved Family of Molecular Chaperones......Page 975
37.1.2 Hsp90 Structure and Function......Page 976
37.1.3 Regulation of Hsp90 Expression......Page 978
37.1.4 The Hsp90 Chaperone Cycle......Page 980
37.2.2 Hsp90 Inhibitors......Page 983
37.2.3 Potential Application of Hsp90 Inhibitors in the Treatment of Cancer......Page 987
37.3 Molecular and Cellular Consequences of Hsp90 Inhibition......Page 988
37.3.1 The Apoptotic Pathway......Page 989
37.4.1 PI3K-mediated Survival Signaling......Page 991
37.4.2 Signaling through Ras/Raf/MEK......Page 994
37.5 Hsp90 and the Apoptotic Machinery......Page 995
37.6.1 Induction of Hsp27 Following Hsp90 Inhibition......Page 996
37.6.2 Induction of Hsp70 Expression Following Hsp90 Inhibition......Page 997
37.7 Summary......Page 1001
38.1 Regulation and Function of the Phosphoinositide-3-kinase (PI3K)/Akt/Mammalian Target of Rapamycin (mTOR) Pathway......Page 1008
38.2.2 Prognostic Significance of PI3K/Akt Pathway Activation......Page 1012
38.2.3 Mechanisms of Activation of the PI3K/Akt Pathway in Cancer......Page 1013
38.2.4 Activation of the PI3K/Akt Pathway is an Early Event in Tumorigenesis......Page 1016
38.3 Inhibition of PI3K/Akt/mTOR for Cancer Therapy......Page 1018
38.3.2 PI3K inhibitors......Page 1019
38.3.3 PDK-1 Inhibitors......Page 1023
38.3.4 Akt inhibitors......Page 1025
38.3.5 mTOR Inhibitors......Page 1028
38.4 Considerations in Developing Inhibitors of the PI3K/Akt/mTOR Pathway......Page 1030
38.4.1 Trial Design......Page 1031
38.4.2 Toxicities......Page 1032
38.5 Summary......Page 1033
39.1 Introduction......Page 1039
39.2 Ceramide in Apoptosis......Page 1040
39.3 Formation of Ceramide-enriched Membrane Platforms......Page 1044
39.4 Function of Ceramide-enriched Membrane Domains......Page 1046
39.5 Mitochondrial Ceramide-enriched Membrane Platforms......Page 1048
39.6 Summary and Perspectives......Page 1049
40.1 Chromatin Structure......Page 1056
40.2 HDACs and HATs......Page 1057
40.3 HAT and HDAC Alterations in Human Cancers......Page 1059
40.4 HDAC Inhibitors......Page 1060
40.5.1 In Vitro......Page 1063
40.5.2 In Vivo: Tumor-bearing Animals......Page 1067
40.5.3 Clinical Trials with HDAC Inhibitors......Page 1068
40.6 Conclusions and Perspectives......Page 1069
41.1 Introduction......Page 1075
41.2 Activating the p53 pathway......Page 1076
41.3 Overcoming IAP-mediated Protection from Apoptosis......Page 1078
41.4 Modulating Bcl-2 Family Member Activity......Page 1080
41.5.1 Platelet-derived Growth Factor (PDGF)......Page 1081
45.5.2 Epidermal Growth Factor Receptor (EGFR)/Phosphoinositide-3-kinase (PI3K)......Page 1082
41.6.2 APO-2L/TRAIL......Page 1083
41.7 Conclusion......Page 1085
42.1 Molecular Basis for the Biological Modulation of Radiation Response Pathways......Page 1091
42.2.1 Definitions......Page 1093
42.2.2 Radiation-induced Apoptosis......Page 1094
42.2.4 Necrosis......Page 1101
42.3 Relevance of Radiation-induced Cell Death for Radiation Sensitivity......Page 1102
42.3.1 Relevance of Apoptosis for Radiation Sensitivity......Page 1103
42.3.2 Role of Survival Pathways for Inhibition of Apoptosis and Radiation Resistance......Page 1105
42.3.3 Influence of Hypoxia on Sensitivity to Radiation-induced Cell Death......Page 1106
42.4.1 Direct Inducers of Apoptosis......Page 1107
42.4.2 Modulators of the Apoptotic Threshold......Page 1109
42.5 Relevance of Apoptosis for Radiation-induced Side-effects......Page 1118
42.6 Conclusions......Page 1119
43.1 What is Angiogenesis?......Page 1129
43.1.1 Genesis of Blood Vessels (Hemangiogenesis)......Page 1130
43.1.3 Tumor Hemangiogenesis......Page 1131
43.1.4 Tumor Lymphangiogenesis......Page 1132
43.2 Mechanisms of Hemangiogenesis......Page 1133
43.3.1 VEGF-A and its Receptors......Page 1134
43.3.2 Hypoxia-inducible Factors (HIFs)......Page 1136
43.3.3 Angiopoietins......Page 1137
43.3.4 Fibroblast Growth Factors (FGFs)......Page 1138
43.3.5 Ephrins and Eph Receptors......Page 1139
43.3.6 Integrins......Page 1140
43.4.2 Endogenous Inhibitors of Angiogenesis......Page 1141
43.4.3 Nonendogenous Inhibitors of Angiogenesis......Page 1142
43.5 Tumor Lymphangiogenesis......Page 1143
43.5.1 Animal Models of Tumor Lymphangiogenesis......Page 1144
43.5.2 Tumor Lymphangiogenesis in the Human......Page 1145
Index......Page 1149