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Expert Opinion on Drug Delivery Nov 2018A major concern that limits the success of cancer chemotherapy is multidrug resistance (MDR). The drug resistance mechanisms are either host related or tumor related.... (Review)
Review
INTRODUCTION
A major concern that limits the success of cancer chemotherapy is multidrug resistance (MDR). The drug resistance mechanisms are either host related or tumor related. The host tumor interacting factors also contribute to MDR. Multifunctional polymeric micelles offer several advantages in circumventing MDR due to their design, selectivity, and stability in cancer microenvironment.
AREAS COVERED
The review is broadly divided into two parts: the first part covers MDR and its mechanisms; the second part covers multifunctional polymeric micelles in combating MDR through its state-of-the-art design. This part covers various strategies like use of P-gp transporter inhibitors, TPGS, pH & thermo-sensitive, and siRNA for selectivity of PMs against multidrug-resistant tumors.
EXPERT OPINION
Numerous approaches have been tested using polymeric micelles to overcome MDR tumors. However, these are either limited to only in-vitro investigations and/or preliminary preclinical models and do not investigate the underlying biological mechanism. Hence, there exists an unmet need to perform fundamental research that focuses on studying the underlying mechanism and preclinical/clinical testing of the micellar formulations.
Topics: Animals; Antineoplastic Agents; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Micelles; Neoplasms; Polymers
PubMed: 30324813
DOI: 10.1080/17425247.2018.1537261 -
Cellular Signalling Oct 2017The cancer multidrug resistance (MDR) phenotype encompasses a myriad of molecular, genetic and cellular alterations resulting from progressive oncogenic transformation... (Review)
Review
The cancer multidrug resistance (MDR) phenotype encompasses a myriad of molecular, genetic and cellular alterations resulting from progressive oncogenic transformation and selection. Drug efflux transporters, in particular the MDR P-glycoprotein ABCB1, play an important role in MDR but cannot confer the complete phenotype alone indicating parallel alterations are prerequisite. Sphingolipids are essential constituents of lipid raft domains and directly participate in functionalization of transmembrane proteins, including providing an optimal lipid microenvironment for multidrug transporters, and are also perturbed in cancer. Here we postulate that increased sphingomyelin content, developing early in some cancers, recruits and functionalizes plasma membrane ABCB1 conferring a state of partial MDR, which is completed by glycosphingolipid disturbance and the appearance of intracellular vesicular ABCB1. In this review, the independent and interdependent roles of sphingolipid alterations and ABCB1 upregulation during the transformation process and resultant conferment of partial and complete MDR phenotypes are discussed.
Topics: Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Membrane Microdomains; Neoplasms; Phenotype; Sphingolipids
PubMed: 28687494
DOI: 10.1016/j.cellsig.2017.06.017 -
Life Sciences Oct 2019Multidrug resistances against chemotherapeutics are among the major challenges related to cancer treatment. Recent studies have demonstrated that different conditions... (Review)
Review
Multidrug resistances against chemotherapeutics are among the major challenges related to cancer treatment. Recent studies have demonstrated that different conditions may tune the expression and activity of MDR transporters. For instance, inflammation occurs through a complex cytological process and chemical reactions in the most tumor microenvironment; it can play a critical role in cancer development and is capable of altering the expression and function of MDR transporters. Cytokines, interleukins, and prostaglandins are potent inflammatory mediators that can modulate the expression of MDRs at transcriptional and post-transcriptional levels in the most human cancer cells and tissues and potentially contribute to balance bioavailability of chemotherapeutic agents. Since cancer cases are usually accompanied by inflammatory responses, glucocorticoids and NSAIDs are the primary useful combination chemotherapies in a variety of cancer treatment protocols. In addition to the anti-inflammatory activities of these agents, they exert diverse modulatory effects on MDR-mediated drug resistance via specific mechanisms. Several factors, including cell and MDR-protein types, pharmacokinetics, and pharmacogenetics, mainly influence the regulatory mechanisms. Uncovering the networks between inflammation and multidrug resistance will be clinically helpful in the treatment of malignant cancers and decreasing the cancer mortality rates.
Topics: Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Inflammation; Multidrug Resistance-Associated Proteins
PubMed: 31494169
DOI: 10.1016/j.lfs.2019.116825 -
Science Signaling Oct 2018This Editorial discusses the state of research on drug resistance in the fields of cancer, infectious disease, and agriculture. Reaching across the aisle for a more...
This Editorial discusses the state of research on drug resistance in the fields of cancer, infectious disease, and agriculture. Reaching across the aisle for a more cross-collaborative approach may lead to exciting breakthroughs toward tackling the challenges of drug resistance in each field.
Topics: Agriculture; Communicable Diseases; Drug Resistance, Microbial; Drug Resistance, Neoplasm; Humans; Interdisciplinary Communication; Mutation; Neoplasms; Stochastic Processes
PubMed: 30352947
DOI: 10.1126/scisignal.aav0442 -
International Journal of Molecular... Nov 2020Chemotherapy and radiation often induce a number of cellular responses, such as apoptosis, autophagy, and senescence. One of the major regulators of these processes is... (Review)
Review
Chemotherapy and radiation often induce a number of cellular responses, such as apoptosis, autophagy, and senescence. One of the major regulators of these processes is p53, an essential tumor suppressor that is often mutated or lost in many cancer types and implicated in early tumorigenesis. Gain of function (GOF) p53 mutations have been implicated in increased susceptibility to drug resistance, by compromising wildtype anti-tumor functions of p53 or modulating key p53 processes that confer chemotherapy resistance, such as autophagy. Autophagy, a cellular survival mechanism, is initially induced in response to chemotherapy and radiotherapy, and its cytoprotective nature became the spearhead of a number of clinical trials aimed to sensitize patients to chemotherapy. However, increased pre-clinical studies have exemplified the multifunctional role of autophagy. Additionally, compartmental localization of p53 can modulate induction or inhibition of autophagy and may play a role in autophagic function. The duality in p53 function and its effects on autophagic function are generally not considered in clinical trial design or clinical therapeutics; however, ample pre-clinical studies suggest they play a role in tumor responses to therapy and drug resistance. Further inquiry into the interconnection between autophagy and p53, and its effects on chemotherapeutic responses may provide beneficial insights on multidrug resistance and novel treatment regimens for chemosensitization.
Topics: Animals; Autophagy; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Models, Biological; Neoplasms; Tumor Suppressor Protein p53
PubMed: 33256191
DOI: 10.3390/ijms21238991 -
Biomedicine & Pharmacotherapy =... Jul 2020Chemotherapy and targeted therapy can significantly improve survival rates in cancer, but multiple drug resistance (MDR) limits the efficacy of these approaches.... (Review)
Review
Chemotherapy and targeted therapy can significantly improve survival rates in cancer, but multiple drug resistance (MDR) limits the efficacy of these approaches. Understanding the molecular mechanisms underlying MDR is crucial for improving drug efficacy and clinical outcomes of patients with cancer. S100 proteins belong to a family of calcium-binding proteins and have various functions in tumor development. Increasing evidence demonstrates that the dysregulation of various S100 proteins contributes to the development of drug resistance in tumors, providing a basis for the development of predictive and prognostic biomarkers in cancer. Therefore, a combination of biological inhibitors or sensitizers of dysregulated S100 proteins could enhance therapeutic responses. In this review, we provide a detailed overview of the mechanisms by which S100 family members influence resistance of tumors to cancer treatment, with a focus on the development of effective strategies for overcoming MDR.
Topics: Animals; Antineoplastic Agents; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Molecular Targeted Therapy; Neoplasms; S100 Proteins
PubMed: 32335300
DOI: 10.1016/j.biopha.2020.110156 -
Environmental Pollution (Barking, Essex... Nov 2023The surge of Antibiotic Resistant Bacteria (ARB) in the environment is poised to be the next health threat. World Health Organisation's (WHO's) Global Antimicrobial...
The surge of Antibiotic Resistant Bacteria (ARB) in the environment is poised to be the next health threat. World Health Organisation's (WHO's) Global Antimicrobial Surveillance System (GLASS) report indicates that developing countries may be at a greater risk. Among various factors, the major driver here could be untreated wastewater and poor sanitation. Bacteria are extremely adaptable to their surroundings and develop Antimicrobial Resistance (AMR) when exposed to antibiotics and other pollutants that cause microbial stress. Thus, untreated domestic wastewater drains could easily become hotspots for the occurrence of ARBs. This study reports surveillance of sewage-carrying drains across four urban cities in India and demonstrated the presence of ARBs in the bacterial community against 7 classes of antibiotics, namely, β-Lactams, Chloramphenicol, Glycopeptides, Macrolides, Tetracycline, Third Generation Cephalosporin, and Quinolones. Untreated domestic wastewater flowing in target drains was collected twice a month, for a period of six months and the microbial community was subjected to Antibiotic Susceptibility Testing (AST) by plate assays. The zone of inhibition was recorded and interpreted as per the interpretive chart of The Clinical & Laboratory Standards Institute (CLSI) & The European Committee on Antimicrobial Susceptibility Testing (EUCAST). The total number of samples showing resistance against antibiotics was used to define an Antibiotic Resistance Index (ARI), calculated for all 20 sampling sites (drains). Results demonstrated that the highest ARI was observed in Delhi and Mumbai, ranging from 0.81 to 0.92 in Delhi and 0.49-0.56 in Mumbai. This surveillance study reveals the antibiotic resistance pattern of the representative bacterial community in the drains and goes beyond few targeted bacterial species. The alarming presence of antibiotic resistant bacterial community highlights the concern of ARBs being the next looming health threat. This report aims to demonstrates the importance of considering sewage surveillance on routine basis by state authorities.
Topics: Wastewater; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Anti-Bacterial Agents; Drug Resistance, Microbial; Bacteria; Drug Resistance, Bacterial
PubMed: 37741538
DOI: 10.1016/j.envpol.2023.122586 -
International Journal of Cardiology Oct 2016Aspirin is the most widely prescribed drug for the primary and secondary prevention of cardiovascular and cerebrovascular diseases. However, a large number of patients... (Review)
Review
Aspirin is the most widely prescribed drug for the primary and secondary prevention of cardiovascular and cerebrovascular diseases. However, a large number of patients continue to experience thromboembolic events despite aspirin therapy, a phenomenon referred to as aspirin resistance or treatment failure. Aspirin resistance is often observed along with a high incidence of unstable plaque, cardiovascular events and cerebrovascular accident. Studies have shown that aspirin reduces the production of TXA2, but not totally inhibits the activation of platelets. In this review, we analyze current and past research on aspirin resistance, presenting important summaries of results regarding the potential contributive roles of single nucleotide polymorphisms, inflammation, metabolic syndrome and miRNAs. The aim of this article is to provide a brief review on aspirin resistance and platelet function, which will provide important insights into the research of aspirin resistance.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Blood Platelets; Drug Resistance; Humans; Inflammation Mediators; MicroRNAs; Platelet Aggregation Inhibitors; Polymorphism, Single Nucleotide
PubMed: 27372038
DOI: 10.1016/j.ijcard.2016.06.104 -
Nature Reviews. Microbiology Sep 2020Antibiotic treatment failure is of growing concern. Genetically encoded resistance is key in driving this process. However, there is increasing evidence that bacterial... (Review)
Review
Antibiotic treatment failure is of growing concern. Genetically encoded resistance is key in driving this process. However, there is increasing evidence that bacterial antibiotic persistence, a non-genetically encoded and reversible loss of antibiotic susceptibility, contributes to treatment failure and emergence of resistant strains as well. In this Review, we discuss the evolutionary forces that may drive the selection for antibiotic persistence. We review how some aspects of antibiotic persistence have been directly selected for whereas others result from indirect selection in disparate ecological contexts. We then discuss the consequences of antibiotic persistence on pathogen evolution. Persisters can facilitate the evolution of antibiotic resistance and virulence. Finally, we propose practical means to prevent persister formation and how this may help to slow down the evolution of virulence and resistance in pathogens.
Topics: Anti-Bacterial Agents; Bacteria; Drug Resistance, Bacterial; Evolution, Molecular
PubMed: 32461608
DOI: 10.1038/s41579-020-0378-z -
Drug Resistance Updates : Reviews and... Sep 2016Efficacy of chemotherapy in the treatment of distinct malignancies is often hampered by drug resistance arising in the tumor. Understanding the molecular basis of drug... (Review)
Review
Efficacy of chemotherapy in the treatment of distinct malignancies is often hampered by drug resistance arising in the tumor. Understanding the molecular basis of drug resistance and translating this knowledge into personalized treatment decisions can enhance therapeutic efficacy and even curative outcome. Over the years, multiple drug resistance mechanisms have been identified that enable tumors to cope with the damage instigated by a specific drug or group of anti-tumor agents. Here we provide an overview of the molecular pathways leading to resistance against conventional anti-cancer drugs, with emphasis on the utility of these pathways for rational selection of treatments for individual cancer patients. We further complement the review by discussing the pitfalls and difficulties in translating these findings into novel treatment strategies for cancer patients.
Topics: Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Cisplatin; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Molecular Targeted Therapy; Neoplasm Proteins; Neoplasms; Precision Medicine; Signal Transduction
PubMed: 27620955
DOI: 10.1016/j.drup.2016.07.001