Molecular Exploitation of Apoptosis Pathways in Prostate Cancer (Molecular Medicine and Medicinal Chemistry) 1st Edition

Molecular Exploitation of Apoptosis Pathways in Prostate 1st EditionThis book focuses on the functional significance of targeting apoptosis for the treatment of prostate cancer. New concepts on the challenges relating to the development of resistance by androgen-independent tumors are introduced, in terms of the contribution of anoikis and cross-talk of androgens with key growth factor signaling pathways.

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This volume also provides insightful discussion on the exploitation of the apoptotic and angiogenic synergism towards complete eradication of prostate tumors. Last but not least, it includes reflections on the drug development challenge based on analysis of data from existing clinical trials.

Molecular Exploitation of Apoptosis Pathways in Prostate 1st Edition
by Natasha Kyprianou (Author)
ISBN-13: 978-1848164499
ISBN-10: 1848164491

Molecular Exploitation of Apoptosis Pathways in Prostate 1st Edition – Content

Preface vii
Chapter 1 Introduction: Prostate Cancer 1
Chapter 2 The Prostate Gland Dynamics 13
Chapter 3 Apoptosis Pathways Signaling Execution of Cancer Cells 21
3.1 Cell Choices of Life and Death 21
3.1.1 “Classic” apoptosis 24
3.1.2 Anoikis 28
3.2 Caspases: The Apoptosis Executioners in a Therapeutic
Setting 28
3.3 The Mitochondrion: A Convenient Cell-Killing
Platform 32
3.4 Cell Surface Death Receptors and the FAS Ligand 33
3.5 Meet the BCL-2 Family: Governors of Cell Survival
and Death 33
3.6 The Transcriptional Controllers 36
3.7 The p53 Tumor Suppressor 37
3.8 PTEN/PI3K/AKT: The Downstream Intracellular
Players 38
3.9 The Antagonists of Death: Inhibitors of Apoptosis
Proteins (IAPs) 40
3.10 Apoptosis Signaling in the Endoplasmic Reticulum:
A Death Platform for Stress 41
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x Contents
3.11 The Tumor Microenvironment: Extracellular Forces
Control Intracellular Death Outcomes 43
3.11.1 Role of hypoxia 44
3.11.2 The key growth factors 44
3.11.3 Inflammation 48
Chapter 4 Androgen Receptor-Mediated Apoptosis: Significance in
Development of Castration-Resistant Prostate Cancer 53
4.1 The Androgen Receptor (AR) 53
4.2 Androgen Ablation: The Glory and the Failures 54
4.3 AR Status in Castration-Resistant Prostate Cancer 56
4.4 AR Interactions with Growth Factor Signaling Leads to
Apoptosis 58
4.4.1 AR connects with EGF 59
4.4.2 AR and IGF interactions 61
4.4.3 AR and TGF-β: partners in life and death
(of the cell) 62
4.4.4 AR and FGF interactions 67
4.4.5 AR and VEGF: Vascular exchanges for the “road” 68
4.4.6 AR and growth factor interplay in the stroma 69
Chapter 5 Anoikis in Prostate Cancer Metastasis 71
5.1 Anoikis Interrupted: Survival of the Homeless (Cells) 71
5.2 The Integrin Connection 73
5.3 Impairing the Route to Angiogenesis 75
5.3.1 Doxazosin 78
5.3.2 Suramin 79
5.3.3 Thalidomide 79
5.3.4 Bevacizumab 80
5.3.5 SU5416 80
5.4 Anoikis and the Tumor Microenvironment:
No “Resting” in the Stroma 80
5.5 Signaling the “Homeless” State: Intracellular
Anoikis Effectors 82
5.6 Significance of Apoptosis in Cytoskeleton and
Microtubule Targeting 88
5.7 Autophagy: The Cellular Benefits of Starving to
Death 91
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Contents xi
Chapter 6 Epithelial–Mesenchymal Transition (EMT) in Prostate
Cancer Metastasis 95
Chapter 7 Novel Molecular Therapeutics for Targeting
Castration-Resistant Prostate Cancer 103
7.1 Therapeutic Targeting of TGF-β Signaling 103
7.2 Exploitation of Quinazolines: Lifting Anoikis
Resistance to Impair Metastasis 107
7.3 Receptor Tyrosine Kinase Targeting 109
7.4 Histone Deacetylase Inhibitors (HDACs): Therapeutic
Inhibitors 110
7.5 Selective Death Action by Cancer-Specific PAR-4 in
Prostate Tumors 112
7.6 Death Synergy Between Proteosome and Death
Receptor Leads to Tumor Regression 113
7.7 The SERCA Pump as a Therapeutic Target 115
7.8 Endothelin-Receptor Antagonists 117
7.9 The Power of Sex Steroid Targeting 118
Chapter 8 Apoptotic-Based Molecular Markers of Therapeutic
Response 121
Chapter 9 Role of Apoptosis in Prostate Cancer Prevention 125
9.1 Aspirin and Non-Aspirin Nonsteroidal
Anti-Inflammatory Drugs (NSAIDs) 127
9.2 Statins 130
9.3 Antioxidants 131
9.4 5α-Reductase Inhibitors 134
Chapter 10 Summary and Future Directions 137
Bibliography 149
Abbreviations 211
Index 215
Acknowledgements 219

Molecular Exploitation of Apoptosis Pathways in Prostate 1st Edition – Introduction: Prostate Cancer 

Normal cellular physiology is a tightly regulated process, with positive and negative feedback loops that decide whether a cell should differentiate, divide, adapt to its microenvironment or commit suicidal death via apoptosis.

The biochemical events controlling the cellular responses during normal organ homeostasis and disease development involve post-translational modifications of newly synthesized proteins; functional interactions between enzymatic and structurally scaffolding proteins; sequestration within specialized subcellular compartments; intracellular transport; and secretion into the extracellular space targeting key biological processes such as cell growth, apoptosis, neovascularization, and membrane trafficking. Alterations in cell metabolism affect development of human disease; this is the fundamental principle driving biomedical research and discovery.

Cancer development is a multistep process, involving multiple genetic alterations that drive normal cells into a highly malignant, multicompetent phenotype. Hanahan and Weinberg (2000) eloquently proposed that tumorigenesis involves six essential physiological processes becoming deregulated in terms of cell behavior: self-sufficiency in growth signals, insensitivity to
growth-inhibitory (anti-growth) signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis.

In each of these steps, the tumor microenvironment is a critical participant, through the extracellular matrix (ECM) maintenance and remodeling as well as cell–cell interactions. The striking ability of a tumor cell population to grow exponentially represents an imbalance between cellular proliferation and cell death, in favor of cell proliferation and at the expense of cell death, but growth pressure alone will not cause a mass of cells to be malignant.

While enjoying extensive communications with the ECM, cancer cells migrate autonomously
across tissue boundaries, and have the audacious capacity to survive and grow among foreign cell populations. The true life-threatening behavior of malignant Apoptosis.indd 1 1/9/2012 3:52:05 PM 2 Molecular Exploitation of Apoptosis Pathways in Prostate Cancer cells is their propensity to infiltrate and usurp the “sovereignty” of host tissue societies.

Although some Mendelian cancer susceptibility genes are involved in tumor initiation, others probably act at later stages in tumorigenesis. Most Mendelian susceptibility genes are tumor suppressors that cause dominantly inherited disease. The protein products of these genes are inactivated by a “second hit”, often a loss of heterozygosity in somatic progenitor cells.

Another classification divides the cancer susceptibility genes into gatekeepers (genes that regulate essential cellular functions such as growth and apoptosis control), caretakers (genes that maintain genomic integrity), and landscapers (genes that restrain tumorigenesis by providing the suitable microenvironment) (Kinzler and Vogelstein, 1998)……………

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