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Proceedings. Biological Sciences Mar 2017Why is drug resistance common and vaccine resistance rare? Drugs and vaccines both impose substantial pressure on pathogen populations to evolve resistance and indeed,... (Review)
Review
Why is drug resistance common and vaccine resistance rare? Drugs and vaccines both impose substantial pressure on pathogen populations to evolve resistance and indeed, drug resistance typically emerges soon after the introduction of a drug. But vaccine resistance has only rarely emerged. Using well-established principles of population genetics and evolutionary ecology, we argue that two key differences between vaccines and drugs explain why vaccines have so far proved more robust against evolution than drugs. First, vaccines tend to work prophylactically while drugs tend to work therapeutically. Second, vaccines tend to induce immune responses against multiple targets on a pathogen while drugs tend to target very few. Consequently, pathogen populations generate less variation for vaccine resistance than they do for drug resistance, and selection has fewer opportunities to act on that variation. When vaccine resistance has evolved, these generalities have been violated. With careful forethought, it may be possible to identify vaccines at risk of failure even before they are introduced.
Topics: Drug Resistance, Microbial; Evolution, Molecular; Vaccines
PubMed: 28356449
DOI: 10.1098/rspb.2016.2562 -
Scientific Reports Dec 2019One of the hallmarks of cancers is their ability to develop resistance against therapeutic agents. Therefore, developing effective in vitro strategies to identify drug...
One of the hallmarks of cancers is their ability to develop resistance against therapeutic agents. Therefore, developing effective in vitro strategies to identify drug resistance remains of paramount importance for successful treatment. One of the ways cancer cells achieve drug resistance is through the expression of efflux pumps that actively pump drugs out of the cells. To date, several studies have investigated the potential of using 3-dimensional (3D) multicellular tumor spheroids (MCSs) to assess drug resistance; however, a unified system that uses MCSs to differentiate between multi drug resistance (MDR) and non-MDR cells does not yet exist. In the present report we describe MCSs obtained from post-diagnosed, pre-treated patient-derived (PTPD) cell lines from head and neck squamous cancer cells (HNSCC) that often develop resistance to therapy. We employed an integrated approach combining response to clinical drugs and screening cytotoxicity, monitoring real-time drug uptake, and assessing transporter activity using flow cytometry in the presence and absence of their respective specific inhibitors. The report shows a comparative response to MDR, drug efflux capability and reactive oxygen species (ROS) activity to assess the resistance profile of PTPD MCSs and two-dimensional (2D) monolayer cultures of the same set of cell lines. We show that MCSs provide a robust and reliable in vitro model to evaluate clinical relevance. Our proposed strategy can also be clinically applicable for profiling drug resistance in cancers with unknown resistance profiles, which consequently can indicate benefit from downstream therapy.
Topics: Antineoplastic Agents; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Head and Neck Neoplasms; Humans; Spheroids, Cellular; Tumor Cells, Cultured
PubMed: 31882620
DOI: 10.1038/s41598-019-56273-6 -
BMC Biology Feb 2018Paraphrasing Dobzhansky's famous dictum, I discuss how interrogating cancer through the lens of evolution has transformed our understanding of its development, causality... (Review)
Review
Paraphrasing Dobzhansky's famous dictum, I discuss how interrogating cancer through the lens of evolution has transformed our understanding of its development, causality and treatment resistance. The emerging picture of cancer captures its extensive diversity and therapeutic resilience, highlighting the need for more innovative approaches to control.
Topics: Animals; Biological Evolution; Drug Resistance; Humans; Mutation; Neoplasms; Selection, Genetic
PubMed: 29466995
DOI: 10.1186/s12915-018-0493-8 -
British Journal of Cancer Apr 1993
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Antineoplastic Agents; Drug Resistance; Humans; Membrane Glycoproteins; Neoplasms
PubMed: 8097103
DOI: 10.1038/bjc.1993.119 -
PLoS Medicine Nov 2017Resistance to first-line treatments for Plasmodium falciparum malaria and the insecticides used for Anopheles vector control are threatening malaria elimination efforts.... (Review)
Review
Resistance to first-line treatments for Plasmodium falciparum malaria and the insecticides used for Anopheles vector control are threatening malaria elimination efforts. Suboptimal responses to drugs and insecticides are both spreading geographically and emerging independently and are being seen at increasing intensities. Whilst resistance is unavoidable, its effects can be mitigated through resistance management practices, such as exposing the parasite or vector to more than one selective agent. Resistance contributed to the failure of the 20th century Global Malaria Eradication Programme, and yet the global response to this issue continues to be slow and poorly coordinated-too often, too little, too late. The Malaria Eradication Research Agenda (malERA) Refresh process convened a panel on resistance of both insecticides and antimalarial drugs. This paper outlines developments in the field over the past 5 years, highlights gaps in knowledge, and proposes a research agenda focused on managing resistance. A deeper understanding of the complex biological processes involved and how resistance is selected is needed, together with evidence of its public health impact. Resistance management will require improved use of entomological and parasitological data in decision making, and optimisation of the useful life of new and existing products through careful implementation, combination, and evaluation. A proactive, collaborative approach is needed from basic science and the development of new tools to programme and policy interventions that will ensure that the armamentarium of drugs and insecticides is sufficient to deal with the challenges of malaria control and its elimination.
Topics: Animals; Antimalarials; Disease Eradication; Drug Resistance; Humans; Insecticide Resistance; Insecticides; Malaria; Mosquito Control
PubMed: 29190671
DOI: 10.1371/journal.pmed.1002450 -
Sheng Wu Gong Cheng Xue Bao = Chinese... Dec 2020The discovery of antibiotics is a big revolution in human history, and its clinical application has saved countless lives. However, with the widespread and abuse of... (Review)
Review
The discovery of antibiotics is a big revolution in human history, and its clinical application has saved countless lives. However, with the widespread and abuse of antibiotics, many pathogens have developed resistance, and even "Super Bacteria" resistance to multiple drugs have evolved. In the arms race between humans and pathogens, humans are about to face a situation where no medicine is available. Research on microbial antibiotic resistance genes, resistance mechanisms, and the spread of resistance has attracted the attention of many scientific researchers, and various antibiotic resistance gene databases and analysis tools have emerged. In this review, we collect the current databases that focus on antibiotics resistance genes, and discuss these databases in terms of database types, data characteristics, antibiotics resistance gene prediction models and the types of analyzable sequences. In addition, a few gene databases of anti-metal ions and anti-biocides are also involved. It is believed that this summary will provide a reference for how to select and use antibiotic resistance gene databases.
Topics: Anti-Bacterial Agents; Bacterial Infections; Drug Resistance, Bacterial; Drug Resistance, Microbial; Humans; Metals
PubMed: 33398956
DOI: 10.13345/j.cjb.200375 -
Malaria Journal Mar 2016Plasmodium falciparum resistance to artemisinins, the most potent and fastest acting anti-malarials, threatens malaria elimination strategies. Artemisinin resistance is... (Review)
Review
Plasmodium falciparum resistance to artemisinins, the most potent and fastest acting anti-malarials, threatens malaria elimination strategies. Artemisinin resistance is due to mutation of the PfK13 propeller domain and involves an unconventional mechanism based on a quiescence state leading to parasite recrudescence as soon as drug pressure is removed. The enhanced P. falciparum quiescence capacity of artemisinin-resistant parasites results from an increased ability to manage oxidative damage and an altered cell cycle gene regulation within a complex network involving the unfolded protein response, the PI3K/PI3P/AKT pathway, the PfPK4/eIF2α cascade and yet unidentified transcription factor(s), with minimal energetic requirements and fatty acid metabolism maintained in the mitochondrion and apicoplast. The detailed study of these mechanisms offers a way forward for identifying future intervention targets to fend off established artemisinin resistance.
Topics: Antimalarials; Artemisinins; Drug Resistance; Humans; Malaria, Falciparum; Models, Biological; Plasmodium falciparum
PubMed: 26955948
DOI: 10.1186/s12936-016-1206-9 -
Current Opinion in Microbiology Oct 2023Our ability to fight infectious diseases is being increasingly compromised due to the emergence and spread of pathogens that become resistant to one or several drugs.... (Review)
Review
Our ability to fight infectious diseases is being increasingly compromised due to the emergence and spread of pathogens that become resistant to one or several drugs. This phenomenon is ubiquitous among pathogens and has parallels in cancer treatment. Given the urgency of the problem, there is a need for a paradigm shift in drug therapy toward one in which the objective to prevent the evolution of drug resistance is considered alongside the main objective of eliminating the infection or tumor. Here, I stress the importance of considering an evolutionary perspective to achieve this goal, and review recent advances in this direction, including therapies that exploit the fitness trade-offs of resistance.
Topics: Drug Resistance; Biological Evolution
PubMed: 37348192
DOI: 10.1016/j.mib.2023.102350 -
Redox Biology Sep 2020Alterations in ROS metabolism and redox signaling are often observed in cancer cells and play a significant role in tumor development and drug resistance. However, the...
Alterations in ROS metabolism and redox signaling are often observed in cancer cells and play a significant role in tumor development and drug resistance. However, the mechanisms by which redox alterations impact cellular sensitivity to anticancer drugs remain elusive. Here we have identified the mitochondrial isoform of thioredoxin reductase 3 (mtTXNRD3), through RT-PCR microarray screen, as a key molecule that confers drug resistance to sorafenib and other clinical anticancer agents. High expression of mtTXNRD3 is detected in drug-resistant leukemia and hepatocellular carcinoma cells associated with significant metabolic alterations manifested by low mitochondrial respiration and high glycolysis. Mechanistically, high mtTXNRD3 activity keeps the mitochondrial thioredoxin2 (Trx2) in a reduced stage that in turn stabilizes several key survival molecules including HK2, Bcl-XL, Bcl-2, and MCL-1, leading to increased cell survival and drug resistance. Pharmacological inhibition of thioredoxin reductase by auranofin effectively overcomes such drug resistance in vitro and in vivo, suggesting that targeting this redox mechanism may be a feasible strategy to treat drug-resistant cancer.
Topics: Apoptosis; Auranofin; Cell Line, Tumor; Drug Resistance; Drug Resistance, Neoplasm; Mitochondria; Oxidation-Reduction
PubMed: 32750669
DOI: 10.1016/j.redox.2020.101652 -
International Journal of Molecular... Sep 2022As a result of antibiotic overuse, bacterial antibiotic resistance has become a severe threat to worldwide public health. The development of more effective antimicrobial... (Review)
Review
As a result of antibiotic overuse, bacterial antibiotic resistance has become a severe threat to worldwide public health. The development of more effective antimicrobial therapies and alternative antibiotic strategies is urgently required. The role played by bacterial membrane vesicles (BMVs) in antibiotic resistance has become a current focus of research. BMVs are nanoparticles derived from the membrane components of Gram-negative and Gram-positive bacteria and contain diverse components originating from the cell envelope and cytoplasm. Antibiotic stress stimulates the secretion of BMVs. BMVs promote and mediate antibiotic resistance by multiple mechanisms. BMVs have been investigated as conceptually new antibiotics and drug-delivery vehicles. In this article, we outline the research related to BMVs and antibiotic resistance as a reference for the intentional use of BMVs to combat antibiotic resistance.
Topics: Anti-Bacterial Agents; Anti-Infective Agents; Bacteria; Cell Membrane; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial
PubMed: 36232856
DOI: 10.3390/ijms231911553