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Acidic tumor microenvironment exists in many types of cancer. Altered glycolytic metabolism of tumor cells and deficient blood supply in tissues are major causes for this phenomenon. Lymphoma cells may have different responses to chemotherapeutics when they are exposed to acidic tumor microenvironment. Bortezomib (BTZ) is a chemotherapeutic drug already approved by FDA for treating multiple myeloma and mantle cell lymphoma, which can inhibit the 26S proteasome and block the protein degradation process. Ramos parental cells (Human Burkitt's lymphoma cell line) and BTZ-resistant Ramos cells (obtained after chronic selection using low concentration of BTZ) were used in the study. Cells were treated from 2h to 24h with RPMI culture media buffered to pH 7.4 and pH 6.4, with or without chemical therapeutics. Cancer therapeutics tested in this study were BTZ, Cyclophosphamide, Doxorubicin, and ABT-737. MTT assay was utilized to detect cell viability under each treatment condition. Flow cytometry was used to examine changes on apoptosis and cell cycle. Western blots were performed to measure the changes of cellular protein levels. The MTT assays showed the acidic microenvironment could decrease cell proliferation rate, and if combined with BTZ treatment it could notably increase the cytotoxic efficacy of BTZ. After chronic selection under low concentration of BTZ, BTZ-resistant Ramos cells were obtained and were able to survive and grow in the presence of BTZ. However, acidic pH with BTZ could sensitize the BTZ-Resistant Ramos cells to BTZ again. Apoptosis assays demonstrated that acidic pH itself did not significantly induce cell apoptosis within 24h. But the combination of acidic pH with BTZ treatment caused much more apoptosis than BTZ alone. Cell cycle analysis showed that acidic pH could block the cell cycle, which led to cell cycle arrest and reduced percentage of cells in the G2/M phase. Western blots illustrated that acidic pH alone could upregulate the level of p53, Phospho-p53 at Ser15, Phospho-CHK1, Phospho-CHK2, pro-apoptotic proteins of the mitochondrial Bcl-2 family, and the pro-apoptotic Caspase family. In addition, if combined with BTZ treatment, acidosis could further increase phosphorylation of p53 at Ser15, expression of the Bcl-2 family proteins, and level of cleaved caspases. In conclusion, the combination of acidosis and BTZ treatment induce higher level of apoptosis and decrease Ramos cell proliferation. Our study demonstrates that arrested cell proliferation and increased apoptosis occur by the inhibition of cell cycle regulators and the activation of p53-mitochondria-caspase apoptosis pathways respectively.
Cancer is a leading cause of death worldwide and within the US. While cancer initially arises from genetic mutations that transform otherwise healthy cells into cancerous cells, the growth, expansion, and metastasis of malignant tumors is dictated by local mechanical and biological cues, collectively known as the tumor microenvironment. Accordingly, to successfully treat cancer, one must target microenvironmental cues that emerge from tumor-associated stromal cells and extracellular matrix, in addition to the cancer cells. However, most cancer therapeutics do not effectively eradicate the disease, highlighting the need to improve our knowledge of cancer biology and develop novel treatments to target cancerous phenotypes with minimal side effects. Thus, the objectives of this dissertation are two-fold: to expand our current understanding of molecular mechanisms involved in tumor angiogenesis that contribute to cancer progression, and to create a human-based platform to screen anti-cancer therapeutics. During tumor progression, the cancer microenvironment evolves both chemically and mechanically. In line with the first goal above, endothelial cell behavior was investigated as a function of increased extracellular matrix stiffness and elevated vascular endothelial growth factor (VEGF) production, two known characteristics of the tumor microenvironment. My data indicate additive effects from both stimuli on VEGF receptor internalization, endothelial signaling, and proliferation, emphasizing the need to design cancer therapeutics to target multiple signaling pathways. While basic research such as that from goal number one can shed light on therapeutic targets, this basic science must subsequently be utilized in translational studies. Therefore, in line with the second goal, I designed a body-on-a-chip microfluidic device to investigate tumor-specific factors in cancer drug development. Such systems are critical in translating cancer biology research within drug screening models. My design creates a physiologically-relevant model to test both efficacy and toxicity of anti-cancer drugs, promoting unidirectional flow on a pumpless platform and using multicellular tumor spheroids as realistic tumor models. My data reveal both chemotherapeutic-induced cytotoxicity to the intended cancer cells and undesired toxic side effects in distant organs. Collectively, the data in this dissertation present a multifaceted approach to improve cancer treatment where basic science advances are translated to human-based drug screening systems.
Oncothermia is the next generation medical innovation that delivers selective, controlled and deep energy for cancer treatment. The basic principles for oncothermia stem from oncological hyperthermia, the oldest approach to treating cancer. Nevertheless, hyperthermia has been wrought with significant controversy, mostly stemming from shortcomings of controlled energy delivery. Oncothermia has been able to overcome these insufficiencies and prove to be a controlled, safe and efficacious treatment option. This book is the first attempt to elucidate the theory and practice of oncothermia, based on rigorous mathematical and biophysical analysis, not centered on the temperature increase. It is supported by numerous in-vitro and in-vivo findings and twenty years of clinical experience. This book will help scientists, researchers and medical practitioners in understanding the scientific and conceptual underpinnings of oncothermia and will add another valuable tool in the fight against cancer. Professor Andras Szasz is the inventor of oncothermia and the Head of St Istvan University's Biotechnics Department in Hungary. He has published over 300 papers and lectured at various universities around the world. Dr. Oliver Szasz is the managing director of Oncotherm, the global manufacturer and distributor of medical devices for cancer treatment used in Europe & Asia since the late 1980s. Dr. Nora Szasz is currently a management consultant in healthcare for McKinsey & Co.
This first comprehensive overview on nanotechnological approaches to cancer therapy brings together therapeutic oncology and nanotechnology, showing the various strategic approaches to selectively eliminating cancerous cells without damaging the surrounding healthy tissue. The strategies covered include magnetic, optical, microwave and neutron absorption techniques, nanocapsules for active agents, nanoparticles as active agents, and active and passive targeting, while also dealing with fundamental aspects of how nanoparticles cross biological barriers. A valuable single source gathering the many articles published in specialized journals often difficult to locate for members of the other disciplines involved.
Overall, this book presents a detailed and comprehensive overview of the state-of-the-art development of different nanoscale intelligent materials for advanced applications. Apart from fundamental aspects of fabrication and characterization of nanomaterials, it also covers key advanced principles involved in utilization of functionalities of these nanomaterials in appropriate forms. It is very important to develop and understand the cutting-edge principles of how to utilize nanoscale intelligent features in the desired fashion. These unique nanoscopic properties can either be accessed when the nanomaterials are prepared in the appropriate form, e.g., composites, or in integrated nanodevice form for direct use as electronic sensing devices. In both cases, the nanostructure has to be appropriately prepared, carefully handled, and properly integrated into the desired application in order to efficiently access its intelligent features. These aspects are reviewed in detail in three themed sections with relevant chapters: Nanomaterials, Fabrication and Biomedical Applications; Nanomaterials for Energy, Electronics, and Biosensing; Smart Nanocomposites, Fabrication, and Applications.
Get a quick, expert overview of the latest clinical information and guidelines for cancer checkpoint inhibitors and their implications for specific types of cancers. This practical title by Drs. Fumito Ito and Marc Ernstoff synthesizes the most up-to-date research and clinical guidance available on immune checkpoint inhibitors and presents this information in a compact, easy-to-digest resource. It’s an ideal concise reference for trainee and practicing medical oncologists, as well as those in research. Discusses the current understanding of how to best harness the immune system against different types of cancer at various stages. Helps you translate current research and literature into practical information for daily practice. Presents information logically organized by disease site. Covers tumor immunology and biology; toxicities associated with immune checkpoint inhibitors; and future outlooks. Consolidates today’s available information on this timely topic into one convenient resource.
Genetic alterations in cancer, in addition to being the fundamental drivers of tumorigenesis, can give rise to a variety of metabolic adaptations that allow cancer cells to survive and proliferate in diverse tumor microenvironments. This metabolic flexibility is different from normal cellular metabolic processes and leads to heterogeneity in cancer metabolism within the same cancer type or even within the same tumor. In this book, we delve into the complexity and diversity of cancer metabolism, and highlight how understanding the heterogeneity of cancer metabolism is fundamental to the development of effective metabolism-based therapeutic strategies. Deciphering how cancer cells utilize various nutrient resources will enable clinicians and researchers to pair specific chemotherapeutic agents with patients who are most likely to respond with positive outcomes, allowing for more cost-effective and personalized cancer therapeutic strategies.
Antibody-drug conjugates (ADCs) stand at the verge of a transformation. Scores of clinical programs have yielded only a few regulatory approvals, but a wave of technological innovation now empowers us to overcome past technical challenges. This volume focuses on the next generation of ADCs and the innovations that will enable them. The book inspires the future by integrating the field’s history with novel strategies and cutting-edge technologies. While the book primarily addresses ADCs for solid tumors, the last chapter explores the emerging interest in using ADCs to treat other diseases. The therapeutic rationale of ADCs is strong: to direct small molecules to the desired site of action (and away from normal tissues) by conjugation to antibodies or other targeting moieties. However, the combination of small and large molecules imposes deep complexity to lead optimization, pharmacokinetics, toxicology, analytics and manufacturing. The field has made significant advances in all of these areas by improving target selection, ADC design, manufacturing methods and clinical strategies. These innovations will inspire and educate scientists who are designing next-generation ADCs with the potential to transform the lives of patients.