Drug resistance: from bacteria to cancer

AbstractThe phenomenon of drug resistance has been a hindrance to therapeutic medicine since the late 1940s. There is a plethora of factors and mechanisms contributing to progression of drug resistance. From prokaryotes to complex cancers, drug resistance is a prevailing issue in clinical medicine. Although there are numerous factors causing and influencing the phenomenon of drug resistance, cellular transporters contribute to a noticeable majority. Efflux transporters form a huge family of proteins and are found in a vast number of species spanning from prokaryotes to complex organisms such as humans. During the last couple of decades, various approaches in analyses of biochemistry and pharmacology of transporters have led us to understand much more about drug resistance. In this review, we have discussed the structure, function, potential causes, and mechanisms of multidrug resistance in bacteria as well as cancers.

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Expressional Study of Permeability glycoprotein (P-gp) and Multidrug Resistance Protein 1 (MRP-1) in Drug-Resistant Mesial Temporal Lobe Epilepsy

Basic and Clinical Neuroscience Journal ◽

10.32598/bcn.2021.2554.3 ◽

2021 ◽

pp. 1-31

Author(s):

Mandeep Kaur ◽

◽

Tulika Gupta ◽

Mili Gupta ◽

Parampreet S. Kharbanda ◽

...

Keyword(s):

Drug Resistance ◽

Multidrug Resistance ◽

Mesial Temporal Lobe Epilepsy ◽

Efflux Transporters ◽

P Value ◽

Drug Efflux ◽

Drug Resistant ◽

Glycoprotein P ◽

Mesial Temporal Lobe ◽

Drug Efflux Transporters

About 30% of epileptic patients do not react to anti-epileptic drugs leading to refractory seizures. The pathogenesis of drug-resistance in Mesial Temporal Lobe Epilepsy (MTLE) is not completely understood. Increased activity of drug-efflux transporters might be involved, resulting in subclinical concentrations of the drug at the target site. The major drug-efflux transporters are permeability glycoprotein (P-gp) and multidrug-resistance associated protein-1 (MRP-1). The major drawback so far is the expressional analysis of transporters in equal numbers of drug-resistant epileptic tissue and age-matched non-epileptic tissue. We have studied these two transporters in the sclerotic hippocampal tissues resected from the epilepsy surgery (n=15) and compared their expression profile with the tissues resected from non-epileptic autopsy cases (n=15). Statistically significant over expression of both P-gp (p-value <0.0001) and MRP-1 (p-value 0.01) at gene and protein levels was found in the MTLE cases. The fold change of P-gp was more pronounced than MRP-1. Immunohistochemistry of patient group showed increased immunoreactivity of P-gp at blood brain barrier and increased reactivity of MRP-1 in parenchyma. The results were confirmed by confocal immunofluorescence microscopy. The study demonstrated that P-gp in association with MRP-1 might be responsible for the multi-drug resistance in epilepsy

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Distribution and Physiology of ABC-Type Transporters Contributing to Multidrug Resistance in Bacteria

Microbiology and Molecular Biology Reviews ◽

10.1128/mmbr.00001-07 ◽

2007 ◽

Vol 71 (3) ◽

pp. 463-476 ◽

Cited By ~ 167

Author(s):

Jacek Lubelski ◽

Wil N. Konings ◽

Arnold J. M. Driessen

Keyword(s):

Drug Resistance ◽

Multidrug Resistance ◽

Atp Hydrolysis ◽

Vast Number ◽

Active Efflux ◽

Bacterial Drug Resistance ◽

Higher Eukaryotes ◽

Molecular Mode ◽

New Strategies

SUMMARY Membrane proteins responsible for the active efflux of structurally and functionally unrelated drugs were first characterized in higher eukaryotes. To date, a vast number of transporters contributing to multidrug resistance (MDR transporters) have been reported for a large variety of organisms. Predictions about the functions of genes in the growing number of sequenced genomes indicate that MDR transporters are ubiquitous in nature. The majority of described MDR transporters in bacteria use ion motive force, while only a few systems have been shown to rely on ATP hydrolysis. However, recent reports on MDR proteins from gram-positive organisms, as well as genome analysis, indicate that the role of ABC-type MDR transporters in bacterial drug resistance might be underestimated. Detailed structural and mechanistic analyses of these proteins can help to understand their molecular mode of action and may eventually lead to the development of new strategies to counteract their actions, thereby increasing the effectiveness of drug-based therapies. This review focuses on recent advances in the analysis of ABC-type MDR transporters in bacteria.

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Fructose Induces Fluconazole Resistance in Candida albicans through Activation of Mdr1 and Cdr1 Transporters

International Journal of Molecular Sciences ◽

10.3390/ijms22042127 ◽

2021 ◽

Vol 22 (4) ◽

pp. 2127

Author(s):

Jakub Suchodolski ◽

Anna Krasowska

Keyword(s):

Candida Albicans ◽

Multidrug Resistance ◽

Green Fluorescent Protein ◽

Fluorescent Protein ◽

De Novo ◽

Pathogenic Fungus ◽

Serum Levels ◽

Efflux Transporters ◽

Fluconazole Resistance ◽

Green Fluorescent

Candida albicans is a pathogenic fungus that is increasingly developing multidrug resistance (MDR), including resistance to azole drugs such as fluconazole (FLC). This is partially a result of the increased synthesis of membrane efflux transporters Cdr1p, Cdr2p, and Mdr1p. Although all these proteins can export FLC, only Cdr1p is expressed constitutively. In this study, the effect of elevated fructose, as a carbon source, on the MDR was evaluated. It was shown that fructose, elevated in the serum of diabetics, promotes FLC resistance. Using C. albicans strains with green fluorescent protein (GFP) tagged MDR transporters, it was determined that the FLC-resistance phenotype occurs as a result of Mdr1p activation and via the increased induction of higher Cdr1p levels. It was observed that fructose-grown C. albicans cells displayed a high efflux activity of both transporters as opposed to glucose-grown cells, which synthesize Cdr1p but not Mdr1p. Additionally, it was concluded that elevated fructose serum levels induce the de novo production of Mdr1p after 60 min. In combination with glucose, however, fructose induces Mdr1p production as soon as after 30 min. It is proposed that fructose may be one of the biochemical factors responsible for Mdr1p production in C. albicans cells.

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Protected Areas in Forest Conservation: Challenges and Opportunities

Forests ◽

10.3390/f12040488 ◽

2021 ◽

Vol 12 (4) ◽

pp. 488

Author(s):

Panayiotis G. Dimitrakopoulos ◽

Nikoleta Jones

Keyword(s):

Protected Areas ◽

Forest Conservation ◽

Forest Ecosystems ◽

Vast Number ◽

Number Of Species ◽

Challenges And Opportunities

Forest ecosystems are important habitats for a vast number of species worldwide[...]

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Gene transfer of multidrug resistance into a factor-dependent human hematopoietic progenitor cell line: in vivo model for genetically transferred chemoprotection

Blood ◽

10.1182/blood.v87.7.2723.bloodjournal8772723 ◽

1996 ◽

Vol 87 (7) ◽

pp. 2723-2731 ◽

Cited By ~ 16

Author(s):

P Schwarzenberger ◽

S Spence ◽

N Lohrey ◽

T Kmiecik ◽

DL Longo ◽

...

Keyword(s):

Drug Resistance ◽

Multidrug Resistance ◽

Gene Transfer ◽

Hematopoietic Progenitor Cells ◽

Mdr1 Gene ◽

In Vivo Model ◽

Hematopoietic Progenitor ◽

Human Dna

To develop a rapid preclinical in vivo model to study gene transfer into human hematopoietic progenitor cells, MO-7e cells (CD-34+, c-kit+) were infected with multidrug resistance (MDR1)-containing retroviruses and then transplanted into nonobese diabetic severe combined immunodeficient mice (NOD SCID). MO-7e cells infected with a retrovirus encoding the human MDR1 cDNA showed integration, transcription, and expression of the transfered MDR1 gene. This resulted in a 20-fold increase in the resistance of MO-7e cells to paclitaxel in vitro. The expression of the MDR1 gene product was stable over a 6-month period in vitro without selection in colchicine. MO-7e and MDR1-infected MO-7e cells were transplanted into NOD SCID mice to determine whether MDR1 could confer drug resistance in vivo. A sensitive polymerase chain reaction method specific for human sequences was developed to quantitate the level of human cell engraftment in NOD SCID bone marrow (BM) cells. The percentage of human DNA in BM cells from MO-7e- transplanted mice was 10.9% and decreased to 0.7% in mice treated with paclitaxel. The percentage of human DNA in infected-MO-7e transplanted mice was 7.6% and that level was unchanged in mice treated with paclitaxel. These results show that expression of the MDR1 gene in human hematopoietic progenitor cells can confer functional drug resistance in an in vivo model.

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Phosphorylation of MgrA and Its Effect on Expression of the NorA and NorB Efflux Pumps of Staphylococcus aureus

Journal of Bacteriology ◽

10.1128/jb.00018-10 ◽

2010 ◽

Vol 192 (10) ◽

pp. 2525-2534 ◽

Cited By ~ 55

Author(s):

Que Chi Truong-Bolduc ◽

David C. Hooper

Keyword(s):

Staphylococcus Aureus ◽

Multidrug Resistance ◽

Virulence Factors ◽

Double Mutant ◽

Efflux Pumps ◽

Efflux Transporters ◽

Global Regulator ◽

Binding Assays ◽

Genes Encoding ◽

Gel Shift

ABSTRACT MgrA is a global regulator in Staphylococcus aureus that controls the expression of diverse genes encoding virulence factors and multidrug resistance (MDR) efflux transporters. We identified pknB, which encodes the (Ser/Thr) kinase PknB, in the S. aureus genome. PknB was able to autophosphorylate as well as phosphorylate purified MgrA. We demonstrated that rsbU, which encodes a Ser/Thr phosphatase and is involved in the activation of the SigB regulon, was able to dephosphorylate MgrA-P but not PknB-P. Serines 110 and 113 of MgrA were found to be phosphorylated, and Ala substitutions at these positions resulted in reductions in the level of phosphorylation of MgrA. DNA gel shift binding assays using norA and norB promoters showed that MgrA-P was able to bind the norB promoter but not the norA promoter, a pattern which was the reverse of that for unphosphorylated MgrA. The double mutant MgrAS110A-S113A bound to the norA promoter but not the norB promoter. The double mutant led to a 2-fold decrease in norA transcripts and a 2-fold decrease in the MICs of norfloxacin and ciprofloxacin in strain RN6390. Thus, phosphorylation of MgrA results in loss of binding to the norA promoter, but with a gain of the ability to bind the norB promoter. Loss of the ability to phosphorylate MgrA by Ala substitution resulted in increased repression of norA expression and in reductions in susceptibilities to NorA substrates.

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Two Decades of Evolution of Our Understanding of the Transient Receptor Potential Melastatin 2 (TRPM2) Cation Channel

Life ◽

10.3390/life11050397 ◽

2021 ◽

Vol 11 (5) ◽

pp. 397

Author(s):

Andras Szollosi

Keyword(s):

Structure Function ◽

Cell Activation ◽

Transient Receptor Potential ◽

Immune Cell ◽

Receptor Potential ◽

Cation Channel ◽

Biophysical Properties ◽

Vast Number ◽

Transient Receptor Potential Melastatin ◽

Transient Receptor

The transient receptor potential melastatin (TRPM) family belongs to the superfamily of TRP ion channels. It consists of eight family members that are involved in a plethora of cellular functions. TRPM2 is a homotetrameric Ca2+-permeable cation channel activated upon oxidative stress and is important, among others, for body heat control, immune cell activation and insulin secretion. Invertebrate TRPM2 proteins are channel enzymes; they hydrolyze the activating ligand, ADP-ribose, which is likely important for functional regulation. Since its cloning in 1998, the understanding of the biophysical properties of the channel has greatly advanced due to a vast number of structure–function studies. The physiological regulators of the channel have been identified and characterized in cell-free systems. In the wake of the recent structural biochemistry revolution, several TRPM2 cryo-EM structures have been published. These structures have helped to understand the general features of the channel, but at the same time have revealed unexplained mechanistic differences among channel orthologues. The present review aims at depicting the major research lines in TRPM2 structure-function. It discusses biophysical properties of the pore and the mode of action of direct channel effectors, and interprets these functional properties on the basis of recent three-dimensional structural models.

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The Emerging Role of Extracellular Vesicle-Mediated Drug Resistance in Cancers: Implications in Advanced Prostate Cancer

BioMed Research International ◽

10.1155/2015/454837 ◽

2015 ◽

Vol 2015 ◽

pp. 1-13 ◽

Cited By ~ 20

Author(s):

Carolina Soekmadji ◽

Colleen C. Nelson

Keyword(s):

Prostate Cancer ◽

Drug Resistance ◽

Multidrug Resistance ◽

Advanced Prostate Cancer ◽

Control Cell ◽

Extracellular Vesicle ◽

Multidrug Resistance Proteins ◽

Acquired Drug Resistance ◽

Resistance Proteins

Emerging evidence has shown that the extracellular vesicles (EVs) regulate various biological processes and can control cell proliferation and survival, as well as being involved in normal cell development and diseases such as cancers. In cancer treatment, development of acquired drug resistance phenotype is a serious issue. Recently it has been shown that the presence of multidrug resistance proteins such as Pgp-1 and enrichment of the lipid ceramide in EVs could have a role in mediating drug resistance. EVs could also mediate multidrug resistance through uptake of drugs in vesicles and thus limit the bioavailability of drugs to treat cancer cells. In this review, we discussed the emerging evidence of the role EVs play in mediating drug resistance in cancers and in particular the role of EVs mediating drug resistance in advanced prostate cancer. The role of EV-associated multidrug resistance proteins, miRNA, mRNA, and lipid as well as the potential interaction(s) among these factors was probed. Lastly, we provide an overview of the current available treatments for advanced prostate cancer, considering where EVs may mediate the development of resistance against these drugs.

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