The Supramolecular Organization Of Cancer Metabolism
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Author | : Cristina Balcells Nadal |
Publisher | : |
Total Pages | : 348 |
Release | : 2020 |
Genre | : |
ISBN | : |
"Metastasis and drug resistance represent the two main causes of therapeutic failure in oncology. In the present dissertation, the interplay between them has been interrogated using metabolomics, systems biology and biophysical approaches, in an attempt to find common phenotypic adaptations and metabolic vulnerabilities of metastatic and resistant cancer cells, potentially exploitable in novel combination therapies. The obtained results unveil that highly metastatic e-CSC phenotypes of CRPC present particular metabolic vulnerabilities that can potentially lead to establishing putative biomarkers and metabolic targets that are specific for PCa subsets with high tumorigenic potential. Moreover, by generating isogenic cell models of multiplatinum resistance in CRPC and CRC we also identified that metastatic solid tumors with originally opposed metabolic profiles can lead to different metabolic adaptations as they acquire platinum resistance, but that a common metabolic signature of acquired platinum resistance arises, which also includes alterations in proline and one carbon metabolism, glutathione synthesis and ROS production. In addition to characterizing in deep the metabolic reprogramming associated to resistance to platinum compounds already used in the clinics, we also explored the possibility to design of novel platinum drugs able to counter platinum-resistant tumors. In this regard, we identified novel families of cyclometallated platinum (II) and platinum (IV) compounds exhibit strong antiproliferative effects in the low micromolar range against a wide variety of solid tumors. The leading compounds of each series also exhibit remarkable selectivity for cancer cells and the capacity to arrest the cell cycle at S and G2/M phases, induce apoptosis and increase intracellular ROS levels. The multiple combinations of equatorial and axial ligands explored in this work, allowed us to conclude that octahedral Pt (IV) compounds containing tridentate [C,N,N'] ligands are the optimal design to improve efficacy and selectivity against cancer cell lines. Remarkably, we have also identified that these novel cyclometallated Pt (IV) exhibit a complete absence of cross-resistance with the platinum-resistant CRC and CRPC models generated in this work.Indeed, platinum-based chemotherapy can severely affect internal cell architecture, causing fluctuations in the levels of macromolecular crowding inside cells and having an impact on the supramolecular organization of cell metabolism. In turn, this has been proved to have a profound impact on the kinetic behavior of metabolic enzymes that govern the rate of metabolic pathways that we have identified as important throughout this work.Thus, we have explored the kinetic behavior of lactate dehydrogenase (LDH), as a representative of aerobic glycolysis, under the presence of globular obstacles that do not introduce specific interactions with either LDH or its substrates, dextran polymers, obtaining that LDH kinetics is impaired in an obstacle size- and concentration-dependent manner. Additionally, we unveiled that LDH kinetic behavior shifts from activation control to diffusion control as crowding increases, implying that the behavior of LDH inside cells could be significantly different than previous dilute solution kinetic studies of this enzyme had predicted. On the other hand, the effect of macromolecular crowding on glutaminolysis had not been explored prior to this work. By studying the kinetic behavior of glutamate dehydrogenase (GLDH) in crowded media and characterizing its negative cooperativity, we have concluded that its kinetics is impaired by crowding in an obstacle size- and concentration-dependent manner, but that negative cooperativity is not significantly altered by macromolecular crowding. The actual impact of macromolecular crowding on cell metabolism has been scarcely explored and we are just scratching the surface of the understanding of the multiple implications that this phenomenon may entail for cell physiology and, in particular, for the metabolic alterations of cancer cells. Our observations throughout this work will hopefully have contributed to set grounds onto this enthralling enterprise, as long as meaningfully contributed to encounter valuable therapeutic tools against metastatic CRPC and CRC that can circumvent platinum resistance, both with new generations of platinum compounds and novel metabolic targets that selectively target metastatic solid tumors." -- TDX.
Author | : Sybille Mazurek |
Publisher | : Springer |
Total Pages | : 373 |
Release | : 2015-01-19 |
Genre | : Medical |
ISBN | : 3709118247 |
The four sections of this book cover cell and molecular biology of tumor metabolism, metabolites, tumor microenvironment, diagnostics and epigenetics. Written by international experts, it provides a thorough insight into and understanding of tumor cell metabolism and its role in tumor biology. The book is intended for scientists in cancer cell and molecular biology, scientists in drug and diagnostic development, as well as for clinicians and oncologists.
Author | : Jianwei Xu |
Publisher | : Elsevier |
Total Pages | : 698 |
Release | : 2022-04-17 |
Genre | : Technology & Engineering |
ISBN | : 0128243368 |
Aggregation-Induced Emission (AIE): A Practical Guide introduces readers to the topic, guiding them through fundamental concepts and the latest advances in applications. The book covers concepts, principles and working mechanisms of AIE in AIE-active luminogens, with different classes of AIE luminogens reviewed, including polymers, three-dimensional frameworks (MOFs and COFs) and supramolecular gels. Special focus is given to the structure-property relationship, structural design strategies, targeted properties and application performance. The book provides readers with a deep understanding, not only on the fundamental principles of AIE, but more importantly, on how AIE luminogens and AIE properties can be incorporated in material development. Provides the fundamental principles, design and synthesis strategies of aggregation induced emission materials Reviews the most relevant applications in materials design for stimuli-responsive materials, biomedical applications, chemo-sensing and optoelectronics Emphasizes structural design and its connection to aggregation induced emission properties, also exploring the structure-property relationship
Author | : Athel Cornish-Bowden |
Publisher | : Springer Science & Business Media |
Total Pages | : 366 |
Release | : 2012-12-06 |
Genre | : Medical |
ISBN | : 9401140723 |
Two decades have passed since the mechanisms of protein synthesis became well enough understood to permit the genetic modification oforganisms. An impressive amount of new knowledge has emerged from the new technology, but much ofthe promise of20years ago has notyet been fulfilled. In biotechnology, efforts to increase the yields of commercially valuable metabolites have been less successful than ex pected, and when they have succeeded it has often been as much from selective breeding as from new methods. The cell is more complicated than what is presented in the classical teaching of biochemistry, it contains more structure than was dreamed of 20 years ago, and the behaviour ofany systemofenzymes is more elaborate than can be explained in terms ofa single supposedly rate-limiting enzyme. Even if classical enzymology and meta bolism may have seemed rather unfashionable during the rise ofmolecular biology, they remain central to any modification ofthe metabolic behaviour oforganisms. As such modification is essential in much ofbiotechnology and drug development, bio technologists can only ignore these topics at their peril.
Author | : |
Publisher | : |
Total Pages | : 1732 |
Release | : 1995 |
Genre | : Medicine |
ISBN | : |
Author | : |
Publisher | : Elsevier |
Total Pages | : 687 |
Release | : 2000-10-25 |
Genre | : Science |
ISBN | : 0080496695 |
This volume contains information on analyzing sphingolipids, sphingolipid transport and trafficking, and sphingolipid-protein interactions and cellular targets. Its companion Volume 311 presents methods used in studying enzymes of sphingolipid biosynthesis and turnover, including inhibitors of some of these enzymes, genetic approaches, and organic and enzymatic syntheses of sphingolipids and analogs. The critically acclaimed laboratory standard for more than forty years, Methods in Enzymology is one of the most highly respected publications in the field of biochemistry. Since 1955, each volume has been eagerly awaited, frequently consulted, and praised by researchers and reviewers alike. Now with more than 300 volumes (all of them still in print), the series contains much material still relevant today--truly an essential publication for researchers in all fields of life sciences.
Author | : Vincenzo Balzani |
Publisher | : John Wiley & Sons |
Total Pages | : 511 |
Release | : 2006-03-06 |
Genre | : Science |
ISBN | : 3527605347 |
The miniaturization of bulky devices and machines is a process that confronts us on a daily basis. However, nanoscale machines with varied and novel characteristics may also result from the enlargement of extremely small building blocks, namely individual molecules. This bottom-up approach to nanotechnology is already being pursued in information technology, with many other branches about to follow. - Written by a team of experienced authors headed by Vincenzo Balzani, one of the pioneers in the development of molecular machines - Covers such diverse aspects as sensors, memory components, solar energy conversion, biomolecules as molecular machines, and much more - Presented in a lucid style and didactically structured, with both the expert and the newcomer in mind - Includes a glossary of terms and numerous references to the recent literature Be among the first to explore the fascinating possibilities of this future-oriented technology! A must-have for every chemist and materials scientist with an interest in nanotechnology.
Author | : Peter J. Cragg |
Publisher | : Springer Science & Business Media |
Total Pages | : 267 |
Release | : 2010-08-26 |
Genre | : Science |
ISBN | : 9048125820 |
The aim of this book is to return to the biomimicry and medicinal potential that inspired many of the early supramolecular chemists and to set it in the context of current advances in the field. Following an overview of supramolecular chemistry, the first section considers the efforts made to synthesize artificial systems that mimic biological entities. The second section addresses the application of supramolecular principles to molecular diagnostics with a particular emphasis on the ‘receptor-relayreporter’ motif. Many of the examples chosen have clinical importance. The third section takes the clinical diagnostic theme further and demonstrates the therapeutic applications of supramolecular chemistry through photodynamic therapy, drug delivery, and the potential for synthetic peptides to form antibiotic tubes. The short epilogue considers the potential for supramolecular solutions to be found for further challenges in biomimetic and therapeutic chemistry.
Author | : Michael D. Waters |
Publisher | : John Wiley & Sons |
Total Pages | : 790 |
Release | : 2018-01-04 |
Genre | : Medical |
ISBN | : 1119023602 |
Written by leading research scientists, this book integrates current knowledge of toxicology and human health through coverage of environmental toxicants, genetic / epigenetic mechanisms, and carcinogenicity. Provides information on lifestyle choices that can reduce cancer risk Offers a systematic approach to identify mutagenic, developmental and reproductive toxicants Helps readers develop new animal models and tests to assess toxic impacts of mutation and cancer on human health Explains specific cellular and molecular targets of known toxicants operating through genetic and epigenetic mechanisms
Author | : Lalita Ledwani |
Publisher | : Springer Nature |
Total Pages | : 605 |
Release | : 2020-03-12 |
Genre | : Technology & Engineering |
ISBN | : 303033774X |
This book examines the potential applications of nanoscience and nanotechnology to promote eco-friendly processes and techniques for energy and environment sustainability. Covering various aspects of both the synthesis and applications of nanoparticles and nanofluids for energy and environmental engineering, its goal is to promote eco-friendly processes and techniques. Accordingly, the book elaborates on the development of reliable, economical, eco-friendly processes through advanced nanoscience and technological research and innovations. Gathering contributions by researchers actively engaged in various domains of nanoscience and technology, it addresses topics such as nanoparticle synthesis (both top-down and bottom-up approaches); applications of nanomaterials, nanosensors and plasma discharge in pollution control; environmental monitoring; agriculture; energy recovery; production enhancement; energy conservation and storage; surface modification of materials for energy storage; fuel cells; pollution mitigation; and CO2 capture and sequestration. Given its scope, the book will be of interest to academics and researchers whose work involves nanotechnology or nanomaterials, especially as applied to energy and/or environmental sustainability engineering. Graduate students in the same areas will also find it a valuable resource.