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Biomedicine & Pharmacotherapy =... Sep 2023Drug resistance is the main obstacle to achieving a cure in many cancer patients. Reactive oxygen species (ROS) are master regulators of cancer development that act... (Review)
Review
Drug resistance is the main obstacle to achieving a cure in many cancer patients. Reactive oxygen species (ROS) are master regulators of cancer development that act through complex mechanisms. Remarkably, ROS levels and antioxidant content are typically higher in drug-resistant cancer cells than in non-resistant and normal cells, and have been shown to play a central role in modulating drug resistance. Therefore, determining the underlying functions of ROS in the modulation of drug resistance will contribute to develop therapies that sensitize cancer resistant cells by leveraging ROS modulation. In this review, we summarize the notable literature on the sources and regulation of ROS production and highlight the complex roles of ROS in cancer chemoresistance, encompassing transcription factor-mediated chemoresistance, maintenance of cancer stem cells, and their impact on the tumor microenvironment. We also discuss the potential of ROS-targeted therapies in overcoming tumor therapeutic resistance.
Topics: Humans; Reactive Oxygen Species; Drug Resistance, Neoplasm; Neoplasms; Tumor Microenvironment
PubMed: 37354814
DOI: 10.1016/j.biopha.2023.115036 -
Biomedicine & Pharmacotherapy =... Oct 2023Despite continuous improvements in research and new cancer therapeutics, the goal of eradicating cancer remains elusive because of drug resistance. For a long time, drug... (Review)
Review
Despite continuous improvements in research and new cancer therapeutics, the goal of eradicating cancer remains elusive because of drug resistance. For a long time, drug resistance research has been focused on tumor cells themselves; however, recent studies have found that the tumor microenvironment also plays an important role in inducing drug resistance. Cancer-associated fibroblasts (CAFs) are a main component of the tumor microenvironment. They cross-talk with cancer cells to support their survival in the presence of anticancer drugs. This review summarizes the current knowledge of the role of CAFs in tumor drug resistance. An in-depth understanding of the mechanisms underlying the cross-talk between CAFs and cancer cells and insight into the importance of CAFs in drug resistance can guide the development of new anticancer strategies.
Topics: Cancer-Associated Fibroblasts; Drug Resistance, Neoplasm; Knowledge; Tumor Microenvironment; Neoplasms
PubMed: 37660643
DOI: 10.1016/j.biopha.2023.115425 -
International Journal of Molecular... Aug 2023Cisplatin is a first-line clinical agent used for treating solid tumors. Cisplatin damages the DNA of tumor cells and induces the production of high levels of reactive... (Review)
Review
Cisplatin is a first-line clinical agent used for treating solid tumors. Cisplatin damages the DNA of tumor cells and induces the production of high levels of reactive oxygen species to achieve tumor killing. Tumor cells have evolved several ways to tolerate this damage. Extracellular vesicles (EVs) are an important mode of information transfer in tumor cells. EVs can be substantially activated under cisplatin treatment and mediate different responses of tumor cells under cisplatin treatment depending on their different cargoes. However, the mechanism of action of tumor-cell-derived EVs under cisplatin treatment and their potential cargoes are still unclear. This review considers recent advances in cisplatin-induced release of EVs from tumor cells, with the expectation of providing a new understanding of the mechanisms of cisplatin treatment and drug resistance, as well as strategies for the combined use of cisplatin and other drugs.
Topics: Humans; Cisplatin; Extracellular Vesicles; Drug Resistance; Neoplasms; Reactive Oxygen Species
PubMed: 37569723
DOI: 10.3390/ijms241512347 -
Cell Reports Oct 2023Acquired drug resistance is a major problem in the treatment of cancer. hTERT-immortalized, untransformed RPE-1 cells can acquire resistance to Taxol by derepressing the...
Acquired drug resistance is a major problem in the treatment of cancer. hTERT-immortalized, untransformed RPE-1 cells can acquire resistance to Taxol by derepressing the ABCB1 gene, encoding for the multidrug transporter P-gP. Here, we investigate how the ABCB1 gene is derepressed. ABCB1 activation is associated with reduced H3K9 trimethylation, increased H3K27 acetylation, and ABCB1 displacement from the nuclear lamina. While altering DNA methylation and H3K27 methylation had no major impact on ABCB1 expression, nor did it promote resistance, disrupting the nuclear lamina component Lamin B Receptor did promote the acquisition of a Taxol-resistant phenotype in a subset of cells. CRISPRa-mediated gene activation supported the notion that lamina dissociation influences ABCB1 derepression. We propose a model in which nuclear lamina dissociation of a repressed gene allows for its activation, implying that deregulation of the 3D genome topology could play an important role in tumor evolution and the acquisition of drug resistance.
Topics: Humans; Drug Resistance, Neoplasm; Paclitaxel; Drug Resistance, Multiple; Neoplasms; DNA Methylation; Cell Line, Tumor
PubMed: 37733591
DOI: 10.1016/j.celrep.2023.113124 -
MBio Aug 2023Conjugative plasmids play a vital role in bacterial evolution and promote the spread of antibiotic resistance. They usually cause fitness costs that diminish the growth...
Conjugative plasmids play a vital role in bacterial evolution and promote the spread of antibiotic resistance. They usually cause fitness costs that diminish the growth rates of the host bacteria. Compensatory mutations are known as an effective evolutionary solution to reduce the fitness cost and improve plasmid persistence. However, whether the plasmid transmission by conjugation is sufficient to improve plasmid persistence is debated since it is an inherently costly process. Here, we experimentally evolved an unstable and costly plasmid pHNSHP24 under laboratory conditions and assessed the effects of plasmid cost and transmission on the plasmid maintenance by the plasmid population dynamics model and a plasmid invasion experiment designed to measure the plasmid's ability to invade a plasmid-free bacterial population. The persistence of pHNSHP24 improved after 36 days evolution due to the plasmid-borne mutation A51G in the 5'UTR of gene . This mutation largely increased the infectious transmission of the evolved plasmid, presumably by impairing the inhibitory effect of FinP on the expression of . We showed that increased conjugation rate of the evolved plasmid could compensate for the plasmid loss. Furthermore, we determined that the evolved high transmissibility had little effect on the -deficient ancestral plasmid, implying that high conjugation transfer is vital for maintaining the -bearing plasmid. Altogether, our findings emphasized that, besides compensatory evolution that reduces fitness costs, the evolution of infectious transmission can improve the persistence of antibiotic-resistant plasmids, indicating that inhibition of the conjugation process could be useful to combat the spread of antibiotic-resistant plasmids. IMPORTANCE Conjugative plasmids play a key role in the spread of antibiotic resistance, and they are well-adapted to the host bacteria. However, the evolutionary adaptation of plasmid-bacteria associations is not well understood. In this study, we experimentally evolved an unstable colistin resistance () plasmid under laboratory conditions and found that increased conjugation rate was crucial for the persistence of this plasmid. Interestingly, the evolved conjugation was caused by a single-base mutation, which could rescue the unstable plasmid from extinction in bacterial populations. Our findings imply that inhibition of the conjugation process could be necessary for combating the persistence of antibiotic-resistance plasmids.
Topics: Plasmids; Drug Resistance, Microbial; Bacteria; Mutation; Anti-Bacterial Agents
PubMed: 37314200
DOI: 10.1128/mbio.00442-23 -
International Journal of Molecular... Jul 2023Antimicrobial resistance is presently one of the greatest threats to public health. The excessive and indiscriminate use of antibiotics imposes a continuous selective...
Antimicrobial resistance is presently one of the greatest threats to public health. The excessive and indiscriminate use of antibiotics imposes a continuous selective pressure that triggers the emergence of multi-drug resistance. We performed a large-scale analysis of closed bacterial genomes to identify multi-drug resistance considering the ResFinder antimicrobial classes. We found that more than 95% of the genomes harbor genes associated with resistance to disinfectants, glycopeptides, macrolides, and tetracyclines. On average, each genome encodes resistance to more than nine different classes of antimicrobial drugs. We found higher-than-expected co-occurrences of resistance genes in both plasmids and chromosomes for several classes of antibiotic resistance, including classes categorized as critical according to the World Health Organization (WHO). As a result of antibiotic-resistant priority pathogens, higher-than-expected co-occurrences appear in plasmids, increasing the potential for resistance dissemination. For the first time, co-occurrences of antibiotic resistance have been investigated for priority pathogens as defined by the WHO. For critically important pathogens, co-occurrences appear in plasmids, not in chromosomes, suggesting that the resistances may be epidemic and probably recent. These results hint at the need for new approaches to treating infections caused by critically important bacteria.
Topics: Genome, Bacterial; Plasmids; Anti-Bacterial Agents; Computational Biology; Drug Resistance, Multiple; Drug Resistance, Multiple, Bacterial; Drug Resistance, Bacterial
PubMed: 37511196
DOI: 10.3390/ijms241411438 -
Journal of Infection and Public Health Dec 2023The emergence and re-emergence of tick-borne bacteria (TBB) as a public health problem raises the uncertainty of antibiotic resistance in these pathogens, which could be... (Review)
Review
The emergence and re-emergence of tick-borne bacteria (TBB) as a public health problem raises the uncertainty of antibiotic resistance in these pathogens, which could be dispersed to other pathogens. The impact of global warming has led to the emergence of pathogenic TBB in areas where they were not previously present and is another risk that must be taken into account under the One Health guides. This review aimed to analyze the existing information regarding antibiotic-resistant TBB and antibiotic-resistance genes (ARG) present in the tick microbiome, considering the potential to be transmitted to pathogenic microorganisms. Several Ehrlichia species have been reported to exhibit natural resistance to fluoroquinolones and typhus group Rickettsiae are naturally susceptible to erythromycin. TBB have a lower risk of acquiring ARG due to their natural habitat, but there is still a probability of acquiring them; furthermore, studies of these pathogens are limited. Pathogenic and commensal bacteria coexist within the tick microbiome along with ARGs for antibiotic deactivation, cellular protection, and efflux pumps; these ARGs confer resistance to antibiotics such as aminoglycosides, beta-lactamase, diaminopyrimidines, fluoroquinolones, glycopeptides, sulfonamides, and tetracyclines. Although with low probability, TBB can be a reservoir of ARGs.
Topics: Humans; One Health; Bacteria; Anti-Bacterial Agents; Drug Resistance, Microbial; Genes, Bacterial; Fluoroquinolones
PubMed: 37945496
DOI: 10.1016/j.jiph.2023.10.027 -
PLoS Pathogens May 2024With the escalating global antimicrobial resistance crisis, there is an urgent need for innovative strategies against drug-resistant microbes. Accumulating evidence... (Review)
Review
With the escalating global antimicrobial resistance crisis, there is an urgent need for innovative strategies against drug-resistant microbes. Accumulating evidence indicates microbial extracellular vesicles (EVs) contribute to antimicrobial resistance. Therefore, comprehensively elucidating the roles and mechanisms of microbial EVs in conferring resistance could provide new perspectives and avenues for novel antimicrobial approaches. In this review, we systematically examine current research on antimicrobial resistance involving bacterial, fungal, and parasitic EVs, delineating the mechanisms whereby microbial EVs promote resistance. Finally, we discuss the application of bacterial EVs in antimicrobial therapy.
Topics: Extracellular Vesicles; Humans; Bacteria; Fungi; Animals; Anti-Bacterial Agents; Drug Resistance, Microbial; Drug Resistance, Bacterial; Bacterial Infections
PubMed: 38696356
DOI: 10.1371/journal.ppat.1012143 -
Drug Delivery and Translational Research Jun 2024Antimicrobial resistance and tolerance (AMR&T) are urgent global health concerns, with alarmingly increasing numbers of antimicrobial drugs failing and a corresponding... (Review)
Review
Antimicrobial resistance and tolerance (AMR&T) are urgent global health concerns, with alarmingly increasing numbers of antimicrobial drugs failing and a corresponding rise in related deaths. Several reasons for this situation can be cited, such as the misuse of traditional antibiotics, the massive use of sanitizing measures, and the overuse of antibiotics in agriculture, fisheries, and cattle. AMR&T management requires a multifaceted approach involving various strategies at different levels, such as increasing the patient's awareness of the situation and measures to reduce new resistances, reduction of current misuse or abuse, and improvement of selectivity of treatments. Also, the identification of new antibiotics, including small molecules and more complex approaches, is a key factor. Among these, novel DNA- or RNA-based approaches, the use of phages, or CRISPR technologies are some potent strategies under development. In this perspective article, emerging and experienced leaders in drug delivery discuss the most important biological barriers for drugs to reach infectious bacteria (bacterial bioavailability). They explore how overcoming these barriers is crucial for producing the desired effects and discuss the ways in which drug delivery systems can facilitate this process.
Topics: Humans; Anti-Bacterial Agents; Drug Delivery Systems; Animals; Drug Resistance, Microbial; Drug Resistance, Bacterial; Bacteria; Drug Tolerance
PubMed: 38341386
DOI: 10.1007/s13346-023-01513-6 -
Infection, Genetics and Evolution :... Aug 2023Malaria still poses a major burden on human health around the world, especially in endemic areas. Plasmodium resistance to several antimalarial drugs has been one of the... (Review)
Review
Malaria still poses a major burden on human health around the world, especially in endemic areas. Plasmodium resistance to several antimalarial drugs has been one of the major hindrances in control of malaria. Thus, the World Health Organization recommended artemisinin-based combination therapy (ACT) as a front-line treatment for malaria. The emergence of parasites resistant to artemisinin, along with resistant to ACT partner drugs, has led to ACT treatment failure. The artemisinin resistance is mostly related to the mutations in the propeller domain of the kelch13 (k13) gene that encodes protein Kelch13 (K13). The K13 protein has an important role in parasite reaction to oxidative stress. The most widely spread mutation in K13, with the highest degree of resistance, is a C580Y mutation. Other mutations, which are already identified as markers of artemisinin resistance, are R539T, I543T, and Y493H. The objective of this review is to provide current molecular insights into artemisinin resistance in Plasmodium falciparum. The trending use of artemisinin beyond its antimalarial effect is described. Immediate challenges and future research directions are discussed. Better understanding of the molecular mechanisms underlying artemisinin resistance will accelerate implementation of scientific findings to solve problems with malarial infection.
Topics: Humans; Plasmodium falciparum; Artemisinins; Malaria, Falciparum; Antimalarials; Mutation; Protozoan Proteins; Drug Resistance
PubMed: 37269964
DOI: 10.1016/j.meegid.2023.105460