Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents, Vol. 4, No. 4, 2005
Contents
Associations
between Inflammation, Cancer, Neuro-Degenerative Diseases, Ageing and
Autoimmunity
Guest Editor:
Marek Los
The Immune System, Involvement in
Neurodegenerative Diseases, Ageing and Cancer Pp.349-352
Evan P. Booy, Dina Johar, Kamran Kadkhoda, Graham H. Bay and Marek Los
Cancer Immunotherapy: Battling
Tumors with Gene Vaccines Pp.353-365
K. Chlichlia, V. Schirrmacher
and R. Sandaltzopoulos
Immunological Approaches to
Prevent Neuronal Apoptosis During Neuroinflammation Pp.367-381
F.J. Murphy, K.E. Keating, D.
Sheehan and I. Hayes
Induction of Apoptotic Cell Death
in Tumor Cells by S100A8/A9 Released from Inflammatory Cells Upon Cellular
Activation
Pp.383-391
C. Kerkhoff and S. Ghavami
IAPs, their Antagonists and their
Role in Neurological Disease and Cancer Pp.393-406
Robert E. Gerl and Anne M.
Verhagen
Pharmacological Modulation of
Caspase Activation
Pp.407-419
Ute Fischer and Klaus
Schulze-Osthoff
Telomeres, Genomic Instability,
DNA Repair and Breast Cancer Pp.421-428
S. Panigrahi and S. Mai
Apoptosis and Autoimmune Disease Pp.429-437
Mohammad Hashemi and Tadeusz J. Kroczak
Mitochondrial Physiology and
Toxicity (Mitotoxicity); Importance for the Immune System, Programmed Cell
Death and Cancer
Pp.439-448
Hamid Pour-Jafari, Saeid Ghavami and Subbareddy Maddika
Abstracts
[Back to top] The
Immune System, Involvement in Neurodegenerative Diseases, Ageing and Cancer
Evan P. Booy, Dina Johar, Kamran Kadkhoda, Graham H. Bay and Marek Los
This short review was designed to draw the readership’s attention to the following articles in the volume. Instead of providing a full summary of topics such as ageing of the immune system and the role of the immune system in ageing, the role of the immune system in the development of cancer and neurodegenerative diseases, it signalizes these topics and provides links to articles that follow as well as to other available literature. Our intention was to provide a new perspective and strengthen the associations between inflammation, cancer, neuro-degenerative diseases, ageing and autoimmunity. The relationship between inflammation, oxidative stress, apoptosis, neurodegeneration and cancer is already, to a certain extent mirrored by attempts of the pharmacologic industry to cross-apply our current knowledge from these fields to develop new treatment modalities. For instance, strategies that modulate cellular redox potential are being applied to restrain inflammation (antioxidants), or to kill cancer cells (prooxidants). Activation of apoptosis or attenuation of resistance of transformed cells towards cell death induction is perhaps the most promising direction chosen by many pharmaceutical companies to develop new classes of drugs. Furthermore, rapidly developing areas of immunology and virology, combined with the tremendous progress in the field of cancer biology and pharmacogenomics, may lead to the occurrence of an unique treatment, based on anti-cancer viral vectors and even anti-inflammatory strategies, which combine multiple pharmacologic activities in a single bio-molecule.
[Back to top]
Cancer Immunotherapy: Battling Tumors with Gene Vaccines
K. Chlichlia, V. Schirrmacher and R. Sandaltzopoulos
Gene vaccines against defined antigens represent a novel and promising immunization approach for cancer immunotherapy and for battling infectious diseases. Immunization with plasmid DNA is the simplest gene-based approach. In order to induce protective antitumor immunity, gene vaccines are designed to deliver one or several genes encoding tumor-associated antigens, thereby eliciting or augmenting antigen-specific immune responses. The efficacy of gene vaccines can be significantly improved through integration of advances in immunology and molecular biology. Recent evidences point out the central role of dendritic cells and show the importance of innate immune responses in the induction and enhancement of antigen-specific adaptive immune responses. Hence, manipulations that integrate both tumor-associated antigens and ‘danger’ signals in the vaccine design, can achieve activation of both innate and adaptive immune responses, thereby overcoming the self-tolerance towards many tumor antigens. Coadministration of genetic adjuvants and optimized prime-boost strategies enhance the efficacy of gene vaccines. In this context, strategies that target antigens of choice to dendritic cells and induce, in vivo, antitumor immune responses are discussed. This review highlights vaccine strategies based on transfer of nucleic acid sequences encoding well-defined tumor-associated antigens and genetic adjuvants to the host in vivo in order to induce successful antitumor immunity.
[Back to top] Immunological
Approaches to Prevent Neuronal Apoptosis During Neuroinflammation
F.J. Murphy, K.E. Keating, D. Sheehan and I. Hayes
Neurodegeneration is set to increase in parallel with society’s age demographics. With the increasing appreciation of the role played by apoptosis in neurodegeneration, much effort has gone into understanding key effectors in this process and to develop therapies that reduce neuronal apoptosis, thus preserving the integrity of the CNS. In contrast to peripheral apoptosis, inflammation is commonly seen to co-localize with apoptotic sites in the CNS however investigators are unsure whether inflammation is the primary cause for neuronal apoptosis induction or whether it is secondary. This current review highlights the role of apoptosis in neurodegenerative diseases, examines the evidence as to whether inflammation is a causative or consequential event in neuronal apoptosis and describes some of the immunological approaches that are currently in the clinic or being developed.
[Back to top]
Induction of Apoptotic Cell Death in Tumor Cells by S100A8/A9 Released from
Inflammatory Cells Upon Cellular Activation
C. Kerkhoff and S. Ghavami
Polymorphonuclear neutrophils (PMNs) have received less attention than other leukocyte subsets as potential mediators of antitumor effects. However, there is a growing body of evidence that PMNs are potential mediators of antitumor effects and play an important role in the antitumor response. A protein complex S100A8/A9, formed by the two low molecular weight calcium-binding proteins S100A8 and S100A9, is released from activated PMNs and has apoptosis/cytotoxicity-inducing activity against tumor cell lines. In this review, we focus on the molecular mechanisms by which S100A8/A9 induces apoptosis. Recent studies point to a yet undefined mechanism, probably relaying on cell surface receptor(s), by which S100A8/A9 induces apoptosis in carcinoma cell lines, in addition to zinc exclusion from target cells. Although a number of putative receptors have been identified, the cell-membrane bindings site(s) involved in the apoptosis-inducing activity of S100A8/A9 remain unknown. The identification of the binding site(s) together with the elucidation of the underlying molecular mechanisms will give new insights in how the adaptive immune system is involved in cancer regression.
[Back to top] IAPs,
their Antagonists and their Role in Neurological Disease and Cancer
Robert E. Gerl and Anne M. Verhagen
Apoptosis is a noninflammatory process used by multicellular organisms to eliminate unwanted cells. It is implemented by a family of cysteine proteases called caspases through their cleavage of cellular proteins. The upstream events leading to caspase activation are controlled at multiple levels by an extensive array of proteins, including death receptors, adapters, transcription factors and Bcl-2 family members, while acting downstream to curb caspase activity are the inhibitor of apoptosis proteins (IAPs). Since their initial discovery much has been learned about how IAPs regulate cell death and are themselves regulated. Structural studies have given us insight into how IAPs interact with and neutralise caspase activity, proteomic approaches have uncovered IAP interacting molecules, such as DIABLO/SMAC, that can antagonise IAP function, and additional modes of IAP regulation at the transcriptional and post translational level have been identified. Their potential involvement in conferring cancer cell resistance to apoptotic stimuli, e.g. chemotherapeutic drugs, has presented them as plausible targets for cancer therapy. Conversely, they may be beneficial in protecting neuronal cells from inappropriate apoptosis observed in many different neurological diseases. What follows is a discussion of the various mammalian IAPs and other BIR domain containing proteins (BIRPs), focussing on their structure, function and regulation by antagonists as well as their possible involvement in disease processes.
[Back to top] Pharmacological Modulation of
Caspase Activation
Ute Fischer and Klaus Schulze-Osthoff
Deregulation of apoptosis resulting either in inappropriate loss or accumulation of cells is a major cause of many severe pathological conditions such as cancer, autoimmune diseases, microbial infections and degenerative disorders. Consequently, great interest has emerged in devising therapeutic strategies for intervening with cell death, either in a pro- or antiapoptotic direction. Among the different apoptosis-based drug targets, caspases, a family of intracellular cysteine proteases are most promising candidates, because they form the central core of the apoptotic machinery that coordinate cell death from various signals. Inappropriate cell death can be efficiently blocked by caspase inhibitors, whereas caspase activation or the inhibition of endogenous caspase inhibitors might be useful for the eradication of unwanted cells. Currently, numerous novel approaches are being followed employing gene therapy, antisense strategies, recombinant biologics or organic chemistry in order to target caspases or their endogenous inhibitors. Exciting proof-of-principle evidence obtained in several animal models confirms the validity of strategies targeting caspases and their enormous therapeutic potential. Although mostly in preclinical state, several therapeutics have recently progressed to clinical testing or were even approved by drug administration. This review summarizes the recent advances in the field of caspase targeting and discusses its wide-ranging opportunities for different human diseases.
[Back to top] Telomeres, Genomic Instability, DNA Repair
and Breast Cancer
S. Panigrahi and S. Mai
This review describes our current understanding of telomere length polymorphism and organization in breast cancer cells. The key roles of the telomeric DNA protein complexes as protectors of chromosomal ends in normal and cancer cells are under much attention in current research, and here we review some of these issues. In general the functionality of telomeres depends on a number of associated factors, like - (1) the length of the telomeric sequence at a particular chromosomal end, (2) the status of telomerase activity, (3) the telomere associated proteins, (4) the status of sub-telomeric heterochromatinization, (5) or associated chromosomal instability. Specifically, in breast cancer, depending on the presence or absence of the mutations in DNA repair proteins the telomere function becomes much more fragile. Some recent studies using modern high performance three-dimensional (3D) imaging technologies indicate that many exciting aspects of this multifaceted telomere research are going to unfold further in the coming years.
[Back to top] Apoptosis and Autoimmune Disease
Mohammad Hashemi and Tadeusz J. Kroczak
Apoptosis is a physiological mechanism of cell death. Defects in the apoptosis machinery may lead to serious disease such as: autoimmune disease, cancer, drug resistance in tumors, and the acquired immunodeficiency syndrome (AIDS). Autoimmune diseases affect 3-5% of the population and are characterized by the activity of autoreactive lymphocytes that produce antibodies targeting ‘self tissue’ for destruction. Genetic and environmental factors both influence autoimmune disease occurrence. Although the pathogenesis of these diseases is poorly understood, firm evidence links the process of apoptosis to the induction of autoimmune disease. In this review we will attempt to outline the recent findings that highlight the etiologies of some autoimmune diseases such as: Systemic lupus erythematosus (SLE), Type 1 diabetes mellitus (IDDM), Multiple sclerosis (MS), Rheumatoid arthritis (RA) and autoimmune thyroid disease.
[Back to top] Mitochondrial Physiology and
Toxicity (Mitotoxicity); Importance for the Immune System, Programmed Cell
Death and Cancer
Hamid Pour-Jafari, Saeid Ghavami and Subbareddy Maddika
This review focuses on the physiology of mitochondria as well as on the role of mitochondrial changes in cancer and in the immune system. After discussing the origin, structure, function and physiology of mitochondria, we focus on mitochondrial damage induced by antiviral and other drugs, reactive oxygen intermediates, physical tests like heat shock and ionizing radiation, hypoxia and hyperoxia. While discussing the effects of these noxious stimuli on mitochondria, we introduce terms such as “mitotoxicity” and “mitotoxins”. Further parts of the review focus on the role of mitochondria in programmed cell death, and mitochondrial dysfunction observed in cancer. A significant portion of the review discusses the role of mitochondrial changes during the aging of the immune system, age-related changes of mitochondrial physiology, and mitochondrial proteins as auto-antigens. Using primary biliary cirrhosis as an example, we illustrate that the autoimmune condition is perpetuated by a pathologic immune response directed towards mitochondrial antigens. Finally we raise several questions, which we believe, need to be answered in order to improve the therapy of cancer autoimmunity and genetic diseases involving mitochondria.