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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 -
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 -
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 -
Praxis Feb 2020
Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial
PubMed: 32019456
DOI: 10.1024/1661-8157/a003414 -
Drug Resistance Updates : Reviews and... Jan 2023Drug resistance is well-defined as a serious problem in our living world. To survive, microbes develop defense strategies against antimicrobial drugs. Drugs exhibit less... (Review)
Review
Drug resistance is well-defined as a serious problem in our living world. To survive, microbes develop defense strategies against antimicrobial drugs. Drugs exhibit less or no effective results against microbes after the emergence of resistance because they are unable to cross the microbial membrane, in order to alter enzymatic systems, and/or upregulate efflux pumps, etc. Drug resistance issues can be addressed effectively if a "Resistance-Proof" or "Resistance-Resistant" antimicrobial agent is developed. This article discusses first the need for resistance-proof drugs, the imminent properties of resistance-proof drugs, current and future research progress in the discovery of resistance-proof antimicrobials, the inherent challenges, and opportunities. A molecule having imminent resistance-proof properties could target microbes efficiently, increase potency, and rule out the possibility of early resistance. This review triggers the scientific community to think about how an upsurge in drug resistance can be averted and emphasizes the discussion on the development of next-generation antimicrobials that will provide a novel effective solution to combat the global problem of drug resistance. Hence, resistance-proof drug development is not just a requirement but rather a compulsion in the drug discovery field so that resistance can be battled effectively. We discuss several properties of resistance-proof drugs which could initiate new ways of thinking about next-generation antimicrobials to resolve the drug resistance problem. This article sheds light on the issues of drug resistance and discusses solutions in terms of the resistance-proof properties of a molecule. In summary, the article is a foundation to break new ground in the development of resistance-proof therapeutics in the field of infection biology.
Topics: Humans; Anti-Bacterial Agents; Drug Resistance, Bacterial; Anti-Infective Agents; Drug Resistance; Drug Discovery
PubMed: 36455341
DOI: 10.1016/j.drup.2022.100890 -
Life Sciences Jan 2021Cytotoxic drugs remain the first-line option for cancer therapy but the development of drug-resistance by tumor cells represents a primary obstacle for successful... (Review)
Review
Cytotoxic drugs remain the first-line option for cancer therapy but the development of drug-resistance by tumor cells represents a primary obstacle for successful chemotherapy. Autophagy is a physiological mechanism of cell survival efficiently used by tumor cells to avoid cell death and to induce drug-resistance. It is a macromolecular process, in which cells degrade and recycle intracellular substrates and damaged organelles to alleviate cell stress caused by nutritional deprivation, hypoxia, irradiation, and cytotoxic agents, as well. There is evidence that autophagy prevents cancer during the early steps of carcinogenesis, but once transformed, these cells show enhanced autophagy capacity and use it to survive, grow, and facilitate metastasis. Current basic studies and clinical trials show the feasibility of using pharmacological or molecular blockage of autophagy to improve the anticancer therapy efficiency. In this review, we overviewed the pathways and molecular aspects of autophagy, its role in carcinogenesis, and the evidence for its role in cancer adaptation and drug-resistance. Finally, we reviewed the clinical findings on how the autophagy interference helps to improve conventional anticancer therapy.
Topics: Antineoplastic Agents; Autophagy; Cell Death; Cell Survival; Drug Resistance, Neoplasm; Humans; Neoplasms; Signal Transduction
PubMed: 33186569
DOI: 10.1016/j.lfs.2020.118745 -
Molecular Medicine Reports Apr 2020Epilepsy is a common, serious neurological disorder worldwide. Although this disease can be successfully treated in most cases, not all patients respond favorably to... (Review)
Review
Epilepsy is a common, serious neurological disorder worldwide. Although this disease can be successfully treated in most cases, not all patients respond favorably to medical treatments, which can lead to pharmacoresistant epilepsy. Drug‑resistant epilepsy can be caused by a number of mechanisms that may involve environmental and genetic factors, as well as disease‑ and drug‑related factors. In recent years, numerous studies have demonstrated that genetic variation is involved in the drug resistance of epilepsy, especially genetic variations found in drug resistance‑related genes, including the voltage‑dependent sodium and potassium channels genes, and the metabolizer of endogenous and xenobiotic substances genes. The present review aimed to highlight the genetic variants that are involved in the regulation of drug resistance in epilepsy; a comprehensive understanding of the role of genetic variation in drug resistance will help us develop improved strategies to regulate drug resistance efficiently and determine the pathophysiological processes that underlie this common human neurological disease.
Topics: Drug Resistance; Epilepsy; Genetic Variation; Humans
PubMed: 32319641
DOI: 10.3892/mmr.2020.10999 -
Mini Reviews in Medicinal Chemistry 2023Multidrug Resistance (MDR) in tumor cells, a phenomenon in which tumor cells become resistant to chemotherapeutic drugs with different chemical structures and mechanisms...
Multidrug Resistance (MDR) in tumor cells, a phenomenon in which tumor cells become resistant to chemotherapeutic drugs with different chemical structures and mechanisms of action, is a major obstacle to tumor therapy and is an urgent problem to be addressed. Autophagy, widely found in eukaryotic cells, is a lysosome-dependent pathway of self-degradation. In different environments, autophagy can play different roles in the self-protection of cells. At different stages of tumorigenesis, autophagy can play two distinct roles: inhibition of cancer and promotion of cancer. The relationship between autophagy and drug resistance in tumor cells is complex. Moreover, autophagy can play a role in promoting drug resistance and drug sensitivity through different molecular pathways. This study aimed to investigate the relationship between autophagy and drug resistance in tumor cells from the perspective of molecular mechanisms.
Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Drug Resistance, Multiple; Cell Line, Tumor; Autophagy
PubMed: 36065919
DOI: 10.2174/1389557522666220905090732