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Inhibition Of Telomerase From Human Ovarian Cancer Cells Via The Stabalization Of G Quadruplex Structures By Various Chemotheraputic Agents
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Book Synopsis Inhibition of Telomerase from Human Ovarian Cancer Cells Via the Stabalization of G-quadruplex Structures by Various Chemotheraputic Agents by : Paul Edrick Schutt
Download or read book Inhibition of Telomerase from Human Ovarian Cancer Cells Via the Stabalization of G-quadruplex Structures by Various Chemotheraputic Agents written by Paul Edrick Schutt and published by . This book was released on 2001 with total page 74 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Potential Anticancer Activity Via Inhibition of Telomerase Binding: Investigation of Stabilization Factors for G-Quadruplex Structures by : Tamaki Chiba
Download or read book Potential Anticancer Activity Via Inhibition of Telomerase Binding: Investigation of Stabilization Factors for G-Quadruplex Structures written by Tamaki Chiba and published by . This book was released on 2017 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Telomerase activity is expressed in approximately 85 % of human cancer cells. The overexpression of telomerase in cancer cells is sufficient enough to maintain the length of telomeres and overcome cellular senescence or apoptosis, which explains the immortal feature of cancer cells. In order to cease the immortality of cancer cells caused by telomerase, a strategy that focuses on the inhibition of telomerase activity has been developed. Due to the feature of G-rich human telomeric sequence (T2AG3 repeats), the telomeres can form a G-quadruplex secondary structure whose steric hindrance may disrupt the telomerase binding. In this project, in order to prevent telomerase from accessing and elongating the telomeres, we investigated the factors that stabilize G-quadruplex structures by using UV-Vis Spectroscopy, Fluorescence Spectroscopy and Surface Plasmon Resonance (SPR). We showed that, among the monovalent cations, potassium maximized the stabilization. The stabilization of DNA G-quadruplex was further enhanced in the presence of ligands such as TmPyP4 and its manganese derivative, Mn(Ⅲ)TmPyP4. We also compared the stability of DNA quadruplex and RNA quadruplex. Interestingly, RNA quadruplex showed greater thermodynamic stability than DNA quadruplex under the same experimental conditions. However, RNA quadruplex was not stabilized by the porphyrin ligands we used. Although the conformation analysis of G-quadruplex and the modeling of G-quadruplex ligands are still under investigation, this project gives an insight into improving the stability of both DNA and RNA quadruplex structures.
Book Synopsis Stabilization of G-quadruplex Structures by Organometallic Complexes by : Hang Thanh Hoang
Download or read book Stabilization of G-quadruplex Structures by Organometallic Complexes written by Hang Thanh Hoang and published by . This book was released on 2018 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Telomere shortening is primarily involved in cell death and cellular aging. However, telomerase can reverse the shortening process and allow cells to overcome apoptosis. Telomerase activity is expressed in 85-90% of cancer cells. Binding of this enzyme can be prevented by the formation of G-quadruplex structures, which include stacks of G-tetrads formed by telomeric TTAGGG tandem repeats. Therefore, G-quadruplex stability is crucial to the inhibition of telomerase activity and ligand-induced quadruplex stabilization emerges as a potential chemotherapeutic pathway due to its high selectivity and specificity towards cancer cells. Our project aims to understand the stabilization mechanism of DNA/RNA G-quadruplex by organometallic compounds using UV/Vis spectroscopy and Isothermal Titration Calorimetry (ITC). We have shown that quadruplex stability is increased by potassium ions and further enhanced by the cationic porphyrin ligands TMPyP4 and Mn(III) TMPyP4. We also found that the anionic copper (II) phthalocyanine Cu-APC complex, discovered by the Sugimoto group, potentially interacts with both DNA and RNA quadruplexes. The nonionic benzothiophene platinum(II) complex L3, synthesized by the Anderson lab, also interacts with DNA G- quadruplex and potentially stabilizes the structures. Our studies have provided insights into improving quadruplex stability by organometallic ligands and how their stabilizing effects differ due to structural differences.
Book Synopsis Telomeres and Telomerase in Cancer by : Keiko Hiyama
Download or read book Telomeres and Telomerase in Cancer written by Keiko Hiyama and published by Springer Science & Business Media. This book was released on 2009-03-18 with total page 375 pages. Available in PDF, EPUB and Kindle. Book excerpt: Telomerase, an enzyme that maintains telomeres and endows eukaryotic cells with immortality, was first discovered in tetrahymena in 1985. In 1990s, it was proven that this enzyme also plays a key role in the infinite proliferation of human cancer cells. Now telomere and telomerase are widely accepted as important factors involved in cancer biology, and as promising diagnostic tools and therapeutic targets. Recently, role of telomerase in “cancer stem cells” has become another attractive story. Until now, there are several good books on telomere and telomerase focusing on biology in ciliates, yeasts, and mouse or basic sciences in human, providing basic scientists or students with updated knowledge.
Book Synopsis Telomerase Inhibition by : Lucy Andrews
Download or read book Telomerase Inhibition written by Lucy Andrews and published by Springer Science & Business Media. This book was released on 2007-11-29 with total page 197 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume presents a compendium of the most recent and advanced methods applied to the rapidly expanding field of telomerase inhibition. The techniques described provide the researcher with a diverse and comprehensive set of tools for the study of telomerase inhibition. The volume is aimed at biochemists, molecular biologists, cancer researchers, and geneticists.
Book Synopsis Quadruplex Nucleic Acids by : Stephen Neidle
Download or read book Quadruplex Nucleic Acids written by Stephen Neidle and published by Royal Society of Chemistry. This book was released on 2007-10-31 with total page 317 pages. Available in PDF, EPUB and Kindle. Book excerpt: Guanine rich DNA has been known for decades to form unusual structures, although their biological relevance was little understood. Recent advances have demonstrated that quadruplex structures can play a role in gene expression and provide opportunities for a new class of anticancer therapeutics. A number of quadruplex-specific proteins have also been discovered. Quadruplex Nucleic Acids discusses all aspects of the fundamentals of quadruplex structures, including their structure in solution and the crystalline state, the kinetics of quadruplex folding, and the role of cations in structure and stability. The biology of quadruplexes and G-rich genomic regions and G-quartets in supramolecular chemistry and nanoscience are also considered. Surveying the current state of knowledge, and with contributions from leading experts, this is the first comprehensive review of this rapidly growing area. Quadruplex Nucleic Acids is ideal for researchers interested in areas related to chemistry, chemical biology, medicinal chemistry, molecular pharmacology, and structural and molecular biology.
Book Synopsis Telomerase Inhibition and Sensitization of Breast Tumor Cells by : Ann Kennon Rigby Poynter
Download or read book Telomerase Inhibition and Sensitization of Breast Tumor Cells written by Ann Kennon Rigby Poynter and published by . This book was released on 2007 with total page 294 pages. Available in PDF, EPUB and Kindle. Book excerpt: Telomerase, a ribonucleoprotein enzyme minimally composed of an RNA template (hTR) and a catalytically active protein subunit (hTERT), synthesizes telomeric repeats onto chromosome ends and is obligatory for continuous tumor cell proliferation, as well as malignant progression of breast cancer cells. Telomerase is an attractive anticancer therapeutic target because its activity is present in over 90% of human cancers, including more than 95% of breast carcinomas, but undetectable in most somatic cells. Traditions chemo- and radio-therapies lack the ability to effectively control and cure breast cancer, in part because residual cells are or become resistant to DNA damaging modalities. While various telomerase inhibition strategies cause cancer cells to undergo apoptosis car senescence, there is often a lag period between administration and biologic effect (Corey, 2002). Our goal in this study was to compare the efficacy of different telomerase inhibition strategies in concert with standard chemotherapeutic agents at triggering senescence and/or apoptosis in cultures of breast cancer cells. We hypothesized that telomerase inhibition strategies will sensitize breast cancer cells to traditional chemotherapies, potentially reducing the lag phase, allowing for more potent anti-tumor effects at lower doses, and therefore ultimately imparting less toxicity to the patient. We blocked telomerase by targeting hTR and hTERT, individually and collectively utilizing synthetic short interfering RNA (siRNA), short hairpin RNA (siRNA), and a dominant negative form of hTERT (DN-hTERT) in MCF-7 breast cancer cells. We analyzed the efficiency of telomerase inhibition for each strategy alone and then treated the cells with two mainstay chemotherapeutic agents, Adriamycin (AdR) and Taxol. The most effective telomerase inhibition strategies were synthetic siRNA and DN-hTERT, individually. After treatment with various concentrations of AdR or Taxol, breast cancer cells with inhibited telomerase grew significantly slower and exhibited widespread senescence or apoptosis within a much shorter time period and at a dose that is insufficient to trigger cytostasis. In addition, we provide evidence that cells in which telomerase was inhibited were more sensitive to anti-cancer agents, whether the drug inhibited topoisomerase II resulting in DNA damage (AdR) or blocked mitosis via protracted microtubule stabilization (Taxol). Collectively, our data indicate that alone, anti-telomerase inhibition strategies differ in their efficacy. However, when used in the adjuvant setting with diverse acting chemotherapeutic agents, there is a potent synergy resulting in chemotherapeutic sensitization characterized in part by widespread senescence and/or apoptosis.
Book Synopsis Inhibition of Human Telomerase by Targeting Its Transitory RNA/DNA Heteroduplex by : Rawle Francis
Download or read book Inhibition of Human Telomerase by Targeting Its Transitory RNA/DNA Heteroduplex written by Rawle Francis and published by . This book was released on 2005 with total page 708 pages. Available in PDF, EPUB and Kindle. Book excerpt: Telomerase is a target of intense scientific interest largely because of its implicated role in human carcinogenesis. The inactivation of this enzyme is widely believed to be a promising method to selectively destroy neoplastic cells, while leaving normal cells mostly unaffected. In this dissertation work, the inactivation of human telomerase by molecules based on nucleic acid intercalator structures is presented. The process of cell division shortens the distal portion of linear chromosomes (the telomere). Human telomerase, a special DNA polymerase which functions to maintain telomere length, is composed of RNA and protein subunits. Upon binding to its telomeric DNA substrate, a RNA/DNA heteroduplex is formed. The working hypothesis pursued here is that molecules which target this specific RNA/DNA heteroduplex will stabilize this structure and effectively stall telomerase polymerase activity. Since telomere maintenance is paramount for the survival of rapidly dividing cancer cells, the prevention of telomere maintenance, via inhibition of the telomerase enzyme, is a promising approach to cancer treatment. There are several other approaches to telomerase inhibition presented in the literature. However, targeting the RNA/DNA heteroduplex with the use of modified DNA intercalating agents is a novel and attractive approach to telomerase inhibition. A multifaceted methodology was undertaken to achieve the goal of producing specific inhibitors of human telomerase. First, commercially available nucleic acid intercalators were tested to obtain lead compounds with good inhibitory effect on telomerase activity. Secondly, utilizing techniques of enzyme kinetics, investigations were carried out to determine whether the telomerase RNA/DNA heteroduplex was the target of these lead compounds. Finally, the generation of more potent inhibitors of telomerase was attempted through the use of combinatorial peptide synthesis using lead intercalator(s) as the base structure. It was demonstrated in vitro, that more potent inhibitors of human telomerase could be developed by this approach. Using previously existing assay methods, in addition to original methods developed, relevant experiments were carried out to investigate the stated working hypothesis. During the course of these experiments many interesting observations were made, some of which were pursued and dealt with in these chapters.
Book Synopsis Genome Stability and Human Diseases by : Heinz-Peter Nasheuer
Download or read book Genome Stability and Human Diseases written by Heinz-Peter Nasheuer and published by Springer Science & Business Media. This book was released on 2009-12-11 with total page 346 pages. Available in PDF, EPUB and Kindle. Book excerpt: Since the establishment of the DNA structure researchers have been highly interested in the molecular basis of the inheritance of genes and of genetic disorders. Scientific investigations of the last two decades have shown that, in addition to oncogenic viruses and signalling pathways alterations, genomic instability is important in the development of cancer. This view is supported by the findings that aneuploidy, which results from chromosome instability, is one of the hallmarks of cancer cells. Chromosomal instability also underpins our fundamental principles of understanding tumourigenesis: It thought that cancer arises from the sequential acquisition of genetic alterations in specific genes. In this hypothesis, these rare genetic events represent rate-limiting ‘bottlenecks’ in the clonal evolution of a cancer, and pre-cancerous cells can evolve into neoplastic cells through the acquisition of somatic mutations. This book is written by international leading scientists in the field of genome stability. Chapters are devoted to genome stability and anti-cancer drug targets, histone modifications, chromatin factors, DNA repair, apoptosis and many other key areas of research. The chapters give insights into the newest development of the genome stability and human diseases and bring the current understanding of the mechanisms leading to chromosome instability and their potential for clinical impact to the reader.
Book Synopsis Characterizing and Targeting Unique Features of Telomeres and Telomere Maintenance by : Johanna Mancini
Download or read book Characterizing and Targeting Unique Features of Telomeres and Telomere Maintenance written by Johanna Mancini and published by . This book was released on 2016 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "Telomere maintenance, achieved by the binding of protective shelterin capping proteins and by either telomerase or homologous recombination-based alternative lengthening of telomere (ALT) mechanisms, is critical for cell proliferation and survival. Loss of telomeric integrity or extensive telomere shortening activates DNA damage checkpoints, leading to the initiation of genomic instability, cell senescence, or death. Although telomerase is an attractive target for anti-cancer therapy, the lag associated with telomere shortening poses a challenge. An alternative approach is to modify telomere interactions with binding proteins (telomere uncapping) or to interfere with telomerase access. This can be accomplished through the use of G-quadruplex ligands that stabilize structures from single-stranded G-rich 3′-telomere end (G-quadruplex) folding, which cannot be elongated by telomerase and which can mediate rapid anti-proliferative effects by telomere uncapping. Inhibition of telomerase may also cause the onset of ALT. Despite its potential to serve as a target for anti-cancer therapy, the ALT pathway remains poorly characterized. The ALT pathway maintains telomeres using homologous recombination, which also occurs throughout the genome in order to repair sites of DNA damage due to or resulting in replication fork stalling. Although ALT is often associated with high levels of small ubiquitin-related modifier (SUMO), decreased levels of SUMO1 were observed in a telomerase-positive human breast cancer cell line harboring an ALT phenotype. In yeast, sumoylation of the DNA replication/repair machinery has been shown to recruit an anti-recombinogenic helicase. Recent identification of the human orthologue, Proliferating Cell Nuclear Antigen (PCNA)-Interacting Protein (PARI), led us to investigate the role of sumoylation in the regulation of ALT and to suggest a role for PARI in regulating telomeric recombination in ALT cells.Our results confirm that G-quadruplex ligands PIN, PIP, PII, PIQ, SIP, and CLIP can inhibit telomerase activity in vitro. Treatment with PIP is able to significantly reduce proliferation of A549 lung cancer cells and to cause a significant decrease in the average telomere length of these cells. Although the growth of normal primary cells with a limited capacity for replication was also affected, their telomere length of was not significantly decreased. While treatment with PIP failed to induce apoptosis and DNA damage localized at the telomere; positive staining for [beta]-galactosidase, in telomerase positive A549 and Huh7 cells, confirmed the onset of cellular senescence. Interestingly, expression of the inactive -[beta] splice variant of hTERT was increased after short-term treatment with PIP. These results suggest that the observed anti-proliferative effects are unlikely due to telomere uncapping but rather due to the inhibition of telomerase activity, leading to cellular senescence. Preliminary results investigating the role of PARI at the telomere suggest it is capable of repressing homologous recombination. Overexpression of PARI inhibited homologous recombination at telomeres, observed by a decrease in C-circle expression, the most robust method of measuring ALT. Moreover, PARI containing mutations in critical SUMO- ([DELTA]SIM) and PCNA- ([DELTA]PIP) interacting sites were less effective at inhibiting homologous recombination activity; thus supporting the characterization of PARI and its potential role in telomeric recombination. These studies validate the development of novel and specific therapeutic ligands that target G-quadruplex structures at the telomere. Moreover, they identify potential novel targets of the ALT pathway, providing evidence that PARI can inhibit recombination at the telomere; thus improving our understanding of the mechanisms regulating telomere maintenance." --
Book Synopsis Quadruplex Nucleic Acids As Targets For Medicinal Chemistry by :
Download or read book Quadruplex Nucleic Acids As Targets For Medicinal Chemistry written by and published by Academic Press. This book was released on 2020-08-26 with total page 564 pages. Available in PDF, EPUB and Kindle. Book excerpt: The realisation that human, animal, viral and bacterial genomes all contain over-representation of higher-order quadruplex structures in regulatory and other pharmacologically-useful regions, has led to a large number of studies aimed at exploiting this findings for therapeutic and diagnostic purposes. Quadruplex-binding small molecules are starting to be evaluated in human clinical trials. Provides the authority and expertise of leading contributors from an international board of authors Presents the latest release in the Annual Reports in Medicinal Chemistry series
Book Synopsis Mechanism of Telomerase Inhibition Using a Small Inhibitory RNAs and Induction of Breast Tumor Cell Sensitization by :
Download or read book Mechanism of Telomerase Inhibition Using a Small Inhibitory RNAs and Induction of Breast Tumor Cell Sensitization written by and published by . This book was released on 2007 with total page 53 pages. Available in PDF, EPUB and Kindle. Book excerpt: Telomerase, a ribonucleoprotein enzyme minimally composed of an RNA template (hTR) and a catalytically active protein subunit (hTERT), synthesizes telomeric repeats onto chromosome ends and is obligatory for continuous tumor cell proliferation, as well as malignant progression of breast cancer cells. Telomerase is an attractive anti-cancer therapeutic target because its activity is present in over 90% of human cancers, including more than 95% of breast carcinomas, but undetectable in most somatic cells. Traditional chemo- and radiotherapies lack the ability to effectively control and cure breast cancer, in part because residual cells are or become resistant to DNA damaging modalities. While various telomerase inhibition strategies cause cancer cells to undergo apoptosis or senescence, there is often a lag period between administration and biologic effect (Corey, 2002). Our goal in this study was to compare the efficacy of different telomerase inhibition strategies in concert with standard chemotherapeutic agents at triggering senescence and/or apoptosis in cultures of breast cancer cells. We hypothesized that telomerase inhibition strategies will sensitize breast cancer cells to traditional chemotherapies, potentially reducing the lag phase, allowing for more potent anti-tumor effects at lower doses, and therefore ultimately imparting less toxicity to the patient.
Book Synopsis Telomerase Inhibition and Chemosensitization of Prostate Cancer Cells by :
Download or read book Telomerase Inhibition and Chemosensitization of Prostate Cancer Cells written by and published by . This book was released on 2004 with total page 17 pages. Available in PDF, EPUB and Kindle. Book excerpt: We hypothesize that telomerase inhibition (telomere shortening) can sensitize human tumor cells to existing anticancer drugs. During the period of the grant we made the following findings-: 1) 2'-methoxy ethyl oligonucleotides inhibit - -telomerase in prostate cancer cells, cause telomeres to shorten, and cause cell- proliferation to decrease; -2) Cell proliferation in culture is -more pronounced when cells are grown under conditions that mimic tumor growth; 3) Cell proliferation is dramatically reduced in a xenograft model using LNCAP cells, and 4) We did not observe significant synergy with standard chemotherapy agents. The ability of relatively short-term treatments with telomerase inhibitors to slow tumor growth in vivo suggests that telomerase inhibitors are a reasonable approach to prostate cancer therapy.
Book Synopsis The Organic Chemistry of Drug Design and Drug Action by : Richard B. Silverman
Download or read book The Organic Chemistry of Drug Design and Drug Action written by Richard B. Silverman and published by Elsevier. This book was released on 2012-12-02 with total page 650 pages. Available in PDF, EPUB and Kindle. Book excerpt: Standard medicinal chemistry courses and texts are organized by classes of drugs with an emphasis on descriptions of their biological and pharmacological effects. This book represents a new approach based on physical organic chemical principles and reaction mechanisms that allow the reader to extrapolate to many related classes of drug molecules. The Second Edition reflects the significant changes in the drug industry over the past decade, and includes chapter problems and other elements that make the book more useful for course instruction. New edition includes new chapter problems and exercises to help students learn, plus extensive references and illustrations Clearly presents an organic chemist's perspective of how drugs are designed and function, incorporating the extensive changes in the drug industry over the past ten years Well-respected author has published over 200 articles, earned 21 patents, and invented a drug that is under consideration for commercialization
Book Synopsis Therapeutic Applications of Quadruplex Nucleic Acids by : Stephen Neidle
Download or read book Therapeutic Applications of Quadruplex Nucleic Acids written by Stephen Neidle and published by Academic Press. This book was released on 2012 with total page 210 pages. Available in PDF, EPUB and Kindle. Book excerpt: "Therapeutic applications of quadruplex nucleic acids provides a single comprehensive survey that describes and assesses recent advances in quadruplex therapeutics and targeting strategies. It also covers the underlying fundamentals of such topics as quadruplex structure, small-molecule recognition, biological roles of genomic quadruplexes, and quadruplex informatics"--P. [4] of cover.
Book Synopsis Telomeres and Telomerase by : Predrag Slijepcevic
Download or read book Telomeres and Telomerase written by Predrag Slijepcevic and published by S. Karger AG (Switzerland). This book was released on 2008 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Telomeres are essential functional elements of eukaryotic chromosomes. Their fundamental biological role as protectors of chromosome stability was identified for the first time in the 1930s by Hermann Muller and Barbara McClintock based on pioneering cytological experiments. Modern molecular research carried out more recently revealed that telomeres and telomerase play important roles in processes such as carcinogenesis and cellular senescence. This special issue presents the most recent developments in this highly active field of research. It is becoming increasingly clear that molecular pathways involved in regulation of telomere length and structure are functionally linked with pathways involved in DNA damage response, cellular stress response, chromatin organization and perhaps even pathways that regulate evolutionary chromosome rearrangements. The above functional link is explored by the leading experts in the field of telomere biology. Cell biologists, molecular biologists, oncologists, gerontologists, and radiobiologists with an interest in the role of telomeres/telomerase will appreciate the up-to-date information in this publication.
Book Synopsis Molecular Therapies of Cancer by : Georg F. Weber
Download or read book Molecular Therapies of Cancer written by Georg F. Weber and published by Springer. This book was released on 2015-07-22 with total page 486 pages. Available in PDF, EPUB and Kindle. Book excerpt: Molecular Therapies of Cancer comprehensively covers the molecular mechanisms of anti-cancer drug actions in a comparably systematic fashion. While there is currently available a great deal of literature on anti-cancer drugs, books on the subject are often concoctions of invited review articles superficially connected to one another. There is a lack of comprehensive and systematic text on the topic of molecular therapies in cancer. A further deficit in the relevant literature is a progressive sub-specialization that typically limits textbooks on cancer drugs to cover either pharmacology or medicinal chemistry or signal transduction, rather than explaining molecular drug actions across all those areas; Molecular Therapies of Cancer fills this void. The book is divided into five sections: 1. Molecular Targeting of Cancer Cells; 2. Emerging and Alternative Treatment Modalities; 3. Molecular Targeting of Tumor-Host Interactions; 4. Anti-Cancer Drug Pharmacokinetics; and 5. Supportive Therapies.
