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Methods in Molecular Biology (Clifton,... 2022Understanding drug resistance in cancer is paramount to improving patient outcomes, quality of life and reducing toxicities in patients receiving chemotherapy....
Understanding drug resistance in cancer is paramount to improving patient outcomes, quality of life and reducing toxicities in patients receiving chemotherapy. Pharmacogenomic methods seek to understand the interaction of genomic variation and response to chemotherapeutic treatment. This chapter presents a workflow to interrogate multiple genomic inputs and individually assess their relationship with the phenotype of drug resistance using hierarchical clustering to determine the set of features that can best describe what features are associated with drug resistance. Then in a gene-centric manner regulatory features such as miRNAs, SNPs, or DNA methylation can be related back to the differential expression of genes to give understanding to the mechanism underlying resistance. In this chapter, we describe a computational method that can be adapted to a number of different diseases and phenotypes in which there are multiple genomic data types available with concordant phenotypic drug resistance information.
Topics: Drug Resistance; Genomics; Pharmacogenetics; Phenotype; Quality of Life
PubMed: 35867232
DOI: 10.1007/978-1-0716-2513-2_15 -
Pharmacological Reports : PR Oct 2020Drug resistance developed towards conventional therapy is one of the important reasons for chemotherapy failure in cancer. The various underlying mechanism for drug... (Review)
Review
Drug resistance developed towards conventional therapy is one of the important reasons for chemotherapy failure in cancer. The various underlying mechanism for drug resistance development in tumor includes tumor heterogeneity, some cellular levels changes, genetic factors, and others novel mechanisms which have been highlighted in the past few years. In the present scenario, researchers have to focus on these novel mechanisms and their tackling strategies. The small molecules, peptides, and nanotherapeutics have emerged to overcome the drug resistance in cancer. The drug delivery systems with targeting moiety enhance the site-specificity, receptor-mediated endocytosis, and increase the drug concentration inside the cells, thus minimizing drug resistance and improve their therapeutic efficacy. These therapeutic approaches work by modulating the different pathways responsible for drug resistance. This review focuses on the different mechanisms of drug resistance and the recent advancements in therapeutic approaches to improve the sensitivity and effectiveness of chemotherapeutics.
Topics: Antineoplastic Agents; Drug Delivery Systems; Drug Resistance, Neoplasm; Humans; Neoplasms
PubMed: 32700248
DOI: 10.1007/s43440-020-00138-7 -
Epilepsia Dec 2022Although approximately 10%-15% of patients with idiopathic generalized epilepsy (IGE)/genetic generalized epilepsy remain drug-resistant, there is no consensus or... (Review)
Review
Although approximately 10%-15% of patients with idiopathic generalized epilepsy (IGE)/genetic generalized epilepsy remain drug-resistant, there is no consensus or established concept regarding the underlying mechanisms and prevalence. This review summarizes the recent data and the current hypotheses on mechanisms that may contribute to drug-resistant IGE. A literature search was conducted in PubMed and Embase for studies on mechanisms of drug resistance published since 1980. The literature shows neither consensus on the definition nor a widely accepted model to explain drug resistance in IGE or one of its subsyndromes. Large-scale genetic studies have failed to identify distinct genetic causes or affected genes involved in pharmacokinetics. We found clinical and experimental evidence in support of four hypotheses: (1) "network hypothesis"-the degree of drug resistance in IGE reflects the severity of cortical network alterations, (2) "minor focal lesion in a predisposed brain hypothesis"-minor cortical lesions are important for drug resistance, (3) "interneuron hypothesis"-impaired functioning of γ-aminobutyric acidergic interneurons contributes to drug resistance, and (4) "changes in drug kinetics"-genetically impaired kinetics of antiseizure medication (ASM) reduce the effectiveness of available ASMs. In summary, the exact definition and cause of drug resistance in IGE is unknown. However, published evidence suggests four different mechanisms that may warrant further investigation.
Topics: Humans; Epilepsy, Generalized; Drug Resistance
PubMed: 36102351
DOI: 10.1111/epi.17410 -
Frontiers in Cellular and Infection... 2024
Topics: Humans; Anti-Bacterial Agents; Drug Resistance, Bacterial; Drug Resistance, Microbial; Anti-Infective Agents; Bacterial Infections; Bacteria
PubMed: 38895736
DOI: 10.3389/fcimb.2024.1434140 -
Drug Metabolism and Disposition: the... Aug 2023Over the past two decades, technological advances in membrane protein structural biology have provided insight into the molecular mechanisms that transporters use to... (Review)
Review
Over the past two decades, technological advances in membrane protein structural biology have provided insight into the molecular mechanisms that transporters use to move diverse substrates across the membrane. However, the plasticity of these proteins' ligand binding pockets, which allows them to bind a range of substrates, also poses a challenge for drug development. Here we highlight the structure, function, and transport mechanism of ATP-binding cassette/solute carrier transporters that are related to several diseases and multidrug resistance: ABCB1, ABCC1, ABCG2, SLC19A1, and SLC29A1. SIGNIFICANCE STATEMENT: ATP-binding cassette transporters and solute carriers play vital roles in clinical chemotherapeutic outcomes. This paper describes the current understanding of the structure of five pharmacologically relevant transporters and how they interact with their ligands.
Topics: Membrane Transport Proteins; Cryoelectron Microscopy; Multidrug Resistance-Associated Proteins; ATP-Binding Cassette Transporters; Drug Resistance, Multiple; Drug Resistance, Neoplasm
PubMed: 37438132
DOI: 10.1124/dmd.122.001004 -
The FEBS Journal Oct 2020Drug-resistant bacterial infections have led to a global health crisis. Although much effort is placed on the development of new antibiotics or variants that are less... (Review)
Review
Drug-resistant bacterial infections have led to a global health crisis. Although much effort is placed on the development of new antibiotics or variants that are less subject to existing resistance mechanisms, history shows that this strategy by itself is unlikely to solve the problem of drug resistance. Here, we discuss inhibiting evolution as a strategy that, in combination with antibiotics, may resolve the problem. Although mutagenesis is the main driver of drug resistance development, attacking the drivers of genetic diversification in pathogens has not been well explored. Bacteria possess active mechanisms that increase the rate of mutagenesis, especially at times of stress, such as during replication within eukaryotic host cells, or exposure to antibiotics. We highlight how the existence of these promutagenic proteins (evolvability factors) presents an opportunity that can be capitalized upon for the effective inhibition of drug resistance development. To help move this idea from concept to execution, we first describe a set of criteria that an 'optimal' evolvability factor would likely have to meet to be a viable therapeutic target. We then discuss the intricacies of some of the known mutagenic mechanisms and evaluate their potential as drug targets to inhibit evolution. In principle, and as suggested by recent studies, we argue that the inhibition of these and other evolvability factors should reduce resistance development. Finally, we discuss the challenges of transitioning anti-evolution drugs from the laboratory to the clinic.
Topics: Anti-Bacterial Agents; Bacterial Infections; Drug Resistance, Bacterial
PubMed: 32434280
DOI: 10.1111/febs.15370 -
Nature Microbiology Aug 2020
Topics: Anti-Bacterial Agents; Drug Resistance; Gram-Negative Bacteria
PubMed: 32710093
DOI: 10.1038/s41564-020-0767-0 -
Infection and Immunity Jun 2023Acinetobacter infections have high rates of mortality due to an increasing incidence of infections by multidrug-resistant (MDR) and extensively-drug-resistant (XDR)... (Review)
Review
Acinetobacter infections have high rates of mortality due to an increasing incidence of infections by multidrug-resistant (MDR) and extensively-drug-resistant (XDR) strains. Therefore, new therapeutic strategies for the treatment of Acinetobacter infections are urgently needed. Acinetobacter spp. are Gram-negative coccobacilli that are obligate aerobes and can utilize a wide variety of carbon sources. Acinetobacter baumannii is the main cause of Acinetobacter infections, and recent work has identified multiple strategies A. baumannii uses to acquire nutrients and replicate in the face of host nutrient restriction. Some host nutrient sources also serve antimicrobial and immunomodulatory functions. Hence, understanding Acinetobacter metabolism during infection may provide new insights into novel infection control measures. In this review, we focus on the role of metabolism during infection and in resistance to antibiotics and other antimicrobial agents and discuss the possibility that metabolism may be exploited to identify novel targets to treat Acinetobacter infections.
Topics: Humans; Anti-Bacterial Agents; Acinetobacter Infections; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Cross Infection; Acinetobacter baumannii
PubMed: 37191522
DOI: 10.1128/iai.00433-22 -
Cells Aug 2019Chemoresistance is a major problem in cancer therapy as cancer cells develop mechanisms that counteract the effect of chemotherapeutic compounds, leading to relapse and... (Review)
Review
Chemoresistance is a major problem in cancer therapy as cancer cells develop mechanisms that counteract the effect of chemotherapeutic compounds, leading to relapse and the development of more aggressive cancers that contribute to poor prognosis and survival rates of treated patients. Cancer stem cells (CSCs) play a key role in this event. Apart from their slow proliferative property, CSCs have developed a range of cellular processes that involve drug efflux, drug enzymatic inactivation and other mechanisms. In addition, the microenvironment where CSCs evolve (CSC niche), effectively contributes to their role in cancer initiation, progression and chemoresistance. In the CSC niche, immune cells, mesenchymal stem cells (MSCs), endothelial cells and cancer associated fibroblasts (CAFs) contribute to the maintenance of CSC malignancy via the secretion of factors that promote cancer progression and resistance to chemotherapy. Due to these factors that hinder successful cancer therapies, CSCs are a subject of intense research that aims at better understanding of CSC behaviour and at developing efficient targeting therapies. In this review, we provide an overview of cancer stem cells, their role in cancer initiation, progression and chemoresistance, and discuss the progress that has been made in the development of CSC targeted therapies.
Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Neoplasms; Neoplastic Stem Cells; Tumor Microenvironment
PubMed: 31426611
DOI: 10.3390/cells8080926 -
Current Opinion in Microbiology Oct 2023Bacterial pathogens are constantly evolving new resistance mechanisms against antibiotics; hence, strategies to potentiate existing antibiotics or combat mechanisms of... (Review)
Review
Bacterial pathogens are constantly evolving new resistance mechanisms against antibiotics; hence, strategies to potentiate existing antibiotics or combat mechanisms of resistance using adjuvants are always in demand. Recently, inhibitors have been identified that counteract enzymatic modification of the drugs isoniazid and rifampin, which have implications in the study of multi-drug-resistant mycobacteria. A wealth of structural studies on efflux pumps from diverse bacteria has also fueled the design of new small-molecule and peptide-based agents to prevent the active transport of antibiotics. We envision that these findings will inspire microbiologists to apply existing adjuvants to clinically relevant resistant strains, or to use described platforms to discover novel antibiotic adjuvant scaffolds.
Topics: Bacteria; Anti-Bacterial Agents; Drug Resistance, Microbial; Biological Transport; Drug Resistance, Multiple, Bacterial
PubMed: 37329679
DOI: 10.1016/j.mib.2023.102334